Change search
ReferencesLink to record
Permanent link

Direct link
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.
Show others and affiliations
2011 (English)In: Nature Chemical Biology, ISSN 1552-4450, 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
URN: urn:nbn:se:su:diva-70677DOI: 10.1038/NCHEMBIO.693ISI: 000297166200019OAI: diva2:482270
Swedish Research Council

authorCount :12

Available from: 2012-01-23 Created: 2012-01-23 Last updated: 2013-09-24Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Stenmark, PålHimo, Fahmi
By organisation
Department of Biochemistry and BiophysicsDepartment of Organic Chemistry
In the same journal
Nature Chemical Biology
Biochemistry and Molecular BiologyStructural Biology

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 29 hits
ReferencesLink to record
Permanent link

Direct link