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Biochemistry_Lippinco. 370) portray the trans fat content of packaged food. By 2018, virtually no industrial trans fatty acids will be permitted in food. 5. Dietary cholesterol: Cholesterol is found only in animal products. The effect of dietary cholesterol on plasma cholesterol (Fig. 27.14) is less important than the amount and types of fatty acids consumed. Many experts recommend ≤300 mg/day. However, having an upper limit has become controversial. concentrations to an increase in dietary cholesterol intake. C. Other dietary factors affecting coronary heart disease


Biochemistry_Lippinco

Biochemistry_Lippinco. concentrations to an increase in dietary cholesterol intake. C. Other dietary factors affecting coronary heart disease Moderate consumption of alcohol (up to 1 drink/day for women and up to 2 drinks/day for men) decreases the risk of CHD, because there is a positive correlation between moderate alcohol (ethanol) consumption and the plasma concentration of HDL-C. However, because of the potential dangers of alcohol abuse, health professionals are reluctant to recommend increased alcohol consumption to their patients. Red wine may provide cardioprotective benefits in addition to those resulting from its alcohol content (for example, red wine contains phenolic compounds that inhibit lipoprotein oxidation; see p. 235). [Note: These antioxidants are also present in raisins and grape juice.] Figure 27.15 summarizes the effects of dietary fats. [Note: Recent studies (including meta-analyses) have raised questions concerning the current guidelines for dietary fat in the prevention of CHD.]


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Biochemistry_Lippinco. VI. DIETARY CARBOHYDRATES The primary role of dietary carbohydrates is to provide energy. Although self-reported caloric intake in the United States peaked in 2003 and is now declining, the incidence of obesity has dramatically increased (see p. 349). During this same period, carbohydrate consumption has significantly increased (as fat consumption decreased), leading some observers to link obesity with carbohydrate consumption. However, obesity has also been related to increasingly inactive lifestyles and to calorie-dense foods served in expanded portion size. Carbohydrates are not inherently fattening. A. Classification Dietary carbohydrates are classified as simple sugars (monosaccharides and disaccharides), complex sugars (polysaccharides), and fiber.


Biochemistry_Lippinco

Biochemistry_Lippinco. A. Classification Dietary carbohydrates are classified as simple sugars (monosaccharides and disaccharides), complex sugars (polysaccharides), and fiber. 1. Monosaccharides: Glucose and fructose are the principal monosaccharides found in food. Glucose is abundant in fruits, sweet corn, corn syrup, and honey. Free fructose is found together with free glucose in honey and fruits (for example, apples).


Biochemistry_Lippinco

Biochemistry_Lippinco. a. High-fructose corn syrup: High-fructose corn syrups (HFCS) are corn syrups that have undergone enzymatic processing to convert their glucose into fructose and have then been mixed with pure corn syrup (100% glucose) to produce a desired sweetness. In the United States, HFCS 55 (containing 55% fructose and 42% glucose) is commonly used as a substitute for sucrose in beverages, including soft drinks, with HFCS 42 used in processed foods. The composition and metabolism of HFCS and sucrose are similar, the major difference being that HFCS is ingested as a mixture of monosaccharides (Fig. 27.16). Most studies have shown no significant difference between sucrose and HFCS meals in either postprandial glucose or insulin responses. [Note: The rise in the use of HFCS parallels the rise in obesity, but a causal relationship has not been demonstrated.] (B) leads to absorption of glucose plus fructose. 2.


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Biochemistry_Lippinco. 2. Disaccharides: The most abundant disaccharides are sucrose (glucose + fructose), lactose (glucose + galactose), and maltose (glucose + glucose). Sucrose is ordinary table sugar and is abundant in molasses and maple syrup. Lactose is the principal sugar found in milk. Maltose is a product of enzymic digestion of polysaccharides. It is also found in significant quantities in beer and malt liquors. The term “sugar” refers to monosaccharides and disaccharides. “Added sugars” are those sugars and syrups (such as HFCS) added to foods during processing or preparation. 3. Polysaccharides: Complex carbohydrates are polysaccharides (most often polymers of glucose) that do not have a sweet taste. Starch is an example of a complex carbohydrate that is found in abundance in plants. Common sources include wheat and other grains, potatoes, dried peas and beans (legumes), and vegetables. 4.


Biochemistry_Lippinco

Biochemistry_Lippinco. Fiber: Dietary fiber is defined as the nondigestible, nonstarch carbohydrates and lignin (a noncarbohydrate polymer of aromatic alcohols) present intact in plants. Soluble fiber is the edible part of plants that is resistant to digestion and absorption in the human small intestine but is completely or partially fermented by bacteria to short-chain fatty acids in the large intestine. Insoluble fiber passes through the digestive track largely unchanged. Dietary fiber provides little energy but has several beneficial effects. First, it adds bulk to the diet (Fig. 27.17). Fiber can absorb 10–15 times its own weight in water, drawing fluid into the lumen of the intestine and increasing bowel motility and promoting bowel movements (laxation). Soluble fiber delays gastric emptying and can result in a sensation of fullness (satiety). This delayed emptying also results in reduced spikes in blood glucose following a meal. Second, consumption of soluble fiber has been shown to lower LDL-C levels


Biochemistry_Lippinco

Biochemistry_Lippinco. in a sensation of fullness (satiety). This delayed emptying also results in reduced spikes in blood glucose following a meal. Second, consumption of soluble fiber has been shown to lower LDL-C levels by increasing fecal bile acid excretion and interfering with bile acid reabsorption (see p. 225). For example, diets rich (25–50 g/day) in the soluble fiber oat bran are associated with a modest, but significant, reduction in risk for CHD by lowering total cholesterol and LDL-C levels. Also, fiber-rich diets decrease the risk for constipation, hemorrhoids, and diverticulosis. The AI for dietary fiber is 25 g/day for women and 38 g/day for men. However, most American diets are far lower in fiber at ~15 g/day. [Note: “Functional fiber” is the term used for isolated fiber that has proven health benefits such as commercially available fiber supplements.]


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Biochemistry_Lippinco. B. Dietary carbohydrate and blood glucose Some carbohydrate-containing foods produce a rapid rise followed by a steep fall in blood glucose concentration, whereas others result in a gradual rise followed by a slow decline (Fig. 27.18). Thus, they differ in their glycemic response (GR). [Note: Fiber blunts the GR.] The glycemic index (GI) ranks carbohydrate-rich foods on a scale of 0–100 based on the GR they cause relative to the GR caused by the same amount (50 g) of carbohydrate eaten in the form of white bread or glucose. A low GI is <55, whereas a high GI is ≥70. Evidence suggests that a low-GI diet improves glycemic control in diabetic individuals. Food with a low GI tends to create a sense of satiety over a longer period of time and may be helpful in limiting caloric intake. [Note: How much a typical serving size of a food raises blood glucose is referred to as the glycemic load (GL). A food (for example, carrots) can have a high GI and a low GL.] C. Carbohydrate requirements


Biochemistry_Lippinco

Biochemistry_Lippinco. C. Carbohydrate requirements Carbohydrates are not essential nutrients, because the carbon skeletons of most amino acids can be converted into glucose (see p. 261). However, the absence of dietary carbohydrate leads to ketogenesis (see p. 195) and degradation of body protein whose constituent amino acids provide carbon skeletons for gluconeogenesis (see p. 118). The RDA for carbohydrate is set at 130 g/day for adults and children, based on the amount of glucose used by carbohydrate-dependent tissues, such as the brain and erythrocytes. However, this level of intake is usually exceeded. Adults should consume 45%–65% of their total calories from carbohydrates. It is now recommended that added sugars represent no more than 10% of total energy intake because of concerns that they may displace nutrient-rich foods from the diet. [Note: Added sugars are associated with increased body weight and type 2 diabetes.] D. Simple sugars and disease


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Biochemistry_Lippinco. D. Simple sugars and disease There is no direct evidence that the consumption of simple sugars naturally present in food is harmful. Contrary to folklore, diets high in sucrose do not lead to diabetes or hypoglycemia. Also contrary to popular belief, carbohydrates are not inherently fattening. They yield 4 kcal/g (the same as protein and less than one half that of fat; see Fig. 27.5) and result in fat synthesis only when consumed in excess of the body’s energy needs. However, there is an association between sucrose consumption and dental caries, particularly in the absence of fluoride treatment (see p. 405). VII. DIETARY PROTEIN The AMDR for protein is 10%–35%. Dietary protein provides the essential amino acids (see Fig. 20.2, p. 262). Nine of the 20 amino acids needed for the synthesis of body proteins are essential (that is, they cannot be synthesized in humans). A. Protein quality


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Biochemistry_Lippinco. A. Protein quality The quality of a dietary protein is a measure of its ability to provide the essential amino acids (EAA) required for tissue maintenance. Most government agencies have adopted the Protein Digestibility–Corrected Amino Acid Score (PDCAAS) as the standard by which to evaluate protein quality. PDCAAS is based on the profile of EAA after correcting for the digestibility of the protein. The highest possible score under these guidelines is 1.00. This amino acid score provides a method to balance intakes of poorer-quality proteins with high-quality dietary proteins. 1.


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Biochemistry_Lippinco. 1. Proteins from animal sources: Proteins from animal sources (meat, poultry, milk, and fish) have a high quality because they contain all the EAA in proportions similar to those required for synthesis of human tissue proteins (Fig. 27.19), and they are more readily digested. [Note: Gelatin prepared from animal collagen is an exception. It has a low biologic value as a result of deficiencies in several EAA.] 2. Proteins from plant sources: Plant proteins have a lower quality than do animal proteins. However, proteins from different plant sources may be combined in such a way that the result is equivalent in nutritional value to animal protein. For example, wheat (lysine deficient but methionine rich) may be combined with kidney beans (methionine poor but lysine rich) to produce a higher biologic value than either of the component proteins (Fig. 27.20). [Note: Animal proteins can also complement the biologic value of plant proteins.] B. Nitrogen balance


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Biochemistry_Lippinco. B. Nitrogen balance Nitrogen balance occurs when the amount of nitrogen consumed equals that of the nitrogen excreted in the urine (primarily as urinary urea nitrogen, or UUN), sweat, and feces. Most healthy adults are normally in nitrogen balance. [Note: There is, on average, 1 g nitrogen in 6.25 g protein.] 1. Positive nitrogen balance: This occurs when nitrogen intake exceeds nitrogen excretion. It is observed during situations in which tissue growth occurs, for example, in childhood, pregnancy, or during recovery from an emaciating illness. 2. Negative nitrogen balance: This occurs when nitrogen loss is greater than nitrogen intake. It is associated with inadequate dietary protein; lack of an essential amino acid; or during physiologic stresses, such as trauma, burns, illness, or surgery.


Biochemistry_Lippinco

Biochemistry_Lippinco. Nitrogen (N) balance (g Nin – g Nout) in a 24-hour period can be determined by the formula, N balance = protein intake in g/6.25 – (UUN + 4 g), where 4 g accounts for urinary loss in forms other than UUN plus loss in skin and feces. C. Protein requirements


Biochemistry_Lippinco

Biochemistry_Lippinco. C. Protein requirements The amount of dietary protein required in the diet varies with its biologic value. The greater the proportion of animal protein in the diet, the less protein is required. The RDA for protein is computed for proteins of mixed biologic value at 0.8 g/kg of body weight for adults, or ~56 g of protein for a 70-kg individual. People who exercise strenuously on a regular basis may benefit from extra protein to maintain muscle mass, and a daily intake of ~1 g/kg has been recommended for athletes. Women who are pregnant or lactating require up to 30 g/day in addition to their basal requirements. To support growth, infants should consume 2 g/kg/day. [Note: Disease states influence protein needs. Protein restriction may be needed in kidney disease, whereas burns require increased protein intake.] 1.


Biochemistry_Lippinco

Biochemistry_Lippinco. Consumption of excess protein: There is no physiologic advantage to the consumption of more protein than the RDA. Protein consumed in excess of the body’s needs is deaminated, and the resulting carbon skeletons are metabolized to provide energy or acetyl coenzyme A for fatty acid synthesis. When excess protein is eliminated from the body as urinary nitrogen, it is often accompanied by increased urinary calcium, thereby increasing the risk of nephrolithiasis (kidney stones) and osteoporosis. 2.


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Biochemistry_Lippinco. 2. The protein-sparing effect of carbohydrates: The dietary protein requirement is influenced by the carbohydrate content of the diet. When the intake of carbohydrates is low, amino acids are deaminated to provide carbon skeletons for the synthesis of glucose that is needed as a fuel by the central nervous system. If carbohydrate intake is <130 g/day, substantial amounts of protein are metabolized to provide precursors for gluconeogenesis. Therefore, carbohydrate is considered to be “protein-sparing,” because it allows amino acids to be used for repair and maintenance of tissue protein rather than for gluconeogenesis. D. Protein-energy (calorie) malnutrition


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Biochemistry_Lippinco. D. Protein-energy (calorie) malnutrition In developed countries, protein-energy malnutrition (PEM), also known as protein-energy undernutrition (PEU), is most commonly seen in patients with medical conditions that decrease appetite or alter how nutrients are digested or absorbed or in hospitalized patients with major trauma or infections. [Note: Such highly catabolic patients frequently require intravenous (IV, or parenteral) or tube-based (enteral) administration of nutrients.] PEM may also be seen in children or the elderly who are malnourished. In developing countries, an inadequate intake of protein and/or calories is the primary cause of PEM. Affected individuals show a variety of symptoms, including a depressed immune system with a reduced ability to resist infection. Death from secondary infection is common. PEM is a spectrum of degrees of malnutrition, and two extreme forms are kwashiorkor and marasmus (Fig. 27.21). [Note: Marasmic kwashiorkor has features of both forms.] 1.


Biochemistry_Lippinco

Biochemistry_Lippinco. Kwashiorkor: Kwashiorkor occurs when protein deprivation is relatively greater than the reduction in total calories. Protein deprivation is associated with severely decreased synthesis of visceral protein. Kwashiorkor is commonly seen in developing countries in children after weaning at about age 1 year, when their diet consists predominantly of carbohydrates. Typical symptoms include stunted growth, skin lesions, depigmented hair, anorexia, fatty liver, bilateral pitting edema, and decreased serum albumin concentration. Edema results from the lack of adequate blood proteins, primarily albumin, to maintain the distribution of water between blood and tissues. It may mask muscle and fat loss. Therefore, chronic malnutrition is reflected in the level of serum albumin. [Note: Because caloric intake from carbohydrates may be adequate, insulin levels suppress lipolysis and proteolysis. Kwashiorkor is, therefore, nonadapted malnutrition.] 2.


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Biochemistry_Lippinco. Marasmus: Marasmus occurs when calorie deprivation is relatively greater than the reduction in protein. It usually occurs in developing countries in children younger than age 1 year when breast milk is supplemented or replaced with watery gruels of native cereals that are usually deficient in both protein and calories. Typical symptoms include arrested growth, extreme muscle wasting and depletion of subcutaneous fat (emaciation), weakness, and anemia (Fig. 27.22). Individuals with marasmus do not show the edema observed in kwashiorkor. [Note: Refeeding severely malnourished individuals can result in hypophosphatemia (see p. 400), because any available phosphate is used to phosphorylate carbohydrate intermediates. Milk is frequently given because it is rich in phosphate.]


Biochemistry_Lippinco

Biochemistry_Lippinco. Cachexia, a wasting disorder characterized by loss of appetite and muscle atrophy (with or without increased lipolysis) that cannot be reversed by conventional nutritional support, is seen with a number of chronic diseases, such as cancer and chronic pulmonary and renal disease. It is associated with decreased treatment tolerance and response and decreased survival time. VIII. NUTRITION TOOLS A set of tools has been developed that gives consumers information about what (and how much) they should eat as well as the nutritional content of the foods they do eat. Additional tools allow medical professionals to assess whether or not the nutritional needs of an individual are being met. A. MyPlate


Biochemistry_Lippinco

Biochemistry_Lippinco. A. MyPlate MyPlate was designed by the U.S. Department of Agriculture (USDA) to graphically illustrate its recommendations as to what food groups and how much of each should be consumed daily. In MyPlate, the relative amounts of each of five food groups (vegetables, grains, protein, fruit, and dairy) are represented by the relative size of their section on the plate (Fig. 27.23). The number of servings depends on variables that include age and sex. [Note: MyPlate replaced MyPyramid in 2011.] B. Nutrition facts label Most types of packaged goods are required to have a Nutrition Facts label, or “food label” (Fig. 27.24), that includes the size of a single serving, the Cal it provides, and the number of servings per container. In addition, a percent daily value (%DV) is shown for most nutrients listed. [Note: The %DV is based on a 2,000-Cal diet for healthy adults.] 1.


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Biochemistry_Lippinco. Percent daily value: The %DV compares the amount of a given nutrient in a single serving of a product to the recommended daily intake for that nutrient. For example, the %DV for the micronutrients listed, as well as for total carbohydrates and fiber, are based on their recommended minimum daily intake. Thus, if the label lists 20% for calcium, one serving provides 20% of the minimum recommended amount of calcium needed each day. In contrast, the %DV for saturated fat, cholesterol, and sodium are based on their recommended maximum daily intake, and the %DV reflects what percentage of this maximum a serving provides. There is no %DV for protein because the recommended intake depends on body weight (see p. 367). [Note: “Sugars” represents mono-and disaccharides. The remainder of the carbohydrate (total carbohydrate – [fiber + sugars]) is the oligo-and polysaccharides.] 2.


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Biochemistry_Lippinco. Proposed revisions: In 2014, the USDA proposed the following changes to the Nutrition Facts label for implementation by 2018: Added sugars, vitamin D, and potassium are to be included; vitamins A and C, total fat, and Cal from fat are to be removed; and serving size is to be adjusted to reflect the amounts people are now consuming. Additionally, design changes to highlight key parts of the label were proposed (Fig. 27.25). [Note: The proposed addition/removal of certain micronutrients is based on newer data on the risk for underingestion.] C. Nutrition assessment


Biochemistry_Lippinco

Biochemistry_Lippinco. C. Nutrition assessment Nutrition assessment evaluates nutritional status based on clinical information. It includes (but is not limited to) dietary history, anthropometric measures, and laboratory data. [Note: Assessment findings may result in medical nutrition therapy, which is the treatment of medical conditions through changes in diet (for example, replacement of long-chain TAG with medium-chain TAG in malabsorption disorders) and/or the method of intake (for example, enteral [tube] or parenteral [IV] feeding).] 1.


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Biochemistry_Lippinco. Dietary history: This is a record of food intake over a period of time. For a food diary, the specific types and exact amounts of food eaten are recorded in “real time” (as soon as possible after eating) for a period of 3–7 days. Retrospective approaches include a food frequency questionnaire (for example, what fruits were eaten and how often they were eaten in a typical day, week, or month) and a 24-hour recall of the specific foods and the amounts eaten in the last 24 hours. 2.


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Biochemistry_Lippinco. 2. Anthropometric measures: These are physical measures of the body. They include (but are not limited to) weight, height, body mass index (an indicator of obesity, see p. 349), skin-fold thickness (an indicator of subcutaneous fat), and waist circumference (an indicator of abdominal fat, see p. 349). [Note: Ideal body weight can be calculated using the Hamwi method: 106 lb (for males) or 100 lb (for females) for the first 5 ft of height + 5 lb for every inch over 5 ft, with an adjustment of −10% for a small frame and + 10% for a large one.] 3.


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Biochemistry_Lippinco. Laboratory data: These are obtained by tests performed on body fluids, tissues, and waste. They can include plasma LDL-C (for cardiovascular risk), fecal fat (for malabsorption), red cell indices (for vitamin deficiencies), and N balance and serum proteins (such as albumin and transthyretin [prealbumin]) for protein–energy status. [Note: These proteins are made in the liver and transport molecules such as fatty acids and thyroxine (see p. 406) through blood. Low albumin levels correlate with increased morbidity and mortality in hospitalized patients. The short half-life (2–3 days) of transthyretin as compared to that of albumin (20 days) has led to its use in monitoring the progress of hospitalized patients.] Nutritional insufficiency can be the result of inadequate nutrient intake (caused, for example, by an inability to eat, loss of appetite, or decreased availability), inadequate absorption, decreased utilization, increased excretion, or increased requirements.


Biochemistry_Lippinco

Biochemistry_Lippinco. IX. NUTRITION AND THE LIFE STAGES Macronutrient energy sources, micronutrients, EFA, and EAA are required at every life stage. Additionally, each stage has specific nutrition needs. A. Infancy, childhood, and adolescence


Biochemistry_Lippinco

Biochemistry_Lippinco. The rapid growth and development in infancy (birth to age 1 year) and childhood (age 1 year to adolescence) necessitate higher energy and protein needs relative to body size than are required in subsequent life stages. In adolescence, the marked increases in height and weight that occur increase nutritional needs. Growth charts (Fig. 27.26) are used to compare an individual’s stature (height) and/or weight to the expected values for others of the same age (≤20 years) and sex. They are based on data from large numbers of normal individuals over time. [Note: Deviations from the expected growth curve, as reflected in the crossing of two or more percentile lines, raise concern.] 1. Infants: Ideal infant nutrition is based on human breast milk because it provides calories and most micronutrients in amounts appropriate for the human infant. Carbohydrates, protein, and fat are present in a 7:3:1 ratio. [Note: In addition to the disaccharide lactose, human milk contains nearly 200 unique


Biochemistry_Lippinco

Biochemistry_Lippinco. in amounts appropriate for the human infant. Carbohydrates, protein, and fat are present in a 7:3:1 ratio. [Note: In addition to the disaccharide lactose, human milk contains nearly 200 unique oligosaccharides. About 90% of the microbiota (the population of microbes) in the breast-fed infant’s intestine is represented by one type, Bifidobacterium infantis, which expresses all the enzymes needed to degrade these complex sugars. The sugars, in turn, act as prebiotics that support the growth of B. infantis, a probiotic (helpful bacteria).] Breast milk is low in vitamin D, however, and exclusively breast-fed babies require vitamin D supplementation. [Note: Human milk provides antibodies and other proteins that reduce the risk of infection.]


