2ivj
From Proteopedia
Current revision
Isopenicillin N Synthase From Aspergillus Nidulans (Anaerobic Ac- cyclopropylglycine Fe Complex)
Structural highlights
FunctionIPNA_EMENI Isopenicillin N synthase; part of the gene cluster that mediates the biosynthesis of penicillin, the world's most important antibiotic (PubMed:3319778, PubMed:11755401). IpnA catalyzes the cyclization of the tripeptide N-[(5S)-5-amino-5-carboxypentanoyl]-L-cysteinyl-D-valine (LLD-ACV or ACV) to form isopenicillin N (IPN) that contains the beta-lactam nucleus (PubMed:3319778, PubMed:11755401, PubMed:28703303). The penicillin biosynthesis occurs via 3 enzymatic steps, the first corresponding to the production of the tripeptide N-[(5S)-5-amino-5-carboxypentanoyl]-L-cysteinyl-D-valine (LLD-ACV or ACV) by the NRPS acvA. The tripeptide ACV is then cyclized to isopenicillin N (IPN) by the isopenicillin N synthase ipnA that forms the beta-lactam nucleus. Finally, the alpha-aminoadipyl side chain is exchanged for phenylacetic acid by the isopenicillin N acyltransferase penDE to yield penicillin in the peroxisomal matrix (By similarity).[UniProtKB:P08703][1] [2] [3] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedIsopenicillin N synthase (IPNS), a non-heme iron oxidase central to penicillin and cephalosporin biosynthesis, catalyzes an energetically demanding chemical transformation to produce isopenicillin N from the tripeptide delta-(l-alpha-aminoadipoyl)-l-cysteinyl-d-valine (ACV). We describe the synthesis of two cyclopropyl-containing tripeptide analogues, delta-(l-alpha-aminoadipoyl)-l-cysteinyl-beta-methyl-d-cyclopropylglycine and delta-(l-alpha-aminoadipoyl)-l-cysteinyl-d-cyclopropylglycine, designed as probes for the mechanism of IPNS. We have solved the X-ray crystal structures of these substrates in complex with IPNS and propose a revised mechanism for the IPNS-mediated turnover of these compounds. Relative to the previously determined IPNS-Fe(II)-ACV structure, key differences exist in substrate orientation and water occupancy, which allow for an explanation of the differences in reactivity of these substrates. Interactions of isopenicillin N synthase with cyclopropyl-containing substrate analogues reveal new mechanistic insight.,Howard-Jones AR, Elkins JM, Clifton IJ, Roach PL, Adlington RM, Baldwin JE, Rutledge PJ Biochemistry. 2007 Apr 24;46(16):4755-62. Epub 2007 Mar 31. PMID:17397141[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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