Molecular evolution within the L-malate and L-lactate dehydrogenase super-family.

The NAD(P)-dependent malate (L-MalDH) and NAD-dependent lactate (L-LDH) form a large super-family that has been characterized in organisms belonging to the three domains of life. In the first part of this study, the group of [LDH-like] L-MalDH, which are malate dehydrogenases resembling lactate dehydrogenase, were analyzed and clearly defined with respect to the other enzymes. In the second part, the phylogenetic relationships of the whole super-family were presented by taking into account the [LDH-like] L-MalDH. The inferred tree unambiguously shows that two ancestral genes duplications, and not one as generally thought, are needed to explain both the distribution into two enzymatic functions and the observation of three main groups within the super-family: L-LDH, [LDH-like] L-MalDH, and dimeric L-MalDH. In addition, various cases of functional changes within each group were observed and analyzed. The direction of evolution was found to always be polarized: from enzymes with a high stringency of substrate recognition to enzymes with a broad substrate specificity. A specific phyletic distribution of the L-LDH, [LDH-like] L-MalDH, and dimeric L-MalDH over the Archaeal, Bacterial, and Eukaryal domains was observed. This was analyzed in the light of biochemical, structural, and genomic data available for the L-LDH, [LDH-like] L-MalDH, and dimeric L-MalDH. This analysis led to the elaboration of a refined evolutionary scenario of the super-family, in which the selection of L-LDH and the fate of L-MalDH during mitochrondrial genesis are presented.