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Biochemistry_Lippinco. The microbiota in and on the human body plus their genomes are referred to as the microbiome. It is acquired at birth from the environment and changes with the life stages. The gut microbiome influences host nutrition by facilitating processing of food consumed and is itself influenced by that food. Its relationship with undernutrition, obesity, and diabetes is under investigation. 2. Children: As with infants, children have increased need for calories and nutrients. The primary concerns in this stage, however, are deficiencies of iron and calcium. 3. Adolescents: In the teen years, the increases in height and weight increase the need for calories, protein, calcium, iron, and phosphorus. Eating patterns in this stage can result in overconsumption of fat, sodium, and sugar and underconsumption of vitamin A, thiamine, and folic acid. [Note: Eating disorders and obesity are concerns in this age group.] B. Adulthood


Biochemistry_Lippinco

Biochemistry_Lippinco. B. Adulthood Overnutrition is a concern in young adults, whereas malnutrition is a concern in older adults. 1. Young adults: Nutrition in young adults focuses on the maintenance of good health and the prevention of disease. The goal is a diet rich in plant-based foods (with a focus on fiber and whole grains), limited intake of saturated fat and trans fatty acids, and balanced intake of ω-3 and ω-6 PUFA. 2. Pregnant or lactating women: The requirements for calories, protein, and virtually all micronutrients increase in pregnancy and lactation. Supplementation with folic acid (to prevent neural tube defects [see p. 379]), vitamin D, calcium, iron, iodine, and DHA is typically recommended. 3.


Biochemistry_Lippinco

Biochemistry_Lippinco. 3. Older adults: Aging increases the risk of malnutrition. Decreased appetite resulting from a reduced sense of taste (dysgeusia) and smell (hyposmia) decreases nutrient intake. [Note: Physical limitations, including problems with dentition, and psychosocial factors, such as isolation, may also play a role in reduced intake.] Inadequate intake of protein, calcium, and vitamins D and B12 is common. B12 deficiency can result from decreased absorption caused by achlorhydria (reduced stomach acid, see p. 381). In aging, lean muscle mass decreases and fat increases, resulting in decreased RMR. [Note: Drug–nutrient interactions can occur at any life stage but are more common as the number of medications increases as in aging.] Monoamine oxidase inhibitors (MAOI), used to treat depression (see p.


Biochemistry_Lippinco

Biochemistry_Lippinco. Monoamine oxidase inhibitors (MAOI), used to treat depression (see p. 287) and early Parkinson disease, can interact with tyramine-containing foods. Tyramine is a monoamine derived from the decarboxylation of tyrosine during the curing, aging, or fermentation of food (Fig. 27.27). It causes the release of norepinephrine, increasing blood pressure and heart rate. Patients who take an MAOI and consume such foods are at risk for a hypertensive crisis. X. CHAPTER SUMMARY


Biochemistry_Lippinco

Biochemistry_Lippinco. The Dietary Reference Intakes (DRI) provide estimates of the amounts of nutrients required to prevent deficiencies and maintain optimal health and growth. They consist of the Estimated Average Requirement (EAR), the average daily nutrient intake level estimated to meet the requirement of 50% of the healthy individuals in a particular life stage (age) and gender group; the Recommended Dietary Allowance (RDA), the average daily dietary intake level that is sufficient to meet the nutrient requirements of nearly all (97%–98%) individuals in a life stage and gender group; the Adequate Intake (AI), which is set instead of an RDA if sufficient scientific evidence is not available to calculate the RDA; and the Tolerable Upper Intake Level (UL), the highest average daily nutrient intake level that is likely to pose no risk of adverse health effects to almost all individuals in the general population. The energy generated by the metabolism of the macronutrients (9 kcal/g of fat and 4 kcal/g of


Biochemistry_Lippinco

Biochemistry_Lippinco. is likely to pose no risk of adverse health effects to almost all individuals in the general population. The energy generated by the metabolism of the macronutrients (9 kcal/g of fat and 4 kcal/g of protein or carbohydrate) is used for three energy-requiring processes that occur in the body: resting metabolic rate, physical activity, and the thermic effect of food. Acceptable Macronutrient Distribution Ranges (AMDR) are defined as the ranges of intake for a particular macronutrient that are associated with reduced risk of chronic disease while providing adequate amounts of essential nutrients. Adults should consume 45%–65% of their total calories from carbohydrates, 20%–35% from fat, and 10%–35% from protein (Fig. 27.28). Elevated levels of cholesterol in low-density lipoproteins (LDL-C) result in increased risk for coronary heart disease (CHD). In contrast, elevated levels of cholesterol in high-density lipoproteins (HDL-C) have been associated with a decreased risk for CHD. Dietary


Biochemistry_Lippinco

Biochemistry_Lippinco. result in increased risk for coronary heart disease (CHD). In contrast, elevated levels of cholesterol in high-density lipoproteins (HDL-C) have been associated with a decreased risk for CHD. Dietary or drug treatment of hypercholesterolemia is effective in decreasing LDL-C, increasing HDLC, and reducing the risk for CHD. Consumption of saturated fats is strongly associated with high levels of total plasma and LDL-C. When substituted for saturated fatty acids in the diet, monounsaturated fats lower both total plasma cholesterol and LDL-C but maintain or increase HDL-C. Consumption of fats containing ω-6 polyunsaturated fatty acids lowers plasma LDL-C, but HDL-C, which protects against CHD, is also lowered. Dietary ω-3 polyunsaturated fats suppress cardiac arrhythmias and reduce plasma triacylglycerols, decrease the tendency for thrombosis, and substantially reduce the risk of cardiovascular mortality. Carbohydrates provide energy and fiber to the diet. When they are consumed as part


Biochemistry_Lippinco

Biochemistry_Lippinco. decrease the tendency for thrombosis, and substantially reduce the risk of cardiovascular mortality. Carbohydrates provide energy and fiber to the diet. When they are consumed as part of a diet in which caloric intake is equal to energy expenditure, they do not promote obesity. Dietary protein provides essential amino acids. Protein quality is a measure of its ability to provide the essential amino acids required for tissue maintenance. Proteins from animal sources, in general, have a higher-quality protein than that derived from plants. However, proteins from different plant sources may be combined in such a way that the result is equivalent in nutritional value to animal protein. Positive nitrogen (N) balance occurs when N intake exceeds N excretion. It is observed in situations in which tissue growth occurs, for example, in childhood, pregnancy, or during recovery from an emaciating illness. Negative N balance occurs when N losses are greater than N intake. It is associated with


Biochemistry_Lippinco

Biochemistry_Lippinco. tissue growth occurs, for example, in childhood, pregnancy, or during recovery from an emaciating illness. Negative N balance occurs when N losses are greater than N intake. It is associated with inadequate dietary protein; lack of an essential amino acid; or during physiologic stresses such as trauma, burns, illness, or surgery. Kwashiorkor occurs when protein deprivation is relatively greater than the reduction in total calories. It is characterized by edema. Marasmus occurs when calorie deprivation is relatively greater than the reduction in protein. No edema is seen. Both are extreme forms of protein-energy malnutrition (PEM). Nutrition Facts labels give consumers information about the nutritional content of packaged foods. Medical assessment of nutritional status includes dietary history, anthropometric measures, and laboratory data. Each life stage has specific nutrition needs. Growth charts are used to monitor the growth pattern of an individual from birth through adolescence.


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Biochemistry_Lippinco. anthropometric measures, and laboratory data. Each life stage has specific nutrition needs. Growth charts are used to monitor the growth pattern of an individual from birth through adolescence. Drug–nutrient interactions are of concern, especially in older adults.


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Biochemistry_Lippinco. Choose the ONE best answer. 7.1. For the child shown at right, which of the statements would support a diagnosis of kwashiorkor? The child: A. appears plump due to increased deposition of fat in adipose tissue. B. displays abdominal and peripheral edema. C. has a serum albumin level above normal. D. has markedly decreased weight for height. The correct answer = B. Kwashiorkor is caused by inadequate protein intake in the presence of fair to good energy (calorie) intake. Typical findings in a patient with kwashiorkor include abdominal and peripheral edema (note the swollen belly and legs) caused largely by a decreased serum albumin concentration. Body fat stores are depleted, but weight for height can be normal because of edema. Treatment includes a diet adequate in calories and protein. 7.2. Which one of the following statements concerning dietary fat is correct? A. Coconut oil is rich in monounsaturated fats, and olive oil is rich in saturated fats.


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Biochemistry_Lippinco. 7.2. Which one of the following statements concerning dietary fat is correct? A. Coconut oil is rich in monounsaturated fats, and olive oil is rich in saturated fats. B. Fatty acids containing trans double bonds, unlike the naturally occurring cis isomers, raise high-density lipoprotein cholesterol levels. C. The polyunsaturated fatty acids linoleic and linolenic acids are required components. D. Triacylglycerols obtained from plants generally contain less unsaturated fatty acids than do those from animals. Correct answer = C. Humans are unable to make linoleic and linolenic fatty acids. Consequently, these fatty acids are essential in the diet. Coconut oil is rich in saturated fats, and olive oil is rich in monounsaturated fats. Trans fatty acids raise plasma levels of low-density lipoprotein cholesterol, not high-density lipoprotein cholesterol. Triacylglycerols obtained from plants generally contain more unsaturated fatty acids than do those from animals.


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Biochemistry_Lippinco. 7.3. Given the information that a 70-kg man is consuming a daily average of 275 g of carbohydrate, 75 g of protein, and 65 g of fat, which one of the following conclusions can reasonably be drawn? A. About 20% of calories are derived from fats. B. The diet contains a sufficient amount of fiber. C. The individual is in nitrogen balance. D. The proportions of carbohydrate, protein, and fat in the diet conform to current recommendations. E. The total energy intake per day is about 3,000 kcal.


Biochemistry_Lippinco

Biochemistry_Lippinco. D. The proportions of carbohydrate, protein, and fat in the diet conform to current recommendations. E. The total energy intake per day is about 3,000 kcal. Correct answer = D. The total energy intake is (275 g carbohydrate × 4 kcal/g) + (75 g protein × 4 kcal/g) + (65 g fat × 9 kcal/g) = 1,100 + 300 + 585 = 1,985 total kcal/day. The percentage of calories derived from carbohydrate is 1,100/1,985 = 55, from protein is 300/1,985 = 15, and from fat is 585/1,985 = 30. These are very close to current recommendations. The amount of fiber or nitrogen balance cannot be deduced from the data presented. If the protein is of low biologic value, a negative nitrogen balance is possible.


Biochemistry_Lippinco

Biochemistry_Lippinco. 7.6. In chronic bronchitis, excessive mucus production causes airway obstruction that results in hypoxemia (low blood oxygen level), impaired expiration, and hypercapnia (carbon dioxide retention). Why might a high-fat, low-carbohydrate diet be recommended for a patient with chronic obstructive pulmonary disease caused by chronic bronchitis? A. Fat contains more oxygen atoms relative to carbon or hydrogen atoms than do carbohydrates. B. Fat is calorically less dense than carbohydrates. C. Fat metabolism generates less carbon dioxide. D. The respiratory quotient (RQ) for fat is higher than the RQ for carbohydrates.


Biochemistry_Lippinco

Biochemistry_Lippinco. C. Fat metabolism generates less carbon dioxide. D. The respiratory quotient (RQ) for fat is higher than the RQ for carbohydrates. Correct answer = C. A treatment goal for the chronic obstructive pulmonary disease (COPD) caused by acute bronchitis is to insure appropriate nutrition without increasing the respiratory quotient (RQ), which is the ratio of carbon dioxide (CO2) produced to oxygen consumed, thereby minimizing the production of CO2. Less CO2 is produced from the metabolism of fat (RQ = 0.7) than from the catabolism of carbohydrate (RQ =1.0). Fat contains fewer oxygen atoms. Fat is calorically denser than is carbohydrate. [Note: RQ is determined by indirect calorimetry.] 7.7. A 32-year-old man who was rescued from a house fire was admitted to the hospital with burns over 45% of his body (severe burns). The man weighs 154 lb (70 kg) and is 72 in (183 cm) tall. Which one of the following is the best rapid estimate of the immediate daily caloric needs of this patient?


