title: Stable analogues of OSB-AMP: potent inhibitors of MenE, the o-succinylbenzoate-CoA synthetase from bacterial menaquinone biosynthesis.
abstract: MenE, the o-succinylbenzoate (OSB)-CoA synthetase from bacterial menaquinone biosynthesis, is a promising new antibacterial target. Sulfonyladenosine analogues of the cognate reaction intermediate, OSB-AMP, have been developed as inhibitors of the MenE enzymes from Mycobacterium tuberculosis (mtMenE), Staphylococcus aureus (saMenE) and Escherichia coli (ecMenE). Both a free carboxylate and a ketone moiety on the OSB side chain are required for potent inhibitory activity. OSB-AMS (4) is a competitive inhibitor of mtMenE with respect to ATP (K(i) =5.4±0.1 nM) and a noncompetitive inhibitor with respect to OSB (K(i) =11.2±0.9 nM). These data are consistent with a Bi Uni Uni Bi Ping-Pong kinetic mechanism for these enzymes. In addition, OSB-AMS inhibits saMenE with K(i)(app) =22±8 nM and ecMenE with K(i)(OSB) =128±5 nM. Putative active-site residues, Arg222, which may interact with the OSB aromatic carboxylate, and Ser302, which may bind the OSB ketone oxygen, have been identified through computational docking of OSB-AMP with the unliganded crystal structure of saMenE. A pH-dependent interconversion of the free keto acid and lactol forms of the inhibitors is also described, along with implications for inhibitor design.
authors: Molecular Pharmacology and Chemistry Program and Tri-Institutional Research Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Xuequan
authors: X
authors: Lu
authors: Rong
authors: R
authors: Zhou
authors: Indrajeet
authors: I
authors: Sharma
authors: Xiaokai
authors: X
authors: Li
authors: Gyanendra
authors: G
authors: Kumar
authors: Subramanyam
authors: S
authors: Swaminathan
authors: Peter J
authors: PJ
authors: Tonge
authors: Derek S
authors: DS
authors: Tan
mesh_terms: D000249:Adenosine Monophosphate / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology / Q000378:metabolism; D010654:Phenylbutyrates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000201:enzymology / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013389:Succinate-CoA Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D024482:Vitamin K 2 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D010654:Phenylbutyrates; D024482:Vitamin K 2; C013691:o-succinylbenzoic acid; D000249:Adenosine Monophosphate; D013389:Succinate-CoA Ligases; C022693:O-succinylbenzoate - CoA ligase