Recent advances in the biosynthesis of unusual polyketide synthase substrates

Ray, Lauren; Moore, Bradley S.

doi:10.1039/c5np00112a

Cited by 73 publications

(56 citation statements)

References 70 publications

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“…). One challenge could be to reliably and consistently incorporate diverse substrates into natural product biosynthetic pathway …”

Section: Biological Synthetic and Semisynthetic Approachesmentioning

confidence: 99%

“…One challenge could be to reliably and consistently incorporate diverse substrates into natural product biosynthetic pathway. 238 If the biosynthetic enzymes in wild organisms are sufficiently flexible as far as substrates are concerned, the exogenous addition of designed and synthesized molecules to the cultures of organisms leads to natural product analogue generation. Unexpected incorporation patterns may be observed.…”

Section: Precursor-directed Biosynthetic Approach and Mutasynthesismentioning

confidence: 99%

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Strategies to diversify natural products for drug discovery

Lou

2017

Medicinal Research Reviews

222

139

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Natural product libraries contain specialized metabolites derived from plants, animals, and microorganisms that play a pivotal role in drug discovery due to their immense structural diversity and wide variety of biological activities. The strategies to greatly extend natural product scaffolds through available biological and chemical approaches offer unique opportunities to access a new series of natural product analogues, enabling the construction of diverse natural product-like libraries. The affordability of these structurally diverse molecules has been a crucial step in accelerating drug discovery. This review provides an overview of various approaches to exploit the diversity of compounds for natural product-based drug development, drawing upon a series of examples to illustrate each strategy.

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“…). One challenge could be to reliably and consistently incorporate diverse substrates into natural product biosynthetic pathway …”

Section: Biological Synthetic and Semisynthetic Approachesmentioning

confidence: 99%

Section: Precursor-directed Biosynthetic Approach and Mutasynthesismentioning

confidence: 99%

Strategies to diversify natural products for drug discovery

Lou

2017

Medicinal Research Reviews

222

139

View full text Add to dashboard Cite

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“…Alkylation of a polyketide chain is an important strategy to generate polyketide diversity. Two systems are known for the α alkylation of a polyketide chain: incorporation of alkylmalonyl‐CoA and methylation of the α‐carbon by using S ‐adenosylmethionine (SAM) . The former is the most commonly observed strategy for polyketide alkylation, and various alkyl groups, such as methyl, ethyl, and methoxy, can be introduced into a polyketide chain with alkylmalonyl‐CoA.…”

Section: Introductionmentioning

confidence: 99%

Involvement of β‐Alkylation Machinery and Two Sets of Ketosynthase‐Chain‐Length Factors in the Biosynthesis of Fogacin Polyketides in Actinoplanes missouriensis

et al. 2019

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Fogacin and two novel fogacin derivatives, fogacins B and C, were isolated from the rare actinomycete Actinoplanes missouriensis. Biosynthesis of fogacin C apparently requires β alkylation of a polyketide chain. The fogacin biosynthetic type II polyketide synthase (PKS) gene cluster contains a hydroxymethylglutaryl‐coenzyme A synthase (HCS) cassette, which is usually responsible for β alkylation in the type I PKS system. Another characteristic of the fog cluster is that it encodes two sets of ketosynthase (KS) and chain‐length factor (CLF). Inactivation of either of the two KS genes in A. missouriensis and heterologous expression of the HCS cassette with either of the two KS‐CLF genes in Streptomyces albus indicated that each KS‐CLF had a different starter substrate specificity: one preferred an unusual β‐alkylated starter and the other preferred a normal acetyl starter. This study expands knowledge of HCS cassette‐dependent β alkylation into the type II PKS system and provides a natural example of combinatorial biosynthesis for producing diverse polyketides from different starter substrates.

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“…1 Remarkable molecular machines known as type I modular polyketide synthases (PKSs) are responsible for the biosynthesis of the overwhelming majority of these natural products. 2 Modular PKSs employ several distinct strategies for the creation of structural diversity, including the utilization of a variety of starter and extender units for assembly of the polyketide chain, 3 diverse mechanisms for release of the fully-assembled chain from the PKS, 4 and a wide range of on- and post-PKS tailoring reactions. Among these, the mechanism of chain release is arguably of prime importance in defining which structural class a metabolite belongs to.…”

Section: Introductionmentioning

confidence: 99%