Understanding how the biological connectivity of genes and gene products affects evolution is an important aspect of understanding evolution. Genes encoding enzymes are frequently used to carry out such analyses. Interestingly, studies have shown that connectivity in the metabolic networks in parasitic protists, including Plasmodium falciparum and Trypanosoma brucei, have been substantially altered as compared to free living eukaryotes, such as Saccharomyces cerevisiae. Herein, we have determined K(a) values, which are a measure of the non-synonymous substitution rate, and used them to examine the differences between the evolution of genes in T. brucei, P. falciparum, S. cerevisiae, and Schizosaccharomyces pombe. All four organisms share similar traits with respect to the evolution of genes encoding metabolic enzymes. First, genes encoding metabolic enzymes have lower K(a) values than genes encoding non-metabolic proteins. In addition, perturbations of the metabolic network appear to have limited affects on the genes encoding enzymes near the perturbation. In most cases, there is a negative relationship between connectivity in the metabolic network of the gene product and the K(a) value for the gene, i.e. examining how much constraint there is on gene evolution when it is connected to many other genes. In addition, we find that the K(a) values of orthologs encoding for metabolic enzymes in each organism are significantly correlated, indicating similar patterns of non-synonymous substitutions. In total, our results indicate that the evolution of genes encoding metabolic enzymes do not tend to be greatly affected by changes in the metabolic network.