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Structural and mechanistic studies of theorf12 gene product from the clavulanic acid biosynthesis pathway
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Valegård, Karin, Iqbal, Aman, Kershaw, Nadia J., Ivison, David, Généreux, Catherine, Dubus, Alain, Blikstad, Cecilia, Demetriades, Marina, Hopkinson, Richard J., Lloyd, Adrian J., Roper, David I., Schofield, Christopher J., Andersson, Inger and McDonough, Michael A. (2013) Structural and mechanistic studies of theorf12 gene product from the clavulanic acid biosynthesis pathway. Acta Crystallographica Section D Biological Crystallography, Volume 69 (Number 8). pp. 1567-1579. doi:10.1107/S0907444913011013 ISSN 0907-4449.
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Official URL: http://dx.doi.org/10.1107/S0907444913011013
Abstract
Structural and biochemical studies of the orf12 gene product (ORF12) from the clavulanic acid (CA) biosynthesis gene cluster are described. Sequence and crystallographic analyses reveal two domains: a C-terminal penicillin-binding protein (PBP)/beta-lactamase-type fold with highest structural similarity to the class A beta-lactamases fused to an N-terminal domain with a fold similar to steroid isomerases and polyketide cyclases. The C-terminal domain of ORF12 did not show beta-lactamase or PBP activity for the substrates tested, but did show low-level esterase activity towards 3'-O-acetyl cephalosporins and a thioester substrate. Mutagenesis studies imply that Ser173, which is present in a conserved SXXK motif, acts as a nucleophile in catalysis, consistent with studies of related esterases, beta-lactamases and d-Ala carboxypeptidases. Structures of wild-type ORF12 and of catalytic residue variants were obtained in complex with and in the absence of clavulanic acid. The role of ORF12 in clavulanic acid biosynthesis is unknown, but it may be involved in the epimerization of (3S,5S)-clavaminic acid to (3R,5R)-clavulanic acid.
| Item Type: | Journal Article | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||
| Journal or Publication Title: | Acta Crystallographica Section D Biological Crystallography | ||||||||
| Publisher: | Wiley-Blackwell Publishing, Inc. | ||||||||
| ISSN: | 0907-4449 | ||||||||
| Official Date: | August 2013 | ||||||||
| Dates: |
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| Volume: | Volume 69 | ||||||||
| Number: | Number 8 | ||||||||
| Page Range: | pp. 1567-1579 | ||||||||
| DOI: | 10.1107/S0907444913011013 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Restricted or Subscription Access |
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