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Cofactor mobility determines reaction outcome in the IMPDH and GMPR (beta-alpha)(8) barrel enzymes
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
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2011 (English)In: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 7, no 12, 950-958 p.Article in journal (Refereed) Published
Abstract [en]

Inosine monophosphate dehydrogenase (IMPDH) and guanosine monophosphate reductase (GMPR) belong to the same structural family, share a common set of catalytic residues and bind the same ligands. The structural and mechanistic features that determine reaction outcome in the IMPDH and GMPR family have not been identified. Here we show that the GMPR reaction uses the same intermediate E-XMP(star) as IMPDH, but in this reaction the intermediate reacts with ammonia instead of water. A single crystal structure of human GMPR type 2 with IMP and NADPH fortuitously captures three different states, each of which mimics a distinct step in the catalytic cycle of GMPR. The cofactor is found in two conformations: an 'in' conformation poised for hydride transfer and an 'out' conformation in which the cofactor is 6 angstrom from IMP. Mutagenesis along with substrate and cofactor analog experiments demonstrate that the out conformation is required for the deamination of GMP. Remarkably, the cofactor is part of the catalytic machinery that activates ammonia.

Place, publisher, year, edition, pages
2011. Vol. 7, no 12, 950-958 p.
National Category
Biochemistry and Molecular Biology Structural Biology
Research subject
Biochemistry; Structural Biology
Identifiers
URN: urn:nbn:se:su:diva-70677DOI: 10.1038/NCHEMBIO.693ISI: 000297166200019OAI: oai:DiVA.org:su-70677DiVA: diva2:482270
Funder
Swedish Research Council
Note

authorCount :12

Available from: 2012-01-23 Created: 2012-01-23 Last updated: 2017-12-08Bibliographically approved

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