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. 2008 Nov 15;18(22):5963-6.
doi: 10.1016/j.bmcl.2008.07.130. Epub 2008 Aug 12.

Mechanism-based inhibitors of MenE, an acyl-CoA synthetase involved in bacterial menaquinone biosynthesis

Xuequan Lu  1 , Huaning Zhang, Peter J Tonge, Derek S Tan
Affiliations

Mechanism-based inhibitors of MenE, an acyl-CoA synthetase involved in bacterial menaquinone biosynthesis

Xuequan Lu et al. Bioorg Med Chem Lett. .

Abstract

Menaquinone (vitamin K(2)) is an essential component of the electron transfer chain in many pathogens, including Mycobacterium tuberculosis and Staphylococcus aureus, and menaquinone biosynthesis is a potential target for antibiotic drug discovery. We report herein a series of mechanism-based inhibitors of MenE, an acyl-CoA synthetase that catalyzes adenylation and thioesterification of o-succinylbenzoic acid (OSB) during menaquinone biosynthesis. The most potent compound inhibits MenE with an IC(50) value of 5.7microM.

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Figures

Figure 1
Figure 1
Bacterial biosynthesis of menaquinone from chorismate. The acyl-CoA synthetase MenE catalyzes initial adenylation of OSB (o-succinyl-1-benzoate) to form an OSB-AMP intermediate, followed by transthioesterification with CoA to form an OSB-CoA thioester adduct. MenB then catalyzes Dieckmann condensation to form DHNA-CoA, which is ultimately converted to menaquinone.
Figure 2
Figure 2
Structures of designed inhibitors of MenE. The sulfamate (1, 4) and sulfamide (2, 5) functionalities (red) are designed to mimic the phosphate group in the cognate OSB-AMP reaction intermediate. The vinyl sulfonamide moiety (3, 6) is designed to trap the incoming CoA nucleophile covalently. The corresponding exo-methylene analogs (4–6) are designed to probe the importance of the aromatic ketone functionality (green) for binding.
Figure 3
Figure 3
Mechanism of covalent inhibition. (left) The CoA thiol nucleophile attacks the carbonyl group in the acyl-AMP intermediate during the second half-reaction catalyzed by acyl-CoA synthetases. (right) A vinyl sulfonamide Michael acceptor is appropriately positioned to trap the incoming nucleophile and form a covalent adduct.
Figure 4
Figure 4
Synthesis of MeOSB (11) and the corresponding exo-methylene analog 12.
Figure 5
Figure 5
Synthesis of vinyl sulfonyl chloride reagents 20 and 21.
See this image and copyright information in PMC

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