3zku

Isopenicillin N synthase with substrate analogue AhCV

spinqualitylabelsall models 3zku, resolution 1.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3zku is a 1 chain structure with sequence from Aspergillus nidulans. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.4Å Ligands: FE, HCV Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function IPNA_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] Publication Abstract from PubMed Isopenicillin N synthase (IPNS) converts the linear tripeptide delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-valine (ACV) into bicyclic isopenicillin N (IPN) in the central step in the biosynthesis of penicillin and cephalosporin antibiotics. Solution-phase incubation experiments have shown that IPNS turns over analogues with a diverse range of side chains in the third (valinyl) position of the substrate, but copes less well with changes in the second (cysteinyl) residue. IPNS thus converts the homologated tripeptides delta-(L-alpha-aminoadipoyl)-L-homocysteinyl-D-valine (AhCV) and delta-(L-alpha-aminoadipoyl)-L-homocysteinyl-D-allylglycine (AhCaG) into monocyclic hydroxy-lactam products; this suggests that the additional methylene unit in these substrates induces conformational changes that preclude second ring closure after initial lactam formation. To investigate this and solution-phase results with other tripeptides delta-(L-alpha-aminoadipoyl)-L-homocysteinyl-D-Xaa, we have crystallised AhCV and delta-(L-alpha-aminoadipoyl)-L-homocysteinyl-D-S-methylcysteine (AhCmC) with IPNS and solved crystal structures for the resulting complexes. The IPNS:Fe :AhCV complex shows diffuse electron density for several regions of the substrate, revealing considerable conformational freedom within the active site. The substrate is more clearly resolved in the IPNS:Fe :AhCmC complex, by virtue of thioether coordination to iron. AhCmC occupies two distinct conformations, both distorted relative to the natural substrate ACV, in order to accommodate the extra methylene group in the second residue. Attempts to turn these substrates over within crystalline IPNS using hyperbaric oxygenation give rise to product mixtures. The Interaction of Isopenicillin N Synthase with Homologated Substrate Analogues delta-(L-alpha-Aminoadipoyl)-L-homocysteinyl-D-Xaa Characterised by Protein Crystallography.,Daruzzaman A, Clifton IJ, Adlington RM, Baldwin JE, Rutledge PJ Chembiochem. 2013 Mar 18;14(5):599-606. doi: 10.1002/cbic.201200728. Epub 2013, Mar 6. PMID:23468426 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Isopenicillin N synthase

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