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Structural Views along the Mycobacterium tuberculosis MenD Reaction Pathway Illuminate Key Aspects of Thiamin Diphosphate-Dependent Enzyme Mechanisms.

Jirgis EN, Bashiri G, Bulloch EM, Johnston JM, Baker EN
Structure 24 1167-77 (2016)
Related entries: 5erx, 5ery, 5esd, 5ess, 5esu

Cited: 7 times
EuropePMC logo PMID: 27291649

Abstract

Menaquinone (MQ) is an essential component of the respiratory chains of many pathogenic organisms, including Mycobacterium tuberculosis (Mtb). The first committed step in MQ biosynthesis is catalyzed by 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexadiene-1-carboxylate synthase (MenD), a thiamin diphosphate (ThDP)-dependent enzyme. Catalysis proceeds through two covalent intermediates as the substrates 2-oxoglutarate and isochorismate are successively added to the cofactor before final cleavage of the product. We have determined a series of crystal structures of Mtb-MenD that map the binding of both substrates, visualizing each step in the MenD catalytic cycle, including both intermediates. ThDP binding induces a marked asymmetry between the coupled active sites of each dimer, and possible mechanisms of communication can be identified. The crystal structures also reveal conformational features of the two intermediates that facilitate reaction but prevent premature product release. These data fully map chemical space to inform early-stage drug discovery targeting MenD.

Reviews - 5eso mentioned but not cited (1)

  1. Sulfur-bridged chromophores for photofunctional materials: using sulfur oxidation state to tune electronic and structural properties. Yuan J, Xu Z, Wolf MO. Chem Sci 13 5447-5464 (2022)


Articles citing this publication (6)

  1. Allosteric regulation of menaquinone (vitamin K2) biosynthesis in the human pathogen Mycobacterium tuberculosis. Bashiri G, Nigon LV, Jirgis ENM, Ho NAT, Stanborough T, Dawes SS, Baker EN, Bulloch EMM, Johnston JM. J Biol Chem 295 3759-3770 (2020)
  2. Discovering protein-ligand chalcogen bonding in the protein data bank using endocyclic sulfur-containing heterocycles as ligand search subsets. Mitchell MO. J Mol Model 23 287 (2017)
  3. Allosteric inhibition of Staphylococcus aureus MenD by 1,4-dihydroxy naphthoic acid: a feedback inhibition mechanism of the menaquinone biosynthesis pathway. Stanborough T, Ho NAT, Bulloch EMM, Bashiri G, Dawes SS, Akazong EW, Titterington J, Allison TM, Jiao W, Johnston JM. Philos Trans R Soc Lond B Biol Sci 378 20220035 (2023)
  4. Alteration of the Route to Menaquinone towards Isochorismate-Derived Metabolites. Fries A, Mazzaferro LS, Grüning B, Bisel P, Stibal K, Buchholz PCF, Pleiss J, Sprenger GA, Müller M. Chembiochem 20 1672-1677 (2019)
  5. Self-control of vitamin K2 production captured in the crystal. Blaise M, Kremer L. J Biol Chem 295 3771-3772 (2020)
  6. Single-Turnover Kinetics Reveal a Distinct Mode of Thiamine Diphosphate-Dependent Catalysis in Vitamin K Biosynthesis. Qin M, Song H, Dai X, Chan CK, Chan W, Guo Z. Chembiochem 19 1514-1522 (2018)


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