2QX1

Crystal structure of the complex between mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III (FABH) and decyl-COA disulfide

Summary for 2QX1

• Entry DOI: 10.2210/pdb2qx1/pdb
• Related: 1HNJ 1HNK 1HZP 1U6E 1U6S
• Descriptor: Beta-ketoacyl-ACP synthase III, COENZYME A, DECANE-1-THIOL, ... (4 entities in total)
• Functional Keywords: fatty acid biosynthesis, myobacterium tuberculosis, structural basis for substrate specificity, enzyme inhibitor complex, mechanism based inhibitor, acyltransferase, lipid synthesis, multifunctional enzyme, transferase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 70923.01

Authors

Sachdeva, S.,Musayev, F.,Alhamadsheh, M.,Scarsdale, J.N.,Wright, H.T.,Reynolds, K.A. (deposition date: 2007-08-10, release date: 2008-03-18, Last modification date: 2024-10-09)

Primary citation

Sachdeva, S.,Musayev, F.,Alhamadsheh, M.M.,Neel Scarsdale, J.,Tonie Wright, H.,Reynolds, K.A.
Probing reactivity and substrate specificity of both subunits of the dimeric Mycobacterium tuberculosis FabH using alkyl-CoA disulfide inhibitors and acyl-CoA substrates
Bioorg.Chem., 36:85-90, 2008

PubMed Abstract: The dimeric Mycobacterium tuberculosis FabH (mtFabH) catalyses a Claisen-type condensation between an acyl-CoA and malonyl-acyl carrier protein (ACP) to initiate the Type II fatty acid synthase cycle. To analyze the initial covalent acylation of mtFabH with acyl-CoA, we challenged it with mixture of C6-C20 acyl-CoAs and the ESI-MS analysis showed reaction at both subunits and a strict specificity for C12 acyl CoA. Crystallographic and ESI-MS studies of mtFabH with a decyl-CoA disulfide inhibitor revealed a decyl chain bound in acyl-binding channels of both subunits through disulfide linkage to the active site cysteine. These data provide the first unequivocal evidence that both subunits of mtFabH can react with substrates or inhibitor. The discrepancy between the observed C12 acyl-CoA substrate specificity in the initial acylation step and the higher catalytic efficiency of mtFabH for C18-C20 acyl-CoA substrates in the overall mtFabH catalyzed reaction suggests a role for M. tuberculosis ACP as a specificity determinant in this reaction.

PubMed: 18096200
DOI: 10.1016/j.bioorg.2007.11.001

Experimental method

X-RAY DIFFRACTION (2.6 Å)