Methylation-Dependent Acyl Transfer between Polyketide Synthase and Nonribosomal Peptide Synthetase Modules in Fungal Natural Product Biosynthesis

Zou, Yi; Xu, Wei; Tsunematsu, Yuta; Tang, Man-Cheng; Watanabe, Kenji; Tang, Yi

doi:10.1021/ol503179v

Cited by 34 publications

(34 citation statements)

References 33 publications

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“…531 The FMO domain was shown to be required for the formation of the oxo-spiro structure of 803 . 531 The proposed mechanism of PsoF is the epoxidation of the endocyclic olefin in the pyrrolidone portion of 801 to yield 802 , which sets up an internal opening/capture by the enol to produce 803 . Recent studies by Watanabe and coworkers show that trans to cis isomerization of the diene portion requires a glutathione S-transferase PsoE.…”

Section: Cyclization Via Epoxidationmentioning

confidence: 99%

Oxidative Cyclization in Natural Product Biosynthesis

et al. 2016

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Oxidative cyclizations are important transformations that occur widely during natural product biosynthesis. The transformations from acyclic precursors to cyclized products can afford morphed scaffolds, structural rigidity and biological activities. Some of the most dramatic structural alterations in natural product biosynthesis occur through oxidative cyclization. In this review, we examine the different strategies used by Nature to create new intra-(inter-)-molecular bonds via redox chemistry. The review will cover both oxidation- and reduction-enabled cyclization mechanisms, with an emphasis on the former. Radical cyclizations catalyzed by P450, nonheme iron, α-KG dependent oxygenases and radical SAM enzymes are discussed to illustrate the use of molecular oxygen and S-adenosylmethionine to forge new bonds at unactivated sites via one-electron manifolds. Nonradical cyclizations catalyzed by flavin-dependent monooxygenases and NAD(P)H-dependent reductases are covered to show the use of two-electron manifolds in initiating cyclization reactions. The oxidative installation of epoxides and halogens into acyclic scaffolds to drive subsequent cyclizations are separately discussed as examples of “disappearing” reactive handles. Lastly, oxidative rearrangement of rings systems, including contractions and expansions will be covered.

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Section: Cyclization Via Epoxidationmentioning

confidence: 99%

Oxidative Cyclization in Natural Product Biosynthesis

et al. 2016

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“…3,13 The importance of methylation modification on the fidelity of other iterative HR-PKSs has also been observed, in which bypassing programmed MT function results in production of shunt products. 14 _ENREF_19 Therefore, the HR-PKSs have clearly evolved to optimize the timing and regioselectivities of the MT domains.…”

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confidence: 99%

Understanding Programming of Fungal Iterative Polyketide Synthases: The Biochemical Basis for Regioselectivity by the Methyltransferase Domain in the Lovastatin Megasynthase

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et al. 2015

J. Am. Chem. Soc.

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Highly-reducing polyketide synthases (HR-PKSs) from fungi synthesize complex natural products using a single set of domains in a highly programmed, iterative fashion. The most enigmatic feature of HR-PKSs is how tailoring domains function selectively during different iterations of chain elongation to afford structural diversity. Using the lovastatin nonaketide synthase LovB as a model system and a variety of acyl substrates, we characterized the substrate specificity of the LovB methyltransferase (MT) domain. We showed that while the MT domain displays methylation activity toward different β-ketoacyl groups, it is exceptionally selective towards its naturally programmed β-keto-dienyltetraketide substrate with respect to both chain length and functionalization. Accompanying characterization of the ketoreductase (KR) domain displays broader substrate specificity towards different β-ketoacyl groups. Our studies indicate that selective modifications by tailoring domains, such as the MTs, are achieved by higher kinetic efficiency on a particular substrate relative to the rate of transformation by other competing domains.

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“…It was well known that the a-pyrones were biosynthesized by polyketide synthetase (PKS) pathway primed with acetyl units which can either be derived from malonyl-CoA or methyl malonyl-CoA. The polyketide chain was assembled, modified and released as the a-pyrone spontaneously [7]. We proposed two new a-pyrones (1 and 2) were produced from nectriapyrone (3) by the hydroxylation of the allylic postion in the side chain ( Figure 2).…”

Section: Resultsmentioning

confidence: 99%