Molecular basis of the functional divergence of fatty acyl-AMP ligase biosynthetic enzymes of Mycobacterium tuberculosis

J Mol Biol. 2012 Feb 17;416(2):221-38. doi: 10.1016/j.jmb.2011.12.031. Epub 2011 Dec 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl Coenzyme A / metabolism*
  • Amino Acid Sequence
  • Coenzyme A Ligases / chemistry
  • Coenzyme A Ligases / metabolism*
  • Crystallography, X-Ray
  • Models, Molecular
  • Molecular Sequence Data
  • Mycobacterium tuberculosis / enzymology*
  • Mycobacterium tuberculosis / metabolism
  • Protein Folding
  • Substrate Specificity

Substances

  • Acyl Coenzyme A
  • Coenzyme A Ligases

Associated data

  • PDB/3T5A
  • PDB/3T5B
  • PDB/3T5C