Biosynthesis of trioxacarcin revealing a different starter unit and complex tailoring steps for type II polyketide synthase

Abstract

Different starter unit and complex tailoring steps for type II polyketide synthase in trioxacarcin biosynthesis.

Activation and Characterization of Cryptic Gene Cluster: Two Series of Aromatic Polyketides Biosynthesized by Divergent Pathways

“…50 kb, Figure B; see Table S1) which contains: i) genes encoding minimal PKS TjhA1, A2, and A3, the specific cyclases TjhC3‐C4, TjhC1, and TjhA5, and the oxygenases Tjh O2/O3, which are highly homologous to OxyA, B, C, and Oxy J‐K (first‐ring cyclase), OxyN (second‐ring cyclase), SsFL2/MtmL (the fourth‐ring cyclase), and oxygenase (OxyL and OxyE), respectively. These components are involved in the biosynthesis of either oxytetracycline or SF2575 and produce the key naphthecene intermediate (see Figure S2A), beyond which, TjhA1/A2, bearing the highest similarity with the minimal PKS, is involved in the biosynthesis of the anticancer agent mithramycin (see Figure S3); ii) tjhO4 encoding a FAD‐dependent oxidase exhibiting homology with either TcmG, for the triple hydroxylation of tetracenomycin A2 to tetracenomycin C, or the Baeyer–Villiger monooxygenase MtmOIV, the key skeleton‐modifying enzyme in mithramycin biosynthesis (see Figure S2B); iii) enzymes encoded by the tjhB9/B10 gene pair, with high homology to either KstD7/D8 or TxnB3/B4, participating in the biosynthesis of γ‐branched octose (see Figures S1 and S2C) . Additionally, the gene product of tjhO1 shows homology to the quinone‐forming monooxygenase AknX, usually involved in catalyzing the oxidization of the second ring of anthracyclines to form the anthraquinone portion of most anthracyclines .…”

“…We have been interested in expanding the natural diversity of complex aromatic polyketides based on biosynthesis, combinatorial biosynthesis, and genome mining for the past ten years . In this study, we report a modified regulator‐activation strategy by variation in the composition and copy number of different promoters for the activation and characterization of a complicated and cryptic BGC, and it resulted in the identification of the natural products 1 – 8 (for structures see Figure B).…”

Thoughts on Natural Medicinal Chemistry

“…Finally, researching into regulable bio--synthesis can attain the target compounds more artificially [12] .…”

A genomics-guided study of the biosynthesis of microbial secondary metabolites

“…In fact, sometimes a few of the ancillary enzymes are capable of imparting extremely uncommon modifications in the small molecule backbone and the know-how of their functional behavior can be of immense use to the field of enzymology. For example, trioxacarcin A contains an unusual polycyclic ring fused to a spiro-epoxide [76]. The synthesis of this compound is accomplished by a type II PKS containing a novel starter unit and series of modifications involving more than 25 tailoring enzymes, many among which seem to be quite unique [76].…”

“…For example, trioxacarcin A contains an unusual polycyclic ring fused to a spiro-epoxide [76]. The synthesis of this compound is accomplished by a type II PKS containing a novel starter unit and series of modifications involving more than 25 tailoring enzymes, many among which seem to be quite unique [76]. [86].…”