Opportunistic Enzyme Evolution

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Science  15 Mar 2002:
Vol. 295, Issue 5562, pp. 1975
DOI: 10.1126/science.295.5562.1975b

Expanding one's biochemical repertoire might be supposed to have occurred by either of two complementary strategies. An enzyme could evolve to catalyze a new transformation of the same compound, gaining the next step in a nascent metabolic pathway, or the substrate-binding site might shift subtly, allowing the enzyme to retain aspects of the original chemistry. Wise et al. have compared the structure of 3-keto-L-gulonate 6-phosphate decarboxylase (KGPDC) to that of orotidine-5'-monophosphate decarboxylase (OMPDC). Although both enzymes catalyze decarboxylation, the mechanisms have no obvious features in common. In KGPDC, the reaction depends on magnesium, whereas in OMPDC the reaction is metal-independent (and a topic of continuing investigation regarding its catalytic proficiency).

Both enzymes display the (β/α)8-barrel fold, and sequence and structural homologies indicate that they are derived from a common ancestor. Amino acids strictly conserved in OMPDCs include an aspartate at the end of the first strand (D11), a lysine at the end of the second strand (K33), and an Asp-X-Lys-X-X-Asp (D60-D65) motif at the end of the third strand. All of these residues are conserved in KGPDC, apart from K33, which is replaced by glutamate. The magnesium ion in KGPDC stabilizes an enediol anion intermediate and is coordinated by carboxylates (D11, E33, and D62). In OMPDC, however, D60 acts to destabilize the substrate, and K33 hinders formation of a vinyl anion intermediate that would be too unstable to be kinetically competent. Thus, a conserved constellation of active site residues appears to have been commandeered opportunistically to implement a disparate mechanism on a dissimilar subtrate, suggesting that inferring function strictly on the basis of homology can be hazardous. — VV

Biochemistry 10.1021/bi012174e (2002).

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