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Yeast beta-alanine synthase shares a structural scaffold and origin with dizinc-dependent exopeptidases
Karolinska Institutet. (Molecular Structural Biology)
2003 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 278, no 51, 51851-51862 p.Article in journal (Refereed) Published
Abstract [en]

beta-Alanine synthase (beta AS) is the final enzyme of the reductive pyrimidine catabolic pathway, which is responsible for the breakdown of pyrimidine bases, including several anticancer drugs. In eukaryotes, beta ASs belong to two subfamilies, which exhibit a low degree of sequence similarity. We determined the structure of beta AS from Saccharomyces kluyveri to a resolution of 2.7 A. The subunit of the homodimeric enzyme consists of two domains: a larger catalytic domain with a dizinc metal center, which represents the active site of beta AS, and a smaller domain mediating the majority of the intersubunit contacts. Both domains exhibit a mixed alpha/beta-topology. Surprisingly, the observed high structural homology to a family of dizinc-dependent exopeptidases suggests that these two enzyme groups have a common origin. Alterations in the ligand composition of the metal-binding site can be explained as adjustments to the catalysis of a different reaction, the hydrolysis of an N-carbamyl bond by beta AS compared with the hydrolysis of a peptide bond by exopeptidases. In contrast, there is no resemblance to the three-dimensional structure of the functionally closely related N-carbamyl-d-amino acid amidohydrolases. Based on comparative structural analysis and observed deviations in the backbone conformations of the eight copies of the subunit in the asymmetric unit, we suggest that conformational changes occur during each catalytic cycle.

Place, publisher, year, edition, pages
2003. Vol. 278, no 51, 51851-51862 p.
National Category
Structural Biology
URN: urn:nbn:se:uu:diva-214440DOI: 10.1074/jbc.M308674200ISI: 000187206300121PubMedID: 14534321OAI: oai:DiVA.org:uu-214440DiVA: diva2:684935
Available from: 2014-01-08 Created: 2014-01-08 Last updated: 2014-01-15Bibliographically approved

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Dobritzsch, Doreen
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