5INF
Structural basis for acyl-CoA carboxylase-mediated assembly of unusual polyketide synthase extender units incorporated into the stambomycin antibiotics
Summary for 5INF
| Entry DOI | 10.2210/pdb5inf/pdb |
| Related | 5ING 5INI |
| Descriptor | Carboxyl transferase, HEXANOYL-COENZYME A (3 entities in total) |
| Functional Keywords | polyketide, crotonase, extender-unit, acyl-coa, transferase |
| Biological source | Streptomyces ambofaciens ATCC 23877 |
| Total number of polymer chains | 6 |
| Total formula weight | 349469.52 |
| Authors | Valentic, T.R.,Ray, L.,Miyazawa, T.,Withall, D.M.,Song, L.,Osada, H.,Tsai, S.C.,Challis, G.L. (deposition date: 2016-03-07, release date: 2016-12-28, Last modification date: 2023-09-27) |
| Primary citation | Ray, L.,Valentic, T.R.,Miyazawa, T.,Withall, D.M.,Song, L.,Milligan, J.C.,Osada, H.,Takahashi, S.,Tsai, S.C.,Challis, G.L. A crotonyl-CoA reductase-carboxylase independent pathway for assembly of unusual alkylmalonyl-CoA polyketide synthase extender units. Nat Commun, 7:13609-13609, 2016 Cited by PubMed Abstract: 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 α, β-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 β-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. PubMed: 28000660DOI: 10.1038/ncomms13609 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.751 Å) |
Structure validation
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