Biochemistry_Lippinco

Biochemistry_Lippinco. A. 1,345 kcal B. 1,680 kcal C. 2,690 kcal D. 3,360 kcal Correct answer = D. A commonly used rough estimate of the total energy expenditure (TEE) for men is 1 kcal/1 kg body weight/24 hours. [Note: It is 0.8 kcal for women.] For this patient, that value is 1,680 kcal (1 kcal/kg/hour × 24 hours × 70 kg). In addition, an injury factor of 2 for severe burns must be included in the calculation: 1,680 kcal × 2 = 3,360 kcal. 7.8. Which one of the following is the best advice to give a patient who asks about the notation “%DV” (percent daily value) on the Nutrition Facts label? A. Achieve 100% daily value for each nutrient each day. B. Select foods that have the highest percent daily value for all nutrients. C. Select foods with a low percent daily value for the micronutrients. D. Select foods with a low percent daily value for saturated fat.


Biochemistry_Lippinco

Biochemistry_Lippinco. C. Select foods with a low percent daily value for the micronutrients. D. Select foods with a low percent daily value for saturated fat. Correct answer = D. The percent daily value (%DV) compares the amount of a given nutrient in a single serving of a product to the recommended daily intake for that nutrient. The %DV for the micronutrients listed on the label, as well as for total carbohydrates and fiber, are based on their recommended minimum daily intake, whereas the %DV for saturated fat, cholesterol, and sodium are based on their recommended maximum daily intake. For Questions 27.7 and 27.8, use the following case.


Biochemistry_Lippinco

Biochemistry_Lippinco. For Questions 27.7 and 27.8, use the following case. A sedentary 50-year-old man weighing 176 lb (80 kg) requests a physical. He denies any health problems. Routine blood analysis is unremarkable except for plasma total cholesterol of 295 mg/dl. (Reference value is <200 mg.) The man refuses drug therapy for his hypercholesterolemia. Analysis of a 1-day dietary recall showed the following: 7.4. Decreasing which one of the following dietary components would have the greatest effect in lowering the patient’s plasma cholesterol? A. Carbohydrates B. Cholesterol C. Fiber D. Monounsaturated fat E. Polyunsaturated fat F. Saturated fat


Biochemistry_Lippinco

Biochemistry_Lippinco. A. Carbohydrates B. Cholesterol C. Fiber D. Monounsaturated fat E. Polyunsaturated fat F. Saturated fat Correct answer = F. The intake of saturated fat most strongly influences plasma cholesterol in this diet. The patient is consuming a high-calorie, high-fat diet with 42% of the fat as saturated fat. The most important dietary recommendations are to lower total caloric intake, substitute monounsaturated and polyunsaturated fats for saturated fats, and increase dietary fiber. A decrease in dietary cholesterol would be helpful but is not a primary objective. 7.5. What information would be necessary to estimate the patient’s total energy expenditure?


Biochemistry_Lippinco

Biochemistry_Lippinco. 7.5. What information would be necessary to estimate the patient’s total energy expenditure? The daily basal energy expenditure (estimated resting metabolic rate/hour × 24 hours) and a physical activity ratio (PAR) based on the type and duration of physical activities are needed variables. An additional 10% would be added to account for the thermic effect of food. Note that if the patient were hospitalized, an injury factor (IF) would be included in the calculation, and the PAR would be modified. Tables of PAR and IF are available. Micronutrients: Vitamins 28 For additional ancillary materials related to this chapter, please visit thePoint. I. OVERVIEW


Biochemistry_Lippinco

Biochemistry_Lippinco. Vitamins are chemically unrelated organic compounds that cannot be synthesized in adequate quantities by humans and, therefore, must be supplied by the diet. Nine vitamins (folic acid, cobalamin, ascorbic acid, pyridoxine, thiamine, niacin, riboflavin, biotin, and pantothenic acid) are classified as water soluble. Because they are readily excreted in the urine, toxicity is rare. However, deficiencies can occur quickly. Four vitamins (A, D, K, and E) are termed fat soluble (Fig. 28.1). They are released, absorbed, and transported (in chylomicrons, see p. 227) with dietary fat. They are not readily excreted, and significant quantities are stored in the liver and adipose tissue. In fact, consumption of vitamins A and D in excess of the Dietary Reference Intakes (see Chapter 27) can lead to accumulation of toxic quantities of these compounds. Vitamins are required to perform specific cellular functions. For example, many of the water-soluble vitamins are precursors of coenzymes for the


Biochemistry_Lippinco

Biochemistry_Lippinco. accumulation of toxic quantities of these compounds. Vitamins are required to perform specific cellular functions. For example, many of the water-soluble vitamins are precursors of coenzymes for the enzymes of intermediary metabolism. In contrast to the water-soluble vitamins, only one fat-soluble vitamin (vitamin K) has a coenzyme function.


Biochemistry_Lippinco

Biochemistry_Lippinco. II. FOLIC ACID (VITAMIN B9) Folic acid (or, folate), which plays a key role in one-carbon metabolism, is essential for the biosynthesis of several compounds. Folic acid deficiency is probably the most common vitamin deficiency in the United States, particularly among pregnant women and individuals with alcoholism. [Note: Leafy, dark-green vegetables are a good source of folic acid.] A. Function Tetrahydrofolate (THF), the reduced, coenzyme form of folate, receives one-carbon fragments from donors such as serine, glycine, and histidine and transfers them to intermediates in the synthesis of amino acids, purine nucleotides, and thymidine monophosphate (TMP), a pyrimidine nucleotide incorporated into DNA (Fig. 28.2). B. Nutritional anemias


Biochemistry_Lippinco

Biochemistry_Lippinco. B. Nutritional anemias Anemia is a condition in which the blood has a lower than normal concentration of hemoglobin, which results in a reduced ability to transport oxygen (O2). Nutritional anemias (that is, those caused by inadequate intake of one or more essential nutrients) can be classified according to the size of the red blood cells (RBC), or mean corpuscular volume (MCV), observed in the blood (Fig. 28.3). Microcytic anemia (MCV below normal), caused by lack of iron, is the most common form of nutritional anemia. The second major category of nutritional anemia, macrocytic (MCV above normal), results from a deficiency in folic acid or vitamin B12. [Note: These macrocytic anemias are commonly called megaloblastic because a deficiency of either vitamin (or both) causes accumulation of large, immature RBC precursors, known as megaloblasts, in the bone marrow and the blood (Fig. 28.4). Hypersegmented neutrophils are also seen.] 1.


Biochemistry_Lippinco

Biochemistry_Lippinco. Folate and anemia: Inadequate serum levels of folate can be caused by increased demand (for example, pregnancy and lactation; see p. 372), poor absorption caused by pathology of the small intestine, alcoholism, or treatment with drugs (for example, methotrexate) that are dihydrofolate reductase inhibitors (see Fig. 28.2). A folate-free diet can cause a deficiency within a few weeks. A primary result of folic acid deficiency is megaloblastic anemia (see Fig. 28.4), caused by diminished synthesis of purine nucleotides and TMP, which leads to an inability of cells (including RBC precursors) to make DNA and, therefore, an inability to divide. 2.


Biochemistry_Lippinco

Biochemistry_Lippinco. Folate and neural tube defects: Spina bifida and anencephaly, the most common neural tube defects (NTD), affect ~3,000 pregnancies in the United States annually. Folic acid supplementation before conception and during the first trimester has been shown to significantly reduce NTD. Therefore, all women of childbearing age are advised to consume 0.4 mg/day (400 µg/day) of folic acid to reduce the risk of having a pregnancy affected by NTD and ten times that amount if a previous pregnancy was affected. Adequate folate nutrition must occur at the time of conception because critical folate-dependent development occurs in the first weeks of fetal life, at a time when many women are not yet aware of their pregnancy. In 1998, the U.S. Food and Drug Administration authorized the addition of folic acid to wheat flour and enriched grain products, resulting in a dietary supplementation of ~0.1 mg/day. This supplementation allows ~50% of all reproductive-aged women to receive 0.4 mg of folate from


Biochemistry_Lippinco

Biochemistry_Lippinco. to wheat flour and enriched grain products, resulting in a dietary supplementation of ~0.1 mg/day. This supplementation allows ~50% of all reproductive-aged women to receive 0.4 mg of folate from all sources.


Biochemistry_Lippinco

Biochemistry_Lippinco. III. COBALAMIN (VITAMIN B12) Vitamin B12 is required in humans for two essential enzymatic reactions: the remethylation of homocysteine (Hcy) to methionine and the isomerization of methylmalonyl coenzyme A (CoA), which is produced during the degradation of some amino acids (isoleucine, valine, threonine, and methionine) and fatty acids (FA) with odd numbers of carbon atoms (Fig. 28.5). When cobalamin is deficient, unusual (branched) FA accumulate and become incorporated into cell membranes, including those of the central nervous system (CNS). This may account for some of the neurologic manifestations of vitamin B12 deficiency. [Note: Folic acid (as N5-methyl THF) is also required in the remethylation of Hcy. Therefore, deficiency of B12 or folate results in elevated Hcy levels.] A. Structure and coenzyme forms


Biochemistry_Lippinco

Biochemistry_Lippinco. Hcy. Therefore, deficiency of B12 or folate results in elevated Hcy levels.] A. Structure and coenzyme forms Cobalamin contains a corrin ring system that resembles the porphyrin ring of heme (see p. 279), but differs in that two of the pyrrole rings are linked directly rather than through a methene bridge. Cobalt (see p. 407) is held in the center of the corrin ring by four coordination bonds with the nitrogens of the pyrrole groups. The remaining coordination bonds of the cobalt are with the nitrogen of 5,6-dimethylbenzimidazole and with cyanide in commercial preparations of the vitamin in the form of cyanocobalamin (Fig. 28.6). The physiologic coenzyme forms of cobalamin are 5′deoxyadenosylcobalamin and methylcobalamin, in which cyanide is replaced with 5′-deoxyadenosine or a methyl group, respectively (see Fig. 28.6). B. Distribution


Biochemistry_Lippinco

Biochemistry_Lippinco. B. Distribution Vitamin B12 is synthesized only by microorganisms, and it is not present in plants. Animals obtain the vitamin preformed from their intestinal microbiota (see p. 371) or by eating foods derived from other animals. Cobalamin is present in appreciable amounts in liver, red meat, fish, eggs, dairy products, and fortified cereals. C. Folate trap hypothesis


Biochemistry_Lippinco

Biochemistry_Lippinco. C. Folate trap hypothesis The effects of cobalamin deficiency are most pronounced in rapidly dividing cells, such as the erythropoietic tissue of bone marrow and the mucosal cells of the intestine. Such tissues need both the N5,N10-methylene and N10-formyl forms of THF for the synthesis of nucleotides required for DNA replication (see pp. 292 and 303). However, in vitamin B12 deficiency, the utilization of the N5-methyl form of THF in the B12 dependent methylation of Hcy to methionine is impaired. Because the methylated form cannot be converted directly to other forms of THF, folate is trapped in the N5-methyl form, which accumulates. The levels of the other forms decrease. Thus, cobalamin deficiency leads to a deficiency of the THF forms needed in purine and TMP synthesis, resulting in the symptoms of megaloblastic anemia. D. Clinical indications for cobalamin


