Alanine dehydrogenase, from Mycobacterium tuberculosis, is an enzyme in the family of highly specific alanine dehydrogenases. Although it shares the same reaction as the amino acid dehydrogenases, alanine dehydrogenases share no sequence or structural similarity with members of the amino acid dehydrogenase family, a sign of convergent evolution. A single mutation in AlaDH, F94S, gave rise to activity with leucine, norleucine, and enhanced activity with norvaline. Saturation mutagenesis libraries of the active site identified double mutants with enhanced activity toward these substrates. Even though this enzyme family has not appeared to have previously evolved activity towards other amino acid substrates, we have demonstrated its capacity to take on these new activities. These results suggest that an enzyme's evolutionary history may not be the best predictor for its ability to evolve towards to new functions.

Alteration of the substrate specificity of alanine dehydrogenase

248th National Meeting (2014)

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