Molecular Basis of the Functional Divergence of Fatty Acyl-AMP Ligase Biosynthetic Enzymes of Mycobacterium tuberculosis

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• 作者：Aneesh Goyal¹ ; ^&dagger ; ; Priyanka Verma² ; ^&dagger ; ; Madhankumar Anandhakrishnan¹ ; Rajesh S. Gokhale² ; ³ ; ^&Dagger ; ; ^{rsg@igib.res.in} ; Rajan Sankaranarayanan¹ ; ^{sankar@ccmb.res.in}
• 关键词：FAAL ; fatty acyl-AMP ligase ; FACL ; fatty acyl-CoA ligase ; Mtb ; Mycobacterium tuberculosis ; PKS ; polyketide synthase ; AAE ; acyl-activating enzyme ; ACS ; acetyl-CoA synthetase ; PDB ; Protein Data Bank ; MS ; mass spectrometry ; DIP2C ; disco-interacting protein 2
• 刊名：Journal of Molecular Biology
• 出版年：2012
• 出版时间：17 February 2012
• 年：2012
• 卷：416
• 期：2
• 页码：221-238
• 全文大小：2678 K

文摘

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.