Abstract
BackgroundThe family of D-isomer specific 2-hydroxyacid dehydrogenases (2HADHs) contains a wide range of oxidoreductases with various metabolic roles as well as biotechnological applications. Despite a vast amount of biochemical and structural data for various representatives of the family, the long and complex evolution and broad sequence diversity hinder functional annotations for uncharacterized members.ResultsWe report an in-depth phylogenetic analysis, followed by mapping of available biochemical and structural data on the reconstructed phylogenetic tree. The analysis suggests that some subfamilies comprising enzymes with similar yet broad substrate specificity profiles diverged early in the evolution of 2HADHs. Based on the phylogenetic tree, we present a revised classification of the family that comprises 22 subfamilies, including 13 new subfamilies not studied biochemically. We summarize characteristics of the nine biochemically studied subfamilies by aggregating all available sequence, biochemical, and structural data, providing comprehensive descriptions of the active site, cofactor-binding residues, and potential roles of specific structural regions in substrate recognition. In addition, we concisely present our analysis as an online 2HADH enzymes knowledgebase.ConclusionsThe knowledgebase enables navigation over the 2HADHs classification, search through collected data, and functional predictions of uncharacterized 2HADHs. Future characterization of the new subfamilies may result in discoveries of enzymes with novel metabolic roles and with properties beneficial for biotechnological applications.
Highlights
The family of D-isomer specific 2-hydroxyacid dehydrogenases (2HADHs) contains a wide range of oxidoreductases with various metabolic roles as well as biotechnological applications
The exact biological function of the majority of these proteins is unknown because functional annotations of 2HADHs in protein databases rely on activities obtained for a small subset of selected substrates or on annotations available for the closest characterized homologs
The 22 identified subfamilies include nine in which at least one member has been studied biochemically. Five of these subfamilies appeared in the previous classification [5]: 3-phosphoglycerate dehydrogenases (SERA), formate dehydrogenases (FDH), C-terminal binding proteins (CTBP), 4-phosphoerythronate dehydrogenase (PDXB), and D-lactate dehydrogenases (LDHD)
Summary
The family of D-isomer specific 2-hydroxyacid dehydrogenases (2HADHs) contains a wide range of oxidoreductases with various metabolic roles as well as biotechnological applications. Despite a vast amount of biochemical and structural data for various representatives of the family, the long and complex evolution and broad sequence diversity hinder functional annotations for uncharacterized members. Most sequenced genomes encode multiple 2HADH paralogs. Better predictions and annotations would be helpful for studies of medically relevant organisms, which often have several 2HADH enzymes with unclear functions. They will help to discover desired enzymes of potential biotechnological applications among a large number of environmental sequences collected from metagenomic samples
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