Enzymatic Carbon–Sulfur Bond Formation in Natural Product Biosynthesis

Dunbar, Kyle L.; Scharf, Daniel H.; Litomska, Agnieszka; Hertweck, Christian

doi:10.1021/acs.chemrev.6b00697

Cited by 471 publications

(294 citation statements)

References 479 publications

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“…However, there are many examples of sulfur‐containing natural products with significant biological activities, such as penicillin, gliotoxin, and yersiniabactin . In the biosyntheses of these sulfur‐containing natural products, C–S bond forming reactions are catalyzed by diverse types of enzymes, including cystathionin β‐synthase in cysteine biosynthesis, S ‐adenosylmethionine (SAM) synthetase, and glutathione‐ S ‐transferases in primary metabolism, and radical SAM enzymes, heterocyclases, nonheme iron‐dependent enzymes, and cytochrome P450 monooxygenases, in secondary metabolism …”

Section: Introductionmentioning

confidence: 99%

Exploiting a C–N Bond Forming Cytochrome P450 Monooxygenase for C–S Bond Formation

et al. 2020

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C–S bond formation reactions are widely distributed in the biosynthesis of biologically active molecules, and thus have received much attention over the past decades. Herein, we report intramolecular C–S bond formation by a P450 monooxygenase, TleB, which normally catalyzes a C−N bond formation in teleocidin biosynthesis. Based on the proposed reaction mechanism of TleB, a thiol‐substituted substrate analogue was synthesized and tested in the enzyme reaction, which afforded the unprecedented sulfur‐containing thio‐indolactam V, in addition to an unusual indole‐fused 6/5/8‐tricyclic product whose structure was determined by the crystalline sponge method. Interestingly, conformational analysis revealed that the SOFA conformation is stable in thio‐indolactam V, in sharp contrast to the major TWIST form in indolactam V, resulting in differences in their biological activities.

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Section: Introductionmentioning

confidence: 99%

Exploiting a C–N Bond Forming Cytochrome P450 Monooxygenase for C–S Bond Formation

et al. 2020

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“…34,35 Finally, there are a growing number of C−S bond forming or cleavage enzymes from natural product biosynthetic pathways, of which the sulfur-incorporating enzymes are very diverse. 36 …”

Section: Resultsmentioning

confidence: 99%

P450-Catalyzed Tailoring Steps in Leinamycin Biosynthesis Featuring Regio- and Stereoselective Hydroxylations and Substrate Promiscuities

Kwong

Pan

et al. 2018

Biochemistry

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Leinamycin (LNM) is a potent antitumor antibiotic produced by Streptomyces atroolivaceus S-140. Both in vivo and in vitro characterization of the LNM biosynthetic machinery have established the formation of the 18-membered macrolactam backbone and the C-3 alkyl branch; the nascent product, LNM E1, of the hybrid nonribosomal peptide synthetase (NRPS)-acyltransferase (AT)-less type I polyketide synthase (PKS); and the generation of the thiol moiety at C-3 of LNM E1. However, the tailoring steps converting LNM E1 to LNM are still unknown. Based on gene inactivation and chemical investigation of three mutant strains, we investigated the tailoring steps catalyzed by two cytochromes P450 (P450s), LnmA and LnmZ, in LNM biosynthesis. Our studies revealed that (i) LnmA and LnmZ regio- and stereoselectively hydroxylate the C-8 and C-4′ positions, respectively, on the scaffold of LNM; (ii) both LnmA and LnmZ exhibit substrate promiscuity, resulting in multiple LNM analogs from several shunt pathways; and (iii) the C-8 and C-4′ hydroxyl groups play important roles in the cytotoxicity of LNM analogs against different cancer cell lines, shedding light on the structure−activity relationships of the LNM scaffold and the LNM-type natural products in general. These studies set the stage for future biosynthetic pathway engineering and combinatorial biosynthesis of the LNM family of natural products for structure diversity and drug discovery.

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“…Compared with lantibiotics, sactibiotics are a smaller family, containing only four analogues: thuricin CD ( 20 ; Figure ), subtilosin A, thurincin H, and propionicin F. The main characteristic of sactibiotics is that the thiol of Cys is linked to the α‐carbon of another residue, thereby resulting in a very particular side chain to backbone cyclic peptide that is mediated through post‐translational modifications . Scheme shows the biosynthetic mechanism for the formation of the thioether bridge in sactibiotics …”

Section: Bacterial Antimicrobial Cyclopeptidesmentioning

confidence: 99%

Bacteria Hunt Bacteria through an Intriguing Cyclic Peptide

et al. 2018

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In the last few decades, peptides have been victorious over small molecules as therapeutics due to their broad range of applications, high biological activity, and high specificity. However, the main challenges to overcome if peptides are to become effective drugs is their low oral bioavailability and instability under physiological conditions. Cyclic peptides play a vital role in this context because they show higher stability under physiological conditions, higher membrane permeability, and greater oral bioavailability than that of their corresponding linear analogues. In this regard, cyclic antimicrobial peptides (AMPs) have gained considerable attention in the field of novel antibiotic development. Bacterial strains produce cyclic AMPs through two pathways: ribosomal and nonribosomal. This review provides an overview of the chemical classification of cyclic AMPs isolated from bacteria, and provides a description of their biological activity and mode of action.

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Enzymatic Carbon–Sulfur Bond Formation in Natural Product Biosynthesis

Cited by 471 publications

References 479 publications

Exploiting a C–N Bond Forming Cytochrome P450 Monooxygenase for C–S Bond Formation

Exploiting a C–N Bond Forming Cytochrome P450 Monooxygenase for C–S Bond Formation

P450-Catalyzed Tailoring Steps in Leinamycin Biosynthesis Featuring Regio- and Stereoselective Hydroxylations and Substrate Promiscuities

Bacteria Hunt Bacteria through an Intriguing Cyclic Peptide

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