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BMC Evol Biol. 2018 Dec 22;18(1):199. doi: 10.1186/s12862-018-1309-8.

Classification, substrate specificity and structural features of D-2-hydroxyacid dehydrogenases: 2HADH knowledgebase.

Author information

1
Department of Molecular Physiology and Biological Physics, University of Virginia, 1340 Jefferson Park Avenue, Charlottesville, VA, 22908, USA.
2
Laboratory of Bioinformatics and Systems Biology, Centre of New Technologies, University of Warsaw, Zwirki i Wigury 93, 02-089, Warsaw, Poland.
3
Center for Structural Genomics of Infectious Diseases (CSGID), Charlottesville, VA, 22908, USA.
4
Laboratory for Structural and Biochemical Research, Biological and Chemical Research Centre, Department of Chemistry, University of Warsaw, Zwirki i Wigury 101, 02-089, Warsaw, Poland.
5
Laboratory of Bioinformatics and Systems Biology, Centre of New Technologies, University of Warsaw, Zwirki i Wigury 93, 02-089, Warsaw, Poland. k.ginalski@cent.uw.edu.pl.
6
Department of Molecular Physiology and Biological Physics, University of Virginia, 1340 Jefferson Park Avenue, Charlottesville, VA, 22908, USA. wladek@iwonka.med.virginia.edu.
7
Center for Structural Genomics of Infectious Diseases (CSGID), Charlottesville, VA, 22908, USA. wladek@iwonka.med.virginia.edu.
8
Department of Chemistry, University of Warsaw, Ludwika Pasteura 1, 02-093, Warsaw, Poland. wladek@iwonka.med.virginia.edu.

Abstract

BACKGROUND:

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.

RESULTS:

We 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.

CONCLUSIONS:

The 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.

KEYWORDS:

D-isomer specific 2-hydroxyacid dehydrogenases; Molecular evolution; Sequence-structure-function relationship; Substrate promiscuity; Substrate specificity

PMID:
30577795
PMCID:
PMC6303947
DOI:
10.1186/s12862-018-1309-8
[Indexed for MEDLINE]
Free PMC Article

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