The theory of evolution by natural selection asserts that the immense molecular variation retained by organisms is potentially important to their ability to adapt (Lewontin 1974), while the theory of neutral evolution asserts that most of this variation has no selective value (Kimura 1968). Recent statistical analyses comparing synonymous and nonsynonymous substitutions in the coding and noncoding regions of protein genes (Kreitman and Hudson 1991; McDonald and Kreitman 1991) indicate that even in the absence of function, there is a selective bias against some amino acids yet retention of others. Because a selective mechanism has not been identified, however, these results are difficult to interpret. Here we quantify two independent and alternative selective factors, bioenergetic costs and biosynthetic complexity, that may account for the retention of apparently ‘‘neutral’’ amino acids, particularly when they are found in highly expressed proteins. The bioenergetic cost of an amino acid can be equated with the energy invested or generated in its synthesis plus the similarly calculated costs of the amino acid’s starting metabolites. For a given family of proteins, the energetic costs of amino acid assembly include energy for activation of each molecule and incorporation into a protein, energy for mRNA synthesis, energy for proofreading at the synthetase and ribosome level, and energy for assembly and modification reactions (Neidhardt, Ingraham, and Schaechter 1990, pp. 94–95). We have assumed that these costs are similar for all amino acids. Therefore, the primary difference in the energetic costs of a family of proteins must be equal to the synthetic costs of its component amino acids. Through the central metabolic pathways, including the Embden-Meyerhof pathway, which converts glucose 6-phosphate to pyruvate, the tricarboxylic acid cycle (TCA), which oxidizes acetyl CoA2 to CO2, and the pentose phosphate pathway, which oxidizes glucose 6-phosphate to CO2, organisms make all of the energy needed for biological work. In addition to their bioenergetic function, however, the intermediate metabolites of these three pathways provide the molecules from which all amino acids are produced. Energy in the form of adenosine triphosphate (ATP) is lost whenever a metabolite is diverted from the oxidation of glucose to the synthesis of an amino acid. Therefore, ATP is the common currency through which the bioenergetic costs of amino
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