Biochemistry_Lippinco

Biochemistry_Lippinco. D. Clinical indications for cobalamin In contrast to other water-soluble vitamins, significant amounts (2–5 mg) of vitamin B12 are stored in the body. As a result, it may take several years for the clinical symptoms of B12 deficiency to develop as a result of decreased intake of the vitamin. [Note: Deficiency happens much more quickly (in months) if absorption is impaired (see below). The Schilling test evaluates B12 absorption.] B12 deficiency can be determined by the level of methylmalonic acid in blood, which is elevated in individuals with low intake or decreased absorption of the vitamin. 1. Pernicious anemia: Vitamin B12 deficiency is most commonly seen in patients who fail to absorb the vitamin from the intestine (Fig. 28.7). B12 is released from food in the acidic environment of the stomach. [Note:


Biochemistry_Lippinco

Biochemistry_Lippinco. Malabsorption of cobalamin in the elderly is most often due to reduced secretion of gastric acid (achlorhydria).] Free B12 then binds a glycoprotein (R-protein or haptocorrin), and the complex moves into the intestine. B12 is released from the R-protein by pancreatic enzymes and binds another glycoprotein, intrinsic factor (IF). The cobalamin–IF complex travels through the intestine and binds to a receptor (cubilin) on the surface of mucosal cells in the ileum. The cobalamin is transported into the mucosal cell and, subsequently, into the general circulation, where it is carried by its binding protein (transcobalamin). B12 is taken up and stored in the liver, primarily. It is released into bile and efficiently reabsorbed in the ileum. Severe malabsorption of vitamin B12 leads to pernicious anemia. This disease is most commonly a result of an autoimmune destruction of the gastric parietal cells that are responsible for the synthesis of IF (lack of IF prevents B12 absorption). [Note:


Biochemistry_Lippinco

Biochemistry_Lippinco. anemia. This disease is most commonly a result of an autoimmune destruction of the gastric parietal cells that are responsible for the synthesis of IF (lack of IF prevents B12 absorption). [Note: Patients who have had a partial or total gastrectomy become IF deficient and, therefore, B12 deficient.] Individuals with cobalamin deficiency are usually anemic (folate recycling is impaired), and they show neuropsychiatric symptoms as the disease develops. The CNS effects are irreversible. Pernicious anemia requires lifelong treatment with either high-dose oral B12 or intramuscular injection of cyanocobalamin. [Note: Supplementation works even in the absence of IF because ~1% of B12 uptake is by IF-independent diffusion.]


Biochemistry_Lippinco

Biochemistry_Lippinco. Folic acid supplementation can partially reverse the hematologic abnormalities of B12 deficiency and, therefore, can mask a cobalamin deficiency. Thus, to prevent the later CNS effects of B12 deficiency, therapy for megaloblastic anemia is initiated with both vitamin B12 and folic acid until the cause of the anemia can be determined. IV. ASCORBIC ACID (VITAMIN C) The active form of vitamin C is ascorbic acid (Fig. 28.8). Its main function is as a reducing agent. Vitamin C is a coenzyme in hydroxylation reactions (for example, hydroxylation of prolyl and lysyl residues in collagen; see p. 47), where its role is to keep the iron (Fe) of hydroxylases in the reduced, ferrous (Fe+2) form. Thus, vitamin C is required for the maintenance of normal connective tissue as well as for wound healing. Vitamin C also facilitates the absorption of dietary nonheme iron from the intestine by reduction of the ferric form (Fe+3) to Fe+2 (see p. 403). A. Deficiency


Biochemistry_Lippinco

Biochemistry_Lippinco. A. Deficiency Ascorbic acid deficiency results in scurvy, a disease characterized by sore and spongy gums, loose teeth, fragile blood vessels, hemorrhage, swollen joints, bone changes, and fatigue (Fig. 28.9). Many of the deficiency symptoms can be explained by the decreased hydroxylation of collagen, resulting in defective connective tissue. A microcytic anemia caused by decreased absorption of iron may also be seen. B. Chronic disease prevention Vitamin C is one of a group of nutrients that includes vitamin E (see p. 395) and β-carotene (see p. 386), which are known as antioxidants. [Note: Vitamin C regenerates the functional, reduced form of vitamin E.] Consumption of diets rich in these compounds is associated with a decreased incidence of some chronic diseases, such as cardiovascular disease (CVD) and certain cancers. However, clinical trials involving supplementation with the isolated antioxidants have failed to demonstrate any convincing preventive effects.


Biochemistry_Lippinco

Biochemistry_Lippinco. V. PYRIDOXINE (VITAMIN B6) Vitamin B6 is a collective term for pyridoxine, pyridoxal, and pyridoxamine, all derivatives of pyridine. They differ only in the nature of the functional group attached to the ring (Fig. 28.10). Pyridoxine occurs primarily in plants, whereas pyridoxal and pyridoxamine are found in foods obtained from animals. All three compounds can serve as precursors of the biologically active coenzyme, pyridoxal phosphate (PLP). PLP functions as a coenzyme for a large number of enzymes, particularly those that catalyze reactions involving amino acids, for example, in the transsulfuration of Hcy to cysteine (see p. 264). [Note: PLP is also required by glycogen phosphorylase (see p. 128).] A. Clinical indications for pyridoxine


Biochemistry_Lippinco

Biochemistry_Lippinco. A. Clinical indications for pyridoxine Isoniazid, a drug commonly used to treat tuberculosis, can induce a vitamin B6 deficiency by forming an inactive derivative with PLP. Thus, dietary supplementation with B6 is an adjunct to isoniazid treatment. Otherwise, dietary deficiencies in pyridoxine are rare but have been observed in newborn infants fed formulas low in B6, in women taking oral contraceptives, and in those with alcoholism. B. Toxicity Vitamin B6 is the only water-soluble vitamin with significant toxicity. Neurologic symptoms (sensory neuropathy) occur at intakes above 500 mg/day, an amount nearly 400 times the recommended dietary allowance (RDA) and over 5 times the tolerable upper limit (UL). (See Chapter 27 for a discussion of RDA and UL.) Substantial improvement, but not complete recovery, occurs when the vitamin is discontinued. VI. THIAMINE (VITAMIN B1)


Biochemistry_Lippinco

Biochemistry_Lippinco. VI. THIAMINE (VITAMIN B1) Thiamine pyrophosphate (TPP) is the biologically active form of the vitamin, formed by the transfer of a pyrophosphate group from ATP to thiamine (Fig. 28.11). TPP serves as a coenzyme in the formation or degradation of α-ketols by transketolase (Fig. 28.12A) and in the oxidative decarboxylation of α-keto acids (Fig. 28.12B). A. Clinical indications for thiamine


Biochemistry_Lippinco

Biochemistry_Lippinco. A. Clinical indications for thiamine The oxidative decarboxylation of pyruvate and α-ketoglutarate, which plays a key role in energy metabolism of most cells, is particularly important in tissues of the CNS. In thiamine deficiency, the activity of these two dehydrogenase-catalyzed reactions is decreased, resulting in decreased production of ATP and, therefore, impaired cellular function. TPP is also required by branched-chain α-keto acid dehydrogenase of muscle (see p. 266). [Note: It is the decarboxylase of each of these α-keto acid dehydrogenase multienzyme complexes that requires TPP.] Thiamine deficiency is diagnosed by an increase in erythrocyte transketolase activity observed with addition of TPP. 1.


Biochemistry_Lippinco

Biochemistry_Lippinco. 1. Beriberi: This severe thiamine-deficiency syndrome is found in areas where polished rice is the major component of the diet. Adult beriberi is classified as dry (characterized by peripheral neuropathy, especially in the legs) or wet (characterized by edema because of dilated cardiomyopathy). 2. Wernicke-Korsakoff syndrome: In the United States, thiamine deficiency, which is seen primarily in association with chronic alcoholism, is due to dietary insufficiency or impaired intestinal absorption of the vitamin. Some individuals with alcoholism develop Wernicke-Korsakoff syndrome, a thiamine-deficiency state characterized by mental confusion, gait ataxia, nystagmus (a to-and-fro motion of the eyeballs), and ophthalmoplegia (weakness of eye muscles) with Wernicke encephalopathy as well as memory problems and hallucinations with Korsakoff dementia. The syndrome is treatable with thiamine supplementation, but recovery of memory is typically incomplete. VII. NIACIN (VITAMIN B3)


Biochemistry_Lippinco

Biochemistry_Lippinco. Niacin, or nicotinic acid, is a substituted pyridine derivative. The biologically active coenzyme forms are nicotinamide adenine dinucleotide (NAD+) and its phosphorylated derivative, nicotinamide adenine dinucleotide phosphate (NADP+), as shown in Figure 28.13. Nicotinamide, a derivative of nicotinic acid that contains an amide instead of a carboxyl group, also occurs in the diet. Nicotinamide is readily deaminated in the body and, therefore, is nutritionally equivalent to nicotinic acid. NAD+ and NADP+ serve as coenzymes in oxidation–reduction reactions in which the coenzyme undergoes reduction of the pyridine ring by accepting two electrons from a hydride ion, as shown in Figure 28.14. The reduced forms of NAD+ and NADP+ are NADH and NADPH, respectively. [Note: A metabolite of tryptophan, quinolinate, can be converted to NAD(P). In comparison, 60 mg of tryptophan = 1 mg of niacin.] to NADH. [Note: The hydride ion consists of a hydrogen (H) atom plus an electron.] = phosphate.


Biochemistry_Lippinco

Biochemistry_Lippinco. A. Distribution Niacin is found in unrefined and enriched grains and cereal, milk, and lean meats (especially liver). B. Clinical indications for niacin 1. Deficiency: A deficiency of niacin causes pellagra, a disease involving the skin, gastrointestinal tract, and CNS. The symptoms of pellagra progress through the three Ds: dermatitis (photosensitive), diarrhea, and dementia. If untreated, death (a fourth D) occurs. Hartnup disorder, characterized by defective absorption of tryptophan, can result in pellagra-like symptoms. [Note: Corn is low in both niacin and tryptophan. Corn-based diets can cause pellagra.] 2.


Biochemistry_Lippinco

Biochemistry_Lippinco. Hyperlipidemia treatment: Niacin at doses of 1.5 g/day, or 100 times the RDA, strongly inhibits lipolysis in adipose tissue, the primary producer of circulating free fatty acids (FFA). The liver normally uses these circulating FFA as a major precursor for triacylglycerol (TAG) synthesis. Thus, niacin causes a decrease in liver TAG synthesis, which is required for very-low-density lipoprotein ([VLDL] see p. 230) production. Low-density lipoprotein (LDL, the cholesterol-rich lipoprotein) is derived from VLDL in the plasma. Thus, both plasma TAG (in VLDL) and cholesterol (in LDL) are lowered. Therefore, niacin is particularly useful in the treatment of type IIb hyperlipoproteinemia, in which both VLDL and LDL are elevated. The high doses of niacin required can cause acute, prostaglandin-mediated flushing. Aspirin can reduce this side effect by inhibiting prostaglandin synthesis (see p. 214). Itching may also occur. [Note: Niacin raises high-density lipoprotein and lowers Lp(a) levels


Biochemistry_Lippinco

Biochemistry_Lippinco. flushing. Aspirin can reduce this side effect by inhibiting prostaglandin synthesis (see p. 214). Itching may also occur. [Note: Niacin raises high-density lipoprotein and lowers Lp(a) levels (see p. 237).]


