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A role for antibiotic biosynthesis monooxygenase domain proteins in fidelity control during aromatic polyketide biosynthesis.

ABSTRACT: The formicamycin biosynthetic gene cluster encodes two groups of type 2 polyketide antibiotics: the formicamycins and their biosynthetic precursors the fasamycins, both of which have activity against methicillin-resistant Staphylococcus aureus. Here, we report the formicapyridines which are encoded by the same gene cluster and are structurally and biosynthetically related to the fasamycins and formicamycins but comprise a rare pyridine moiety. These compounds are trace-level metabolites formed by derailment of the major biosynthetic pathway. Inspired by evolutionary logic we show that rational mutation of a single gene in the biosynthetic gene cluster encoding an antibiotic biosynthesis monooxygenase (ABM) superfamily protein leads to a significant increase both in total formicapyridine production and their enrichment relative to the fasamycins/formicamycins. Our observations broaden the polyketide biosynthetic landscape and identify a non-catalytic role for ABM superfamily proteins in type II polyketide synthase assemblages for maintaining biosynthetic pathway fidelity.

SUBMITTER: Qin Z

PROVIDER: S-EPMC6689052 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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A role for antibiotic biosynthesis monooxygenase domain proteins in fidelity control during aromatic polyketide biosynthesis.

Qin Zhiwei Z Devine Rebecca R Hutchings Matthew I MI Wilkinson Barrie B

Nature communications 20190809 1

The formicamycin biosynthetic gene cluster encodes two groups of type 2 polyketide antibiotics: the formicamycins and their biosynthetic precursors the fasamycins, both of which have activity against methicillin-resistant Staphylococcus aureus. Here, we report the formicapyridines which are encoded by the same gene cluster and are structurally and biosynthetically related to the fasamycins and formicamycins but comprise a rare pyridine moiety. These compounds are trace-level metabolites formed b ...[more]

PMID: 31399587

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Project description:Bacterial aromatic polyketides such as tetracycline and doxorubicin are a medicinally important class of natural products produced as secondary metabolites by actinomyces bacteria. Their backbones are derived from malonyl-CoA units by polyketide synthases (PKSs). The nascent polyketide chain is synthesized by the minimal PKS, a module consisting of four dissociated enzymes. Although the biosynthesis of most aromatic polyketide backbones is initiated through decarboxylation of a malonyl building block (which results in an acetate group), some polyketides, such as the estrogen receptor antagonist R1128, are derived from nonacetate primers. Understanding the mechanism of nonacetate priming can lead to biosynthesis of novel polyketides that have improved pharmacological properties. Recent biochemical analysis has shown that nonacetate priming is the result of stepwise activity of two dissociated PKS modules with orthogonal molecular recognition features. In these PKSs, an initiation module that synthesizes a starter unit is present in addition to the minimal PKS module. Here we describe a general method for the engineered biosynthesis of regioselectively modified aromatic polyketides. When coexpressed with the R1128 initiation module, the actinorhodin minimal PKS produced novel hexaketides with propionyl and isobutyryl primer units. Analogous octaketides could be synthesized by combining the tetracenomycin minimal PKS with the R1128 initiation module. Tailoring enzymes such as ketoreductases and cyclases were able to process the unnatural polyketides efficiently. Based upon these findings, hybrid PKSs were engineered to synthesize new anthraquinone antibiotics with predictable functional group modifications. Our results demonstrate that (i) bimodular aromatic PKSs present a general mechanism for priming aromatic polyketide backbones with nonacetate precursors; (ii) the minimal PKS controls polyketide chain length by counting the number of atoms incorporated into the backbone rather than the number of elongation cycles; and (iii) in contrast, auxiliary PKS enzymes such as ketoreductases, aromatases, and cyclases recognize specific functional groups in the backbone rather than overall chain length. Among the anthracyclines engineered in this study were compounds with (i) more superior activity than R1128 against the breast cancer cell line MCF-7 and (ii) inhibitory activity against glucose-6-phosphate translocase, an attractive target for the treatment of Type II diabetes.

Dataset Information

A role for antibiotic biosynthesis monooxygenase domain proteins in fidelity control during aromatic polyketide biosynthesis.

Publications

A role for antibiotic biosynthesis monooxygenase domain proteins in fidelity control during aromatic polyketide biosynthesis.

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