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Critical residues for structure and catalysis in short-chain dehydrogenases/reductases
Södertörn University, Avdelning Naturvetenskap. Karolinska Intitute.ORCID iD: 0000-0002-3049-967X
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2002 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 277, no 28, 25677-25684 p.Article in journal (Refereed) Published
Abstract [en]

Short-chain dehydrogenases/reductases form a large, evolutionarily old family of NAD(P)(H)-dependent enzymes with over 60 genes found in the human genome. Despite low levels of sequence identity (often 10-30%), the three-dimensional structures display a highly similar alpha/beta folding pattern. We have analyzed the role of several conserved residues regarding folding, stability, steady-state kinetics, and coenzyme binding using bacterial 3beta/17beta-hydroxysteroid dehydrogenase and selected mutants. Structure determination of the wildtype enzyme at 1.2-Angstrom resolution by x-ray crystallography and docking analysis was used to interpret the biochemical data. Enzyme kinetic data from mutagenetic replacements emphasize the critical role of residues Thr-12, Asp-60, Asn-86, Asn-87, and Ala-88 in coenzyme binding and catalysis. The data also demonstrate essential interactions of Asn-111 with active site residues. A general role of its side chain interactions for maintenance of the active site configuration to build up a proton relay system is proposed. This extends the previously recognized catalytic triad of Ser-Tyr-Lys residues to form a tetrad of Asn-Ser-Tyr-Lys in the majority of characterized short-chain dehydrogenases/reductase enzymes.

Place, publisher, year, edition, pages
2002. Vol. 277, no 28, 25677-25684 p.
National Category
Biochemistry and Molecular Biology
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URN: urn:nbn:se:sh:diva-15793DOI: 10.1074/jbc.M202160200ISI: 000176747000107PubMedID: 11976334ScopusID: 2-s2.0-0037067783OAI: oai:DiVA.org:sh-15793DiVA: diva2:508379
Available from: 2012-03-08 Created: 2012-03-07 Last updated: 2016-01-08Bibliographically approved

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Berndt, Kurt D
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