Biochemistry_Lippinco

Biochemistry_Lippinco. VIII. RIBOFLAVIN (VITAMIN B2) The two biologically active forms of B2 are flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), formed by the transfer of an adenosine monophosphate moiety from ATP to FMN (Fig. 28.15). FMN and FAD are each capable of reversibly accepting two hydrogen atoms, forming FMNH2 or FADH2, respectively. FMN and FAD are bound tightly, sometimes covalently, to flavoenzymes (for example, NADH dehydrogenase [FMN] and succinate dehydrogenase [FAD]) that catalyze the oxidation or reduction of a substrate. Riboflavin deficiency is not associated with a major human disease, although it frequently accompanies other vitamin deficiencies. Deficiency symptoms include dermatitis, cheilosis (fissuring at the corners of the mouth), and glossitis (the tongue appearing smooth and dark). [Note: Because riboflavin is light sensitive, phototherapy for hyperbilirubinemia (see p. 285) may require supplementation with the vitamin.] IX. BIOTIN (VITAMIN B7)


Biochemistry_Lippinco

Biochemistry_Lippinco. Biotin is a coenzyme in carboxylation reactions, in which it serves as a carrier of activated carbon dioxide (CO2) (see Fig. 10.3, p. 119, for the mechanism of biotin-dependent carboxylations). Biotin is covalently bound to the ε-amino group of lysine residues in biotin-dependent enzymes (Fig. 28.16). Biotin deficiency does not occur naturally because the vitamin is widely distributed in food. Also, a large percentage of the biotin requirement in humans is supplied by intestinal bacteria. However, the addition of raw egg white to the diet as a source of protein can induce symptoms of biotin deficiency, namely, dermatitis, hair loss, loss of appetite, and nausea. Raw egg white contains the glycoprotein avidin, which tightly binds biotin and prevents its absorption from the intestine. With a normal diet, however, it has been estimated that 20 eggs/day would be required to induce a deficiency syndrome. [Note: Inclusion of raw eggs in the diet is not recommended because of the possibility


Biochemistry_Lippinco

Biochemistry_Lippinco. normal diet, however, it has been estimated that 20 eggs/day would be required to induce a deficiency syndrome. [Note: Inclusion of raw eggs in the diet is not recommended because of the possibility of salmonellosis caused by infection with Salmonella enterica.]


Biochemistry_Lippinco

Biochemistry_Lippinco. Multiple carboxylase deficiency results from decreased ability to add biotin to carboxylases during their synthesis or to remove it during their degradation. Treatment is biotin supplementation. X. PANTOTHENIC ACID (VITAMIN B5) Pantothenic acid is a component of CoA, which functions in the transfer of acyl groups (Fig. 28.17). CoA contains a thiol group that carries acyl compounds as activated thiol esters. Examples of such structures are succinyl CoA, fatty acyl CoA, and acetyl CoA. Pantothenic acid is also a component of the acyl carrier protein domain of fatty acid synthase (see p. 184). Eggs, liver, and yeast are the most important sources of pantothenic acid, although the vitamin is widely distributed. Pantothenic acid deficiency is not well characterized in humans, and no RDA has been established. XI. VITAMIN A


Biochemistry_Lippinco

Biochemistry_Lippinco. XI. VITAMIN A Vitamin A is a fat-soluble vitamin that comes primarily from animal sources as retinol (preformed vitamin A), a retinoid. The retinoids, a family of structurally related molecules, are essential for vision, reproduction, growth, and maintenance of epithelial tissues. They also play a role in immune function. Retinoic acid, derived from oxidation of retinol, mediates most of the actions of the retinoids, except for vision, which depends on retinal, the aldehyde derivative of retinol. A. Structure The retinoids include the natural forms of vitamin A, retinol and its metabolites (Fig. 28.18), and synthetic forms (drugs). 1. Retinol: A primary alcohol containing a β-ionone ring with an unsaturated side chain, retinol is found in animal tissues as a retinyl ester with long-chain FA. It is the storage form of vitamin A. 2. Retinal: This is the aldehyde derived from the oxidation of retinol. Retinal and retinol can readily be interconverted. 3.


Biochemistry_Lippinco

Biochemistry_Lippinco. 2. Retinal: This is the aldehyde derived from the oxidation of retinol. Retinal and retinol can readily be interconverted. 3. Retinoic acid: This is the acid derived from the oxidation of retinal. Retinoic acid cannot be reduced in the body and, therefore, cannot give rise to either retinal or retinol. 4. β-Carotene: Plant foods contain β-carotene (provitamin A), which can be oxidatively and symmetrically cleaved in the intestine to yield two molecules of retinal. In humans, the conversion is inefficient, and the vitamin A activity of β-carotene is only about 1/12 that of retinol. B. Absorption and transport to the liver


Biochemistry_Lippinco

Biochemistry_Lippinco. B. Absorption and transport to the liver Retinyl esters from the diet are hydrolyzed in the intestinal mucosa, releasing retinol and FFA (Fig. 28.19). Retinol derived from esters and from the reduction of retinal from β-carotene cleavage is reesterified to long-chain FA within the enterocytes and secreted as a component of chylomicrons into the lymphatic system. Retinyl esters contained in chylomicron remnants are taken up by, and stored in, the liver. [Note: All fat-soluble vitamins are carried in chylomicrons.] C. Release from the liver


Biochemistry_Lippinco

Biochemistry_Lippinco. C. Release from the liver When needed, retinol is released from the liver and transported through the blood to extrahepatic tissues by retinol-binding protein complexed with transthyretin (see Fig. 28.19). The ternary complex binds to a transport protein on the surface of the cells of peripheral tissues, permitting retinol to enter. An intracellular retinol-binding protein carries retinol to sites in the nucleus where the vitamin regulates transcription in a manner analogous to that of steroid hormones. D. Retinoic acid mechanism of action


Biochemistry_Lippinco

Biochemistry_Lippinco. D. Retinoic acid mechanism of action Retinol is oxidized to retinoic acid. Retinoic acid binds with high affinity to specific receptor proteins (retinoic acid receptors [RAR]) present in the nucleus of target tissues such as epithelial cells (Fig. 28.20). The activated retinoic acid–RAR complex binds to response elements on DNA and recruits activators or repressors to regulate retinoid-specific RNA synthesis, resulting in control of the production of specific proteins that mediate several physiologic functions. For example, retinoids control the expression of the gene for keratin in most epithelial tissues of the body. [Note: The RAR proteins are part of the superfamily of transcriptional regulators that includes the nuclear receptors for steroid and thyroid hormones and vitamin D, all of which function in a similar way (see p. 240).] E. Functions 1.


Biochemistry_Lippinco

Biochemistry_Lippinco. E. Functions 1. Visual cycle: Vitamin A is a component of the visual pigments of rod and cone cells. Rhodopsin, the visual pigment of the rod cells in the retina, consists of 11-cis retinal bound to the protein opsin (see Fig. 28.19). When rhodopsin, a G protein–coupled receptor, is exposed to light, a series of photochemical isomerizations occurs, which results in the bleaching of rhodopsin and release of all-trans retinal and opsin. This process activates the G protein transducin, triggering a nerve impulse that is transmitted by the optic nerve to the brain. Regeneration of rhodopsin requires isomerization of all-trans retinal back to 11-cis retinal. All-trans retinal is reduced to all-trans retinol, esterified, and isomerized to 11-cis retinol that is oxidized to 11-cis retinal. The latter combines with opsin to form rhodopsin, thus completing the cycle. Similar reactions are responsible for color vision in the cone cells. 2.


Biochemistry_Lippinco

Biochemistry_Lippinco. 2. Epithelial cell maintenance: Vitamin A is essential for normal differentiation of epithelial tissues and mucus secretion and, thus, supports the body’s barrier-based defense against pathogens. 3. Reproduction: Retinol and retinal are essential for normal reproduction, supporting spermatogenesis in the male and preventing fetal resorption in the female. Retinoic acid is inactive in maintaining reproduction and in the visual cycle but promotes growth and differentiation of epithelial cells. F. Distribution Liver, kidney, cream, butter, and egg yolk are good sources of preformed vitamin A. Yellow, orange, and dark-green vegetables and fruits are good sources of the carotenes (provitamin A). G. Requirement The RDA for adults is 900 retinol activity equivalents (RAE) for males and 700 RAE for females. In comparison, 1 RAE = 1 µg of retinol, 12 µg of β carotene, or 24 µg of other carotenoids. H. Clinical indications for vitamin A


Biochemistry_Lippinco

Biochemistry_Lippinco. H. Clinical indications for vitamin A Although chemically related, retinoic acid and retinol have distinctly different therapeutic applications. Retinol and its carotenoid precursor are used as dietary supplements, whereas various forms of retinoic acid are useful in dermatology (Fig. 28.21). 1.


Biochemistry_Lippinco

Biochemistry_Lippinco. 1. Deficiency: Vitamin A, administered as retinol or retinyl esters, is used to treat patients who are deficient in the vitamin. Night blindness (nyctalopia) is one of the earliest signs of vitamin A deficiency. The visual threshold is increased, making it difficult to see in dim light. Prolonged deficiency leads to an irreversible loss in the number of visual cells. Severe deficiency leads to xerophthalmia, a pathologic dryness of the conjunctiva and cornea, caused, in part, by increased keratin synthesis. If untreated, xerophthalmia results in corneal ulceration and, ultimately, in blindness because of the formation of opaque scar tissue. The condition is most commonly seen in children in developing tropical countries. Over 500,000 children worldwide are blinded each year by xerophthalmia caused by insufficient vitamin A in the diet. 2.


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Biochemistry_Lippinco. 2. Skin conditions: Dermatologic problems such as acne are effectively treated with retinoic acid or its derivatives (see Fig. 28.21). Mild cases of acne and skin aging are treated with tretinoin (all-trans retinoic acid). Tretinoin is too toxic for systemic (oral) administration in treating skin conditions and is confined to topical application. [Note: Oral tretinoin is used in treating acute promyelocytic leukemia.] In patients with severe cystic acne unresponsive to conventional therapies, isotretinoin (13-cis retinoic acid) is administered orally. An oral synthetic retinoid is used to treat psoriasis. I. Retinoid toxicity 1.


Biochemistry_Lippinco

Biochemistry_Lippinco. I. Retinoid toxicity 1. Vitamin A: Excessive intake of vitamin A (but not carotene) produces a toxic syndrome called hypervitaminosis A. Amounts exceeding 7.5 mg/day of retinol should be avoided. Early signs of chronic hypervitaminosis A are reflected in the skin, which becomes dry and pruritic (because of decreased keratin synthesis); in the liver, which becomes enlarged and can become cirrhotic; and in the CNS, where a rise in intracranial pressure may mimic the symptoms of a brain tumor. Pregnant women, in particular, should not ingest excessive quantities of vitamin A because of its potential for teratogenesis (causing congenital malformations in the developing fetus). UL is 3,000 µg preformed vitamin A/day. [Note: Vitamin A promotes bone growth. In excess, however, it is associated with decreased bone mineral density and increased risk of fractures.] 2.


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Biochemistry_Lippinco. Isotretinoin: The drug, an isomer of retinoic acid, is teratogenic and absolutely contraindicated in women with childbearing potential unless they have severe, disfiguring cystic acne that is unresponsive to standard therapies. Pregnancy must be excluded before treatment begins, and birth control must be used. Prolonged treatment with isotretinoin can result in an increase in TAG and cholesterol, providing some concern for an increased risk of CVD. XII. VITAMIN D The D vitamins are a group of sterols that have a hormone-like function. The active molecule, 1,25-dihydroxycholecalciferol ([1,25-diOH-D3], or calcitriol), binds to intracellular receptor proteins. The 1,25-diOH-D3–receptor complex interacts with response elements in the nuclear DNA of target cells in a manner similar to that of vitamin A (see Fig. 28.20) and either selectively stimulates or represses gene transcription. The most prominent actions of calcitriol are to regulate the serum levels of calcium and phosphorus.


