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Functional annotation of putative fadE9 of Mycobacterium tuberculosis as isobutyryl-CoA dehydrogenase involved in valine catabolism

Author:
Rani, Nidhi, Hazra, Samannaya, Singh, Amrita, Surolia, Avadhesha
Source:
International journal of biological macromolecules 2019 v.122 pp. 45-57
ISSN:
0141-8130
Subject:
Mycobacterium tuberculosis, acyl-CoA dehydrogenase, amino acid metabolism, animal pathogens, cholesterol, hydrogen bonding, mutants, phylogeny, sequence alignment, valine
Abstract:
Members of the Acyl-CoA dehydrogenase (ACADs) family of enzymes play a crucial role in cholesterol and steroid catabolism and are widely studied in the oldest known human pathogen, Mycobacterium tuberculosis (Mtb). However, there is a paucity of information on ACADs involved in branched chain amino acid catabolism. Here we characterized one of the putative ACAD enzyme, fadE9, as “Isobutyryl CoA Dehydrogenase (IBDH)” using a combined computational and experimental approach, guided by homology modeled structural information, affirming its role in valine catabolism. Multiple sequence alignment and phylogenetic analysis place it in a separate cluster from a recently identified family of α2β2-heterotetramer ACADs in Mtb, based on the position of the conserved Arg247 and catalytic Glu368 residues. The conserved Arg247 was predicted to play an essential role at the center of H-bonding network of reaction center and was confirmed by the reduced activity of R247K mutant. Thus, in addition to the finding of an architecturally distinct α2β2-heterotetramer among ACADs, these studies also highlight the differences between MtIBDH, fadE9 from the other ACADs that are involved in cholesterol and steroid catabolism of Mtb.
Agid:
6264697