Enzymatic Synthesis of Dilactone Scaffold of Antimycins

Sandy, Moriah; Rui, Zhe; Gallagher, Joe; Zhang, Wenjun

doi:10.1021/cb300416w

Cited by 64 publications

(88 citation statements)

References 28 publications

(46 reference statements)

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“…1) (12). The antFGHIJKLNO genes specify the biosynthesis of the unusual starter unit 3-formamidosalicyl coenzyme A (CoA) (13–15). AntCD make up the hybrid NRPS/PKS assembly line, while AntE and AntM are crotonyl-CoA reductase and discrete ketoreductase homologs, respectively, and AntB is an acyltransferase responsible for the acyloxyl moiety and the chemical diversity observed at R 1 (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Coordinate Regulation of Antimycin and Candicidin Biosynthesis

McLean

Hoskisson

Seipke

2016

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Natural products produced by members of the phylum Actinobacteria underpin many industrially and medically important compounds; however, the majority of the ~30 biosynthetic pathways harbored by an average species are not expressed in the laboratory. Understanding the diversity of regulatory strategies controlling the expression of these pathways is therefore critical if their biosynthetic potential is to be explored for new drug leads. Our findings reveal that the candicidin cluster-situated regulator FscRI coordinately controls the biosynthesis of both candicidin and antimycin, which is the first observation of cross-regulation of disparate biosynthetic gene clusters specifying unrelated natural products. We anticipate that this will emerge as a major strategy by which members of the phylum Actinobacteria coordinately produce natural products, which will advance our understanding of how the expression of secondary metabolism is controlled and will aid the pursuit of “silent” biosynthetic pathway activation.

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Section: Introductionmentioning

confidence: 99%

“…AntCD make up the hybrid NRPS/PKS assembly line, while AntE and AntM are crotonyl-CoA reductase and discrete ketoreductase homologs, respectively, and AntB is an acyltransferase responsible for the acyloxyl moiety and the chemical diversity observed at R 1 (Fig. 1) (14, 16, 17). …”

Section: Introductionmentioning

confidence: 99%

Coordinate Regulation of Antimycin and Candicidin Biosynthesis

McLean

Hoskisson

Seipke

2016

mSphere

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“…6), antimycins ( n -butylmalonyl-CoA, n -hexylmalony-CoA) (ref. 7), splenocins (benzylmalonyl-CoA) (ref. 8), FK-506 (allylmalonyl-CoA) (ref.…”

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confidence: 99%

A crotonyl-CoA reductase-carboxylase independent pathway for assembly of unusual alkylmalonyl-CoA polyketide synthase extender units

et al. 2016

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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 a, b-unsaturated thioesters catalysed by crotonyl-CoA reductase/carboxylase (CCRC) homologues. Here we show using a chemicallysynthesized 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 b-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.

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“…Although malonyl-CoA and methylmalonyl-CoA are the most common extender units for PKSs, atypical extender units have been found to be incorporated into PKs and PK-NRP hybrids by natively promiscuous AT domains. For example, it has been revealed that the AT domain embedded in AntD from the antimycin biosynthetic pathway tolerated a wide range of atypical fatty acyl extender units with different chain lengths and modifications (Sandy et al, 2012; Yan et al, 2012, 2013). Based on the relaxed substrate specificities of AntD-AT and AntE (a reductase/decarboxylase homolog to generate acylmalonyl-CoAs), Liu's group biosynthesized many terminal alkyne-tagged antimycin analogs after feeding alkynoic acids into the culture of Streptomyces sp .…”

Section: Labeling Of Pks/nrps Through Biosynthesismentioning

confidence: 99%

Tagging polyketides/non-ribosomal peptides with a clickable functionality and applications

Zhu

Zhang

2015

Front. Chem.

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Bioorthogonal chemistry has recently emerged to be one of the most powerful tools in drug discovery and chemical biology. The exploration of it has successfully advanced the field of natural product research. In this Perspective, we survey current strategies for the installation of chemical handles into the molecular scaffolds of several major classes of natural products, including polyketides (PKs), non-ribosomal peptides (NRPs), and their hybrids. By tagging these natural products with chemical handles and coupling them with subsequent bioorthogonal reactions, researchers have visualized and studied the mode of action of natural products, as well as synthesized derivatives with better pharmaceutical properties. We conclude this Perspective by considering two questions: is there a general way to synthesize tagged PKs/NRPs? Does natural product labeling have a broader impact in the field of natural product research beyond current known applications?

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Enzymatic Synthesis of Dilactone Scaffold of Antimycins

Cited by 64 publications

References 28 publications

Coordinate Regulation of Antimycin and Candicidin Biosynthesis

Coordinate Regulation of Antimycin and Candicidin Biosynthesis

A crotonyl-CoA reductase-carboxylase independent pathway for assembly of unusual alkylmalonyl-CoA polyketide synthase extender units

Tagging polyketides/non-ribosomal peptides with a clickable functionality and applications

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