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Biochemistry_Lippinco. A. Distribution 1. Endogenous vitamin precursor: 7-Dehydrocholesterol, an intermediate in cholesterol synthesis, is converted to cholecalciferol in the dermis and epidermis of humans exposed to sunlight and transported to liver bound to vitamin D–binding protein. 2. Diet: Ergocalciferol (vitamin D2), found in plants, and cholecalciferol (vitamin D3), found in animal tissues, are sources of preformed vitamin D activity (Fig. 28.22). Vitamin D2 and vitamin D3 differ chemically only in the presence of an additional double-bond and methyl group in the plant sterol. Dietary vitamin D is packaged into chylomicrons. [Note: Preformed vitamin D is a dietary requirement only in individuals with limited exposure to sunlight.]


Biochemistry_Lippinco

Biochemistry_Lippinco. B. Metabolism 1. 1,25-Dihydroxycholecalciferol formation: Vitamins D2 and D3 are not biologically active but are converted in vivo to calcitriol, the active form of the D vitamin, by two sequential hydroxylation reactions (Fig. 28.23). The first hydroxylation occurs at the 25 position and is catalyzed by a specific 25-hydroxylase in the liver. The product of the reaction, 25hydroxycholecalciferol ([25-OH-D3], calcidiol), is the predominant form of vitamin D in the serum and the major storage form. 25-OH-D3 is further hydroxylated at the 1 position by 25-hydroxycholecalciferol 1 hydroxylase found primarily in the kidney, resulting in the formation of 1,25-diOH-D3 (calcitriol). [Note: Both hydroxylases are cytochrome P450 proteins (see p. 149).] 2. Hydroxylation regulation: Calcitriol is the most potent vitamin D metabolite. Its formation is tightly regulated by the level of serum phosphate (PO43−) and calcium ions (Ca2+) as shown in Figure 28.24. 25


Biochemistry_Lippinco

Biochemistry_Lippinco. Hydroxycholecalciferol 1-hydroxylase activity is increased directly by low serum PO43− or indirectly by low serum Ca2+ , which triggers the secretion of parathyroid hormone (PTH) from the chief cells of the parathyroid gland. PTH upregulates the 1-hydroxylase. Thus, hypocalcemia caused by insufficient dietary Ca2+ results in elevated levels of serum 1,25-diOH-D3. [Note: 1,25-diOH-D3 inhibits expression of PTH, forming a negative feedback loop. It also inhibits activity of the 1-hydroxylase.] C. Function The overall function of calcitriol is to maintain adequate serum levels of Ca2+ . It performs this function by 1) increasing uptake of Ca2+ by the intestine, 2) minimizing loss of Ca2+ by the kidney by increasing reabsorption, and 3) stimulating resorption (demineralization) of bone when blood Ca2+ is low (see Fig. 28.23). 1.


Biochemistry_Lippinco

Biochemistry_Lippinco. 1. Effect on the intestine: Calcitriol stimulates intestinal absorption of Ca2+ by first entering the intestinal cell and binding to a cytosolic receptor. The 1,25-diOH-D3–receptor complex then moves to the nucleus where it selectively interacts with response elements on the DNA. As a result, Ca2+ uptake is enhanced by increased expression of the calcium-binding protein calbindin. Thus, the mechanism of action of 1,25-diOH-D3 is typical of steroid hormones (see p. 240). 2. Effect on bone: Bone is composed of collagen and crystals of Ca5(PO4)3OH (hydroxylapatite). When blood Ca2+ is low, 1,25-diOH-D3 stimulates bone resorption by a process that is enhanced by PTH. The result is an increase in serum Ca2+ . Therefore, bone is an important reservoir of Ca2+ that can be mobilized to maintain serum levels. [Note: PTH and calcitriol also work together to prevent renal loss of Ca2+.] D. Distribution and requirement


Biochemistry_Lippinco

Biochemistry_Lippinco. D. Distribution and requirement Vitamin D occurs naturally in fatty fish, liver, and egg yolk. Milk, unless it is artificially fortified, is not a good source. The RDA for individuals ages 1–70 years is 15 µg/day and 20 µg/day if over age 70 years. Experts disagree, however, on the optimal level of vitamin D needed to maintain health. [Note: 1 µg vitamin D = 40 international units (IU).] Because breast milk is a poor source of vitamin D, supplementation is recommended for breastfed babies.


Biochemistry_Lippinco

Biochemistry_Lippinco. E. Clinical indications for vitamin D 1. Nutritional rickets: Vitamin D deficiency causes a net demineralization of bone, resulting in rickets in children and osteomalacia in adults (Fig. 28.25). Rickets is characterized by the continued formation of the collagen matrix of bone, but incomplete mineralization results in soft, pliable bones. In osteomalacia, demineralization of preexisting bones increases their susceptibility to fracture. Insufficient exposure to daylight and/or deficiencies in vitamin D consumption occur predominantly in infants and the elderly. Vitamin D deficiency is more common in the northern latitudes, because less vitamin D synthesis occurs in the skin as a result of reduced exposure to ultraviolet light. [Note: Loss-of-function mutations in the vitamin D receptor result in hereditary vitamin D– deficient rickets.] 2.


Biochemistry_Lippinco

Biochemistry_Lippinco. Renal osteodystrophy: Chronic kidney disease causes decreased ability to form active vitamin D as well as increased retention of PO43− , resulting in hyperphosphatemia and hypocalcemia. The low blood Ca2+ causes a rise in PTH and associated bone demineralization with release of Ca2+ and PO43− . Supplementation with vitamin D is an effective therapy. However, supplementation must be accompanied by PO43− reduction therapy to prevent further bone loss and precipitation of calcium phosphate crystals. 3. Hypoparathyroidism: Lack of PTH causes hypocalcemia and hyperphosphatemia. [Note: PTH increases phosphate excretion.] Patients may be treated with vitamin D and calcium supplementation. F. Toxicity


Biochemistry_Lippinco

Biochemistry_Lippinco. Hypoparathyroidism: Lack of PTH causes hypocalcemia and hyperphosphatemia. [Note: PTH increases phosphate excretion.] Patients may be treated with vitamin D and calcium supplementation. F. Toxicity Like all fat-soluble vitamins, vitamin D can be stored in the body and is only slowly metabolized. High doses (100,000 IU for weeks or months) can cause loss of appetite, nausea, thirst, and weakness. Enhanced Ca2+ absorption and bone resorption results in hypercalcemia, which can lead to deposition of calcium salts in soft tissue (metastatic calcification). The UL is 100 µg/day (4,000 IU/day) for individuals ages 9 years or older, with a lower level for those under age 9 years. [Note: Toxicity is only seen with use of supplements. Excess vitamin D produced in the skin is converted to inactive forms.] XIII. VITAMIN K


Biochemistry_Lippinco

Biochemistry_Lippinco. XIII. VITAMIN K The principal role of vitamin K is in the posttranslational modification of a number of proteins (most of which are involved with blood clotting), in which it serves as a coenzyme in the carboxylation of certain glutamic acid residues in these proteins. Vitamin K exists in several active forms, for example, in plants as phylloquinone (or vitamin K1), and in intestinal bacteria as menaquinone (or vitamin K2). A synthetic form of vitamin K, menadione, is able to be converted to K2. A. Function 1. γ-Carboxyglutamate formation: Vitamin K is required in the hepatic synthesis of the blood clotting proteins, prothrombin (factor [F]II) and FVII, FIX, and FX. (See online Chapter 35.) Formation of the functional clotting factors requires the vitamin K–dependent carboxylation of several glutamic acid residues to γ-carboxyglutamate (Gla) residues (Fig. 28.26). The carboxylation reaction requires γ-glutamyl carboxylase, O2,


Biochemistry_Lippinco

Biochemistry_Lippinco. CO2, and the hydroquinone form of vitamin K (which gets oxidized to the epoxide form). The formation of Gla residues is sensitive to inhibition by warfarin, a synthetic analog of vitamin K that inhibits vitamin K epoxide reductase (VKOR), the enzyme required to regenerate the functional hydroquinone form of vitamin K. 2. Prothrombin interaction with membranes: The Gla residues are good chelators of positively charged calcium ions, because of their two adjacent, negatively charged carboxylate groups. With prothrombin, for example, the prothrombin–calcium complex is able to bind to negatively charged membrane phospholipids on the surface of damaged endothelium and platelets. Attachment to membrane increases the rate at which the proteolytic conversion of prothrombin to thrombin can occur (Fig. 28.27). 3.


Biochemistry_Lippinco

Biochemistry_Lippinco. 3. γ-Carboxyglutamate residues in other proteins: Gla residues are also present in proteins other than those involved in forming a blood clot. For example, osteocalcin and matrix Gla protein of bone and proteins C and S (involved in limiting the formation of blood clots) also undergo γcarboxylation. Figure28.27RoleofvitaminKinbloodcoagulation.CO2=carbondioxide. B. Distribution and requirement Vitamin K is found in cabbage, kale, spinach, egg yolk, and liver. The adequate intake for vitamin K is 120 µg/day for adult males and 90 µg for adult females. There is also synthesis of the vitamin by the gut microbiota. C. Clinical indications for vitamin K 1.


Biochemistry_Lippinco

Biochemistry_Lippinco. C. Clinical indications for vitamin K 1. Deficiency: A true vitamin K deficiency is unusual because adequate amounts are generally obtained from the diet and produced by intestinal bacteria. If the bacterial population in the gut is decreased (for example, by antibiotics), the amount of endogenously formed vitamin is decreased, and this can lead to hypoprothrombinemia in the marginally malnourished individual (for example, a debilitated geriatric patient). This condition may require supplementation with vitamin K to correct the bleeding tendency. In addition, certain cephalosporin antibiotics (for example, cefamandole) cause hypoprothrombinemia, apparently by a warfarin-like mechanism that inhibits VKOR. Consequently, their use in treatment is usually supplemented with vitamin K. Deficiency can also affect bone health. 2.


Biochemistry_Lippinco

Biochemistry_Lippinco. 2. Deficiency in the newborn: Because newborns have sterile intestines, they initially lack the bacteria that synthesize vitamin K. Because human milk provides only about one fifth of the daily requirement for vitamin K, it is recommended that all newborns receive a single intramuscular dose of vitamin K as prophylaxis against hemorrhagic disease of the newborn. D. Toxicity Prolonged administration of large doses of menadione can produce hemolytic anemia and jaundice in the infant, because of toxic effects on the RBC membrane. Therefore, it is no longer used to treat vitamin K deficiency. No UL for the natural form has been set. XIV. VITAMIN E The E vitamins consist of eight naturally occurring tocopherols, of which αtocopherol is the most active (Fig. 28.28). Vitamin E functions as an antioxidant in prevention of nonenzymic oxidations (for example, oxidation of LDL (see p.


