Molecular basis of the functional divergence of fatty Acyl-AMP ligase biosynthetic Enzymes of mycobacterium tuberculosis

Goyal, Aneesh ; Verma, Priyanka ; Anandhakrishnan, Madhankumar ; Gokhale, Rajesh S. ; Sankaranarayanan, Rajan (2012) Molecular basis of the functional divergence of fatty Acyl-AMP ligase biosynthetic Enzymes of mycobacterium tuberculosis Journal of Molecular Biology, 416 (2). pp. 221-238. ISSN 0022-2836

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Official URL: http://www.sciencedirect.com/science/article/pii/S...

Related URL: http://dx.doi.org/10.1016/j.jmb.2011.12.031

Abstract

Activation of fatty acids as acyl-adenylates by fatty acyl-AMP ligases (FAALs) in Mycobacterium tuberculosis is a variant of a classical theme that involves formation of acyl-CoA (coenzyme A) by fatty acyl-CoA ligases (FACLs). Here, we show that FAALs and FACLs possess similar structural fold and substrate specificity determinants, and the key difference is the absence of a unique insertion sequence in FACL13 structure. A systematic analysis shows a conserved hydrophobic anchorage of the insertion motif across several FAALs. Strikingly, mutagenesis of two phenylalanine residues, which are part of the anchorage, to alanine converts FAAL32 to FACL32. This insertion-based in silico analysis suggests the presence of FAAL homologues in several other non-mycobacterial genomes including eukaryotes. The work presented here establishes an elegant mechanism wherein an insertion sequence drives the functional divergence of FAALs from canonical FACLs.

Item Type:Article
Source:Copyright of this article belongs to Elsevier Science.
Keywords:Crystal Structure; Acyl-Adenylate Enzymes; Pathogenesis; Substrate Specificity; Virulent Lipid Synthesis
ID Code:96460
Deposited On:24 Dec 2012 12:00
Last Modified:24 Dec 2012 12:00

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