ArticleBiochemistry2016
Inhibition of Inosine-5'-monophosphate Dehydrogenase from Bacillus anthracis: Mechanism Revealed by Pre-Steady-State Kinetics.
Article in Biochemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 14 citations in OpenAlex.
- Role of the Mobile Active Site Flap in IMP Dehydrogenase Inhibitor Binding.ACS infectious diseases · 2025Article
- Kinetics of Structural Transitions Induced by Sodium Dodecyl Sulfate in α-Chymotrypsin.ACS omega · 2023Article
- LncRNA UCA1 Participates in De Novo Synthesis of Guanine Nucleotides in Bladder Cancer by Recruiting TWIST1 to Increase IMPDH1/2.International journal of biological sciences · 2023Article
- Structural and molecular determinants of Candida glabrata metacaspase maturation and activation by calcium.Communications biology · 2022Article
- Substrate inhibition by the blockage of product release and its control by tunnel engineering.RSC chemical biology · 2021Article
- MoImd4 mediates crosstalk between MoPdeH-cAMP signalling and purine metabolism to govern growth and pathogenicity in Magnaporthe oryzae.Molecular plant pathology · 2019Article
- Oxanosine Monophosphate Is a Covalent Inhibitor of Inosine 5'-Monophosphate Dehydrogenase.Chemical research in toxicology · 2019Article
- Fragment-Based Approach to Targeting Inosine-5'-monophosphate Dehydrogenase (IMPDH) from Mycobacterium tuberculosis.Journal of medicinal chemistry · 2018Article
- The Inosine Monophosphate Dehydrogenase, GuaB2, Is a Vulnerable New Bactericidal Drug Target for Tuberculosis.ACS infectious diseases · 2017Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Inosine-5'-monophosphate dehydrogenase (IMPDH) catalyzes the conversion of inosine 5'-monophosphate (IMP) to xanthosine 5'-monophosphate (XMP). The enzyme is an emerging target for antimicrobial therapy. The small molecule inhibitor A110 has been identified as a potent and selective inhibitor of IMPDHs from a variety of pathogenic microorganisms. A recent X-ray crystallographic study reported that the inhibitor binds to the NAD(+) cofactor site and forms a ternary complex with IMP. Here we report a pre-steady-state stopped-flow kinetic investigation of IMPDH from Bacillus anthracis designed to assess the kinetic significance of the crystallographic results. Stopped-flow kinetic experiments defined nine microscopic rate constants and two equilibrium constants that characterize both the catalytic cycle and details of the inhibition mechanism. In combination with steady-state initial rate studies, the results show that the inhibitor binds with high affinity (Kd ≈ 50 nM) predominantly to the covalent intermediate on the reaction pathway. Only a weak binding interaction (Kd ≈ 1 μM) is observed between the inhibitor and E·IMP. Thus, the E·IMP·A110 ternary complex, observed by X-ray crystallography, is largely kinetically irrelevant.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.