Unusual Acetylation–Elimination in the Formation of Tetronate Antibiotics

Kanchanabanca, Chompoonik; Wang, Tao; Hong, Hui; Liu, Yajing; Hahn, Frank; Samborskyy, Markiyan; Deng, Zixin; Sun, Yuhui; Leadlay, Peter F.

doi:10.1002/anie.201301680

Cited by 47 publications

(38 citation statements)

References 19 publications

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“…215 The tetronate formed is then acetylated in a post-PKS tailoring step ( 83 → 84 ), and elimination of acetate produces a methylene tetronate ( 84 → 85 ). 186,216 The resulting methylene can then serve as the dienophile in an intramolecular Diels-Alder reaction with the polyunsaturated polyketide ( 85 → 86 ). Likewise, an ACP-bound cysteine ( 81 , X = NH, Z = S) can substitute for the ACP-glycerate resulting in an amidation reaction prior to Dieckmann cyclization and thus elimination of a thiolated tetramate from the ACP.…”

Section: Spirotetronates and Spirotetramatesmentioning

confidence: 99%

Natural [4 + 2]-Cyclases

et al. 2016

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[4 + 2]-Cycloadditions are increasingly being recognized in the biosynthetic pathways of many structurally complex natural products. A relatively small collection of enzymes from these pathways have been demonstrated to increase rates of cyclization and impose stereochemical constraints on the reactions. While mechanistic investigation of these enzymes is just beginning, recent studies have provided new insights with implications for understanding their biosynthetic roles, mechanisms of catalysis and evolutionary origin.

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Section: Spirotetronates and Spirotetramatesmentioning

confidence: 99%

Natural [4 + 2]-Cyclases

et al. 2016

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“…[15] Modeling results on a related process catalyzed by ketosteroid isomerase [44] and also the discovery of a similar novel enzymatic acetylation-elimination process have been reported. [45] Our objective herein is to explain the structural reason behind the dramatic switch of reactions catalyzed by TLL dependent on the ratio of solvents in a system consisting of the same components. Particular steps taken to achieve this goal were: 1) preparation, by means of MD simulation, of virtual structures of TLL solvated in both, methanol and benzene; 2) performing the docking analysis of the substrate 11 Ac-PGE 2 (1) into the active site of solvated TLL structures to identify which of the reactions is suggested by the geometry of the docking poses.…”

Section: Introductionmentioning

confidence: 99%

Thermomyces lanuginosus Lipase with Closed Lid Catalyzes Elimination of Acetic Acid from 11‐Acetyl‐Prostaglandin E₂

et al. 2014

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A lipase may catalyze either one or more of the three reactions of 11‐acetyl‐prostaglandin E2 in methanol‐containing reaction medium: esterification, deacetylation, and/or elimination. The catalytic performance depends on the lipase and on the methanol content. An increase in the methanol concentration in benzene from 5 % to 95 % leads to the exclusive switch of reactions from esterification to elimination catalyzed by Thermomyces lanuginosus lipase (TLL). To explain the switch, molecular dynamics simulations of solvation of TLL in benzene and in methanol were performed. Solvation in methanol leads to the closing of the lid. The repositioning of the oxyanion hole towards the catalytic triad blocks the catalysis of ester synthesis whereas enabling TLL to act as an acetyl‐β‐ketol eliminase. In benzene the lid is open, allowing esterification to occur. Docking analysis of 11‐acetyl‐prostaglandin E2 into the active site of the solvated TLL structures suggested the occurrence of reactions in accordance with the experiment.

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“…1, position C-5 in both 13-dTDM and TDM). Supporting this pathway, putative enzymes necessary for these reactions are encoded by genes in the ted cluster (tedF1 to tedF5) (10,11,30). Other putative proteins in the core of the cluster include a major facilitator superfamily (MFS)-type pump (tedM) and an ABC transporter (tedA1 to tedA4) and three regulatory genes consisting of an LAL family regulator (tedL), a Streptomyces antibiotic regulatory protein (SARP) family regulator (tedR), and a TetR family regulator (tedT), as well as candidate tailoring genes (tedC, -D, -E, -G, -H, -I, and -J).…”

Section: Resultsmentioning

confidence: 99%

Biosynthetic Genes for the Tetrodecamycin Antibiotics

Gverzdys

Nodwell

2016

J Bacteriol

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We recently described 13-deoxytetrodecamycin, a new member of the tetrodecamycin family of antibiotics. A defining feature of these molecules is the presence of a five-membered lactone called a tetronate ring. By sequencing the genome of a producer strain, Streptomyces sp. strain WAC04657, and searching for a gene previously implicated in tetronate ring formation, we identified the biosynthetic genes responsible for producing 13-deoxytetrodecamycin (the ted genes). Using the ted cluster in WAC04657 as a reference, we found related clusters in three other organisms: Streptomyces atroolivaceus ATCC 19725, Streptomyces globisporus NRRL B-2293, and Streptomyces sp. strain LaPpAH-202. Comparing the four clusters allowed us to identify the cluster boundaries. Genetic manipulation of the cluster confirmed the involvement of the ted genes in 13-deoxytetrodecamycin biosynthesis and revealed several additional molecules produced through the ted biosynthetic pathway, including tetrodecamycin, dihydrotetrodecamycin, and another, W5.9, a novel molecule. Comparison of the bioactivities of these four molecules suggests that they may act through the covalent modification of their target(s). IMPORTANCEThe tetrodecamycins are a distinct subgroup of the tetronate family of secondary metabolites. Little is known about their biosynthesis or mechanisms of action, making them an attractive subject for investigation. In this paper we present the biosynthetic gene cluster for 13-deoxytetrodecamycin in Streptomyces sp. strain WAC04657. We identify related clusters in several other organisms and show that they produce related molecules.

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Unusual Acetylation–Elimination in the Formation of Tetronate Antibiotics

Cited by 47 publications

References 19 publications

Natural [4 + 2]-Cyclases

Natural [4 + 2]-Cyclases

Thermomyces lanuginosus Lipase with Closed Lid Catalyzes Elimination of Acetic Acid from 11‐Acetyl‐Prostaglandin E₂

Biosynthetic Genes for the Tetrodecamycin Antibiotics

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Unusual Acetylation–Elimination in the Formation of Tetronate Antibiotics

Cited by 47 publications

References 19 publications

Natural [4 + 2]-Cyclases

Natural [4 + 2]-Cyclases

Thermomyces lanuginosus Lipase with Closed Lid Catalyzes Elimination of Acetic Acid from 11‐Acetyl‐Prostaglandin E2

Biosynthetic Genes for the Tetrodecamycin Antibiotics

Contact Info

Product

Resources

About

Thermomyces lanuginosus Lipase with Closed Lid Catalyzes Elimination of Acetic Acid from 11‐Acetyl‐Prostaglandin E₂