Oxanosine Monophosphate Is a Covalent Inhibitor of Inosine 5'-Monophosphate Dehydrogenase

Journal Article · Tue Feb 12 00:00:00 EST 2019 · Chemical Research in Toxicology

DOI:https://doi.org/10.1021/acs.chemrestox.8b00342· OSTI ID:1510269

Yu, Runhan ^[1]; Kim, Youngchang ^[2]; Maltseva, Natalia ^[3]; Braunstein, Philip ^[1]; Joachimiak, Andrzej ^[2]; Hedstrom, Lizbeth ^[1]

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1. Brandeis Univ., Waltham, MA (United States)
2. Argonne National Lab. (ANL), Argonne, IL (United States). Structural Biology Center; Univ. of Chicago, IL (United States). Center for Structural Genomics of Infectious Diseases, Consortium for Advanced Science and Engineering
3. Univ. of Chicago, IL (United States). Center for Structural Genomics of Infectious Diseases, Consortium for Advanced Science and Engineering

Reactive nitrogen species (RNS) are produced during infection and inflammation, and the effects of these agents on proteins, DNA, and lipids are well recognized. In contrast, the effects of RNS damaged metabolites are less appreciated. 5-Amino-3-beta-(D-ribofuranosyl)-3 H-imidazo-[4,5-d][1,3]oxazine-7-one (oxanosine) and its nucleotides are products of guanosine nitrosation. Here we demonstrate that oxanosine monophosphate (OxMP) is a potent reversible competitive inhibitor of IMPDH. The value of K_i varies from SO to 340 nM among IMPDHs from five different organisms. UV spectroscopy and X-ray crystallography indicate that OxMP forms a ring-opened covalent adduct with the active site Cys (E-OxMP*). Unlike the covalent intermediate of the normal catalytic reaction, E-OxMP* does not hydrolyze, but instead recyclizes to OxMP. IMPDH inhibitors block proliferation and can induce apoptosis, so the inhibition of IMPDH by OxMP presents another potential mechanism for RNS toxicity.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States)
• Sponsoring Organization: National Institutes of Health (NIH)
• Grant/Contract Number: AC02-06CH11357
• OSTI ID: 1510269
• Journal Information: Chemical Research in Toxicology, Journal Name: Chemical Research in Toxicology Journal Issue: 3 Vol. 32; ISSN 0893-228X
• Publisher: American Chemical Society (ACS)
• Country of Publication: United States
• Language: English

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES