5inf

Structural basis for acyl-CoA carboxylase-mediated assembly of unusual polyketide synthase extender units incorporated into the stambomycin antibiotics

spinqualitylabelsall models 5inf, resolution 2.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5inf is a 6 chain structure with sequence from Streptomyces ambofaciens ATCC 23877. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.751Å Ligands: HXC Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0ACI9_STRA7 Publication Abstract from PubMed Type I modular polyketide synthases assemble diverse bioactive natural products. Such multienzymes typically use malonyl and methylmalonyl-CoA building blocks for polyketide chain assembly. However, in several cases more exotic alkylmalonyl-CoA extender units are also known to be incorporated. In all examples studied to date, such unusual extender units are biosynthesized via reductive carboxylation of alpha, beta-unsaturated thioesters catalysed by crotonyl-CoA reductase/carboxylase (CCRC) homologues. Here we show using a chemically-synthesized deuterium-labelled mechanistic probe, and heterologous gene expression experiments that the unusual alkylmalonyl-CoA extender units incorporated into the stambomycin family of polyketide antibiotics are assembled by direct carboxylation of medium chain acyl-CoA thioesters. X-ray crystal structures of the unusual beta-subunit of the acyl-CoA carboxylase (YCC) responsible for this reaction, alone and in complex with hexanoyl-CoA, reveal the molecular basis for substrate recognition, inspiring the development of methodology for polyketide bio-orthogonal tagging via incorporation of 6-azidohexanoic acid and 8-nonynoic acid into novel stambomycin analogues. A crotonyl-CoA reductase-carboxylase independent pathway for assembly of unusual alkylmalonyl-CoA polyketide synthase extender units.,Ray L, Valentic TR, Miyazawa T, Withall DM, Song L, Milligan JC, Osada H, Takahashi S, Tsai SC, Challis GL Nat Commun. 2016 Dec 21;7:13609. doi: 10.1038/ncomms13609. PMID:28000660 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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