Biochemistry_Lippinco

Biochemistry_Lippinco. 232) and peroxidation of polyunsaturated FA by O2 and free radicals). [Note: Vitamin C regenerates active vitamin E.] A. Distribution and requirements Vegetable oils are rich sources of vitamin E, whereas liver and eggs contain moderate amounts. The RDA for α-tocopherol is 15 mg/day for adults. The vitamin E requirement increases as the intake of polyunsaturated FA increases to limit FA peroxidation. B. Deficiency Newborns have low reserves of vitamin E, but breast milk (and formulas) contain the vitamin. Very-low-birth-weight infants may be given supplements to prevent the hemolysis and retinopathy associated with vitamin E deficiency. When observed in adults, deficiency is usually associated with defective lipid absorption or transport. [Note: Abetalipoproteinemia, caused by a defect in the formation of chylomicrons (and VLDL), results in vitamin E deficiency (see p. 231).] C. Clinical indications for vitamin E


Biochemistry_Lippinco

Biochemistry_Lippinco. C. Clinical indications for vitamin E Vitamin E is not recommended for the prevention of chronic disease, such as CVD or cancer. Clinical trials using vitamin E supplementation have been uniformly disappointing. For example, subjects in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study trial who received high doses of vitamin E not only lacked cardiovascular benefit but also had an increased incidence of stroke. [Note: Vitamins E and C are used to slow the progression of age-related macular degeneration.] D. Toxicity Vitamin E is the least toxic of the fat-soluble vitamins, and no toxicity has been observed at doses of 300 mg/day (UL = 1,000 mg/day). Populations consuming diets high in fruits and vegetables show decreased incidence of some chronic diseases. However, clinical trials have failed to show a definitive benefit from supplements of folic acid; vitamins A, C, or E; or antioxidant combinations for the prevention of cancer or CVD. XV. CHAPTER SUMMARY


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Biochemistry_Lippinco. XV. CHAPTER SUMMARY The vitamins are summarized in Figure 28.29 on pp. 396–397. Choose the ONE best answer. For Questions 28.1–28.5, match the vitamin deficiency to the clinical consequence. 8.1. Bleeding 8.2. Diarrhea and dermatitis 8.3. Neural tube defects 8.4. Night blindness (nyctalopia) 8.5. Sore, spongy gums and loose teeth


Biochemistry_Lippinco

Biochemistry_Lippinco. 8.1. Bleeding 8.2. Diarrhea and dermatitis 8.3. Neural tube defects 8.4. Night blindness (nyctalopia) 8.5. Sore, spongy gums and loose teeth Correct answers = H, B, A, C, E. Vitamin K is required for formation of the γcarboxyglutamate residues in several proteins required for blood clotting. Consequently, a deficiency of vitamin K results in a tendency to bleed. Niacin deficiency is characterized by the three Ds: diarrhea, dermatitis, and dementia (and death, a fourth D, if untreated). Folic acid deficiency can result in neural tube defects in the developing fetus. Night blindness is one of the first signs of vitamin A deficiency. Rod cells in the retina detect white and black images and work best in low light, for example, at night. Rhodopsin, the visual pigment of the rod cells, consists of 11-cis retinal bound to the protein opsin. Vitamin C is required for the hydroxylation of proline and lysine during collagen synthesis.


Biochemistry_Lippinco

Biochemistry_Lippinco. Severe vitamin C deficiency (scurvy) results in defective connective tissue, characterized by sore and spongy gums, loose teeth, capillary fragility, anemia, and fatigue. 8.6. A 52-year-old woman presents with fatigue of several months’ duration. Blood studies reveal a macrocytic anemia, reduced levels of hemoglobin, elevated levels of homocysteine, and normal levels of methylmalonic acid. Which of the following is most likely deficient in this woman? A. Folic acid B. Folic acid and vitamin B12 C. Iron D. Vitamin C


Biochemistry_Lippinco

Biochemistry_Lippinco. A. Folic acid B. Folic acid and vitamin B12 C. Iron D. Vitamin C Correct answer = A. Macrocytic anemia is seen with deficiencies of folic acid, vitamin B12, or both. Vitamin B12 is utilized in only two reactions in the body: the remethylation of homocysteine (Hcy) to methionine, which also requires folic acid (as tetrahydrofolate [THF]), and the isomerization of methylmalonyl coenzyme A to succinyl coenzyme A, which does not require THF. The elevated Hcy and normal methylmalonic acid levels in the patient’s blood reflect a deficiency of folic acid as the cause of the macrocytic anemia. Iron deficiency causes microcytic anemia, as can vitamin C deficiency.


Biochemistry_Lippinco

Biochemistry_Lippinco. 8.7. A 10-month-old African American girl, whose family recently located from Maine to Virginia, is being evaluated for the bowed appearance of her legs. The parents report that the baby is still being breastfed and takes no supplements. Radiologic studies confirm the suspicion of rickets caused by vitamin D deficiency. Which one of the following statements concerning vitamin D is correct? A. A deficiency results in an increased secretion of calbindin. B. Chronic kidney disease results in overproduction of 1,25dihydroxycholecalciferol (calcitriol). C. 25-Hydroxycholecalciferol (calcidiol) is the active form of the vitamin. D. It is required in the diet of individuals with limited exposure to sunlight. E. Its actions are mediated through binding to G protein–coupled receptors. F. It opposes the effect of parathyroid hormone.


Biochemistry_Lippinco

Biochemistry_Lippinco. E. Its actions are mediated through binding to G protein–coupled receptors. F. It opposes the effect of parathyroid hormone. Correct answer = D. Vitamin D is required in the diet of individuals with limited exposure to sunlight, such as those living at northern latitudes like Maine and those with dark skin. Note that breast milk is low in vitamin D, and the lack of supplementation increases the risk of a deficiency. Vitamin D deficiency results in decreased synthesis of calbindin. Chronic kidney disease decreases production of calcitriol (1,25-dihydroxycholecalciferol), the active form of the vitamin. Vitamin D binds to nuclear receptors and alters gene transcription. Its effects are synergistic with parathyroid hormone. 8.8. Why might a deficiency of vitamin B6 result in a fasting hypoglycemia? Deficiency of what other vitamin could also result in hypoglycemia?


Biochemistry_Lippinco

Biochemistry_Lippinco. 8.8. Why might a deficiency of vitamin B6 result in a fasting hypoglycemia? Deficiency of what other vitamin could also result in hypoglycemia? Vitamin B6 is required for glycogen degradation by glycogen phosphorylase. A deficiency would result in fasting hypoglycemia. Additionally, a deficiency of biotin (required by pyruvate carboxylase of gluconeogenesis) would also result in fasting hypoglycemia. Micronutrients: Minerals 29 For additional ancillary materials related to this chapter, please visit thePoint. I. OVERVIEW


Biochemistry_Lippinco

Biochemistry_Lippinco. Micronutrients: Minerals 29 For additional ancillary materials related to this chapter, please visit thePoint. I. OVERVIEW Minerals are inorganic substances (elements) required in small amounts by the body. They function in a number of processes including formation of bones and teeth, fluid balance, nerve conduction, muscle contraction, signaling, and catalysis. [Note: Several minerals are essential enzyme cofactors.] Like the organic vitamins (see Chapter 28), minerals are micronutrients required in mg or µg amounts. Those required by adults in the largest amounts (>100 mg/day) are referred to as the macrominerals. Minerals required in amounts between 1 and 100 mg/day are the microminerals (trace minerals). Ultratrace minerals are required in amounts <1 mg/day (Fig. 29.1). [Note: The classification of specific minerals into these categories can vary among sources.] Mineral concentrations in the body are influenced by their rates of absorption and excretion. II. MACROMINERALS


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Biochemistry_Lippinco. II. MACROMINERALS The macrominerals include calcium (Ca2+), phosphorus ([P] as inorganic phosphate [Pi, or PO43−]), magnesium (Mg2+), sodium (Na+), chloride (Cl−), and potassium (K+). [Note: The free ionic forms are electrolytes.] A. Calcium and phosphorus These macrominerals are considered together because they are components of hydroxylapatite (Ca5[PO4]3OH), which makes up bones and teeth.


Biochemistry_Lippinco

Biochemistry_Lippinco. 1. Calcium: Ca2+ is the most abundant mineral in the body, with ~98% being found in bones. The remainder is involved in a number of processes such as signaling, muscle contraction, and blood clotting. Ca2+ binds to a variety of proteins including calmodulin (see p. 133), phospholipase A2 (see p. 213), and protein kinase C (see p. 205) and alters their activity. [Note: Calbindin is a vitamin D–induced intracellular Ca2+-binding protein involved in Ca2+ absorption in the intestine (see p. 392).] Dairy products, many green vegetables (for example, broccoli, but not spinach), and fortified orange juice are good dietary sources. Although dietary deficiency syndromes are unknown, average Ca2+ intake in the United States is insufficient for optimal bone health. Toxicity is seen only with supplements (tolerable upper limit [UL] = 2,500 mg/day for adults). Hypercalcemia (elevated serum Ca2+) can result from overproduction of parathyroid hormone (PTH). This may cause constipation and kidney


Biochemistry_Lippinco

Biochemistry_Lippinco. (tolerable upper limit [UL] = 2,500 mg/day for adults). Hypercalcemia (elevated serum Ca2+) can result from overproduction of parathyroid hormone (PTH). This may cause constipation and kidney stones. Hypocalcemia (low serum Ca2+) can result from a deficiency of PTH or vitamin D. It can lead to bone demineralization (resorption). [Note: The hormonal regulation of serum Ca2+ levels was presented in the vitamin D section of Chapter 28 and is reviewed in 3. below.]


Biochemistry_Lippinco

Biochemistry_Lippinco. Bone mass increases from infancy through the early reproductive years and then shows an age-related loss in both men and women that increases the risk for fracture. This loss is greatest in postmenopausal Caucasian women. Some studies have shown that supplementation with Ca2+ and vitamin D decreases this risk.


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Biochemistry_Lippinco. 2. Phosphorus: Free phosphate (Pi) is the most abundant intracellular anion. However, 85% of the body’s phosphorus is in the form of inorganic hydroxylapatite, with most of the remainder in intracellular organic compounds such as phospholipids, nucleic acids, ATP, and creatine phosphate. Phosphate is supplied as ATP for kinases and as Pi for phosphorylases (for example, glycogen phosphorylase, see p. 128). [Note: Its addition (by kinases) or removal (by phosphatases) is an important means of covalent regulation of enzymes (see Chapter 24).] Phosphorus is widely distributed in food (milk is a good source), and dietary deficiency is rare. Hypophosphatemia can be caused by refeeding carbohydrates to malnourished patients (refeeding syndrome, see p. 369), overuse of aluminum-containing antacids (aluminum chelates Pi), and increased urinary loss in response to increased production of PTH (see below). Muscle weakness is a common symptom. Hyperphosphatemia is caused primarily by decreased


Biochemistry_Lippinco

Biochemistry_Lippinco. (aluminum chelates Pi), and increased urinary loss in response to increased production of PTH (see below). Muscle weakness is a common symptom. Hyperphosphatemia is caused primarily by decreased PTH levels. The excess Pi can combine with Ca2+ and form crystals that deposit in soft tissue (metastatic calcification). [Note: The Ca2+/Pi ratio is important for bone formation (the ratio is ~2/1 in bone), and some experts are concerned that replacement of Ca2+-rich milk by Ca2+-poor, Pi-rich soft drinks can affect bone health.] 3. Hormonal regulation: Serum levels of Ca2+ and Pi are primarily controlled by calcitriol (1,25-dihydroxycholecalciferol, the active form of vitamin D) and PTH, both of which respond to a decrease in serum Ca2+ . Calcitriol, produced by the kidneys, increases serum Ca2+ and Pi by increasing bone resorption and intestinal absorption and renal reabsorption of Ca2+ and Pi (Fig. 29.2). PTH (from the parathyroid glands) increases serum Ca2+ by increasing bone resorption,