Oxazolomycin biosynthesis in Streptomyces albus JA3453 featuring an "acyltransferase-less" type I polyketide synthase that incorporates two distinct extender units.
The oxazolomycins (OZMs) are a growing family of antibiotics produced by several Streptomyces species that show diverse and important antibacterial, antitumor, and anti-human immunodeficiency virus activity. Oxazolomycin A is a peptide-polyketide hybrid compound containing a unique spiro-linked beta-lactone/gamma-lactam, a 5-substituted oxazole ring. The oxazolomycin biosynthetic gene cluster (ozm) was identified from Streptomyces albus JA3453 and localized to 79.5-kb DNA, consisting of 20 open reading frames that encode non-ribosomal peptide synthases, polyketide synthases (PKSs), hybrid non-ribosomal peptide synthase-PKS, trans-acyltransferases (trans-ATs), enzymes for methoxymalonyl-acyl carrier protein (ACP) synthesis, putative resistance genes, and hypothetical regulation genes. In contrast to classical type I polyketide or fatty acid biosynthases, all 10 PKS modules in the gene cluster lack cognate ATs. Instead, discrete ATs OzmM (with tandem domains OzmM-AT1 and OzmM-AT2) and OzmC were equipped to carry out all of the loading functions of both malonyl-CoA and methoxymalonyl-ACP extender units. Strikingly, only OzmM-AT2 is required for OzmM activity for OZM biosynthesis, whereas OzmM-AT1 seemed to be a cryptic AT domain. The above findings, together with previous results using isotope-labeled precursor feeding assays, are assembled for the OZM biosynthesis model to be proposed. The incorporation of both malonyl-CoA (by OzmM-AT2) and methoxymalonyl-ACP (by OzmC) extender units seemed to be unprecedented for this class of trans-AT type I PKSs, which might be fruitfully manipulated to create structurally diverse novel compounds.
Zhao
Chunhua
C
Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiaotong University, Shanghai 200030, China.
Coughlin
Jane M
JM
Ju
Jianhua
J
Zhu
Dongqing
D
Wendt-Pienkowski
Evelyn
E
Zhou
Xiufen
X
Wang
Zhijun
Z
Shen
Ben
B
Deng
Zixin
Z
D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D053898:Biosynthetic Pathways; D017353:Gene Deletion; D023061:Gene Order; D005816:Genetic Complementation Test; D008954:Models, Biological; D005810:Multigene Family; D016366:Open Reading Frames / Q000235:genetics; D010080:Oxazoles / Q000378:metabolism*; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism; D011760:Pyrrolidinones; D013141:Spiro Compounds / Q000378:metabolism*; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity
D001426:Bacterial Proteins; D010080:Oxazoles; D011760:Pyrrolidinones; D013141:Spiro Compounds; C077919:diffusomycin; D048630:Polyketide Synthases; D000217:Acyltransferases
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