Molecular Evolution and Functional Divergence of Heterodisulfide Reductase A (HdrA)

Heterodisulfide reductase is a key enzyme in methanogenesis pathway in archaea, which helps to recycle the coenzymes after methane is formed from C1 carbon sources. Homologous enzymes are observed in non-methanogenic archaea and prokaryotes but their functional and evolutionary details are not fully explored. This report aims at understanding the distribution of one such homologous enzyme, heterodisulfide reductase A (HdrA); its domain architecture, overall structural contribution in biological function and evolutionary details in organisms other than methanogen. Exhaustive sequence analysis from both archaea and prokaryotic lineages reveals the presence of highly conserved homologues which probably have an altered oxido-reductase function. Phylogenetic analysis and co-clustering showed the differential diversity of the homologues enzyme in metabolically diverse groups. The distribution of Heterodisulfide homologues in both archaea and prokaryotes shows differential expansion of this protein by multiple horizontal gene transfer events. Conserved domain analysis and structural modelling of different phylogenetic clades shows sequence and structural diversity at the C-terminal domain. Bimolecular network analysis highlights the functional association and interactions of the heterodisulfide homologues with diverse protein partners which participate in different metabolic function. HdrA involved in species specific metabolic function while the functional conservation is evident between close related species. Analysis of structural domain within HdrAs reveals that clade specific sequence which helps to differentiate structural domain arrangement and contributes to functional constrains. The presence of HdrA protein in methanogenic archaea and non-methanogens suggests that the protein function involving redox reaction and electron transfer shared a common history.