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An Integrated Module Performs Selective 'Online' Epoxidation in the Biosynthesis of the Antibiotic Mupirocin

Winter AJ, de Courcy-Ireland F, Phillips AP, Barker JM, Bakar NA, Akter N, et al.

Angew Chem Int Ed Engl, 2024 Dec 02;63(49):e202410502.
PMID: 39105412 DOI: 10.1002/anie.202410502

The delineation of the complex biosynthesis of the potent antibiotic mupirocin, which consists of a mixture of pseudomonic acids (PAs) isolated from Pseudomonas fluorescens NCIMB 10586, presents significant challenges, and the timing and mechanisms of several key transformations remain elusive. Particularly intriguing are the steps that process the linear backbone from the initial polyketide assembly phase to generate the first cyclic intermediate PA-B. These include epoxidation as well as incorporation of the tetrahydropyran (THP) ring and fatty acid side chain required for biological activity. Herein, we show that the mini-module MmpE performs a rare online (ACP-substrate) epoxidation and is integrated ('in-cis') into the polyketide synthase via a docking domain. A linear polyketide fragment with six asymmetric centres was synthesised using a convergent approach and used to demonstrate substrate flux via an atypical KS0 and a previously unannotated ACP (MmpE_ACP). MmpE_ACP-bound synthetic substrates were critical in demonstrating successful epoxidation in vitro by the purified MmpE oxidoreductase domain. Alongside feeding studies, these results confirm the timing as well as chain length dependence of this selective epoxidation. These mechanistic studies pinpoint the location and nature of the polyketide substrate prior to the key formation of the THP ring and esterification that generate PA-B.

Matched MeSH terms: Epoxy Compounds/metabolism
Fulltext Optimization of lipase-mediated synthesis of 1-nonene oxide using phenylacetic acid and hydrogen peroxide

Abdulmalek E, Arumugam M, Basri M, Rahman MB

Int J Mol Sci, 2012;13(10):13140-9.
PMID: 23202943 DOI: 10.3390/ijms131013140

Herein, an efficient epoxidation of 1-nonene is described. In a simple epoxidation system, commercially available Novozym 435, an immobilized Candida antarctica lipase B, and hydrogen peroxide (H(2)O(2)) were utilized to facilitate the in situ oxidation of phenylacetic acid to the corresponding peroxy acid which then reacted with 1-nonene to give 1-nonene oxide with high yield and selectivity. The aliphatic terminal alkene was epoxidised efficiently in chloroform to give an excellent yield (97%-99%) under the optimum reaction conditions, including temperature (35 °C), initial H(2)O(2) concentration (30%), H(2)O(2) amount (4.4 mmol), H(2)O(2) addition rate (one step), acid amount (8.8 mmol), and stirring speed (250 rpm). Interestingly, the enzyme was stable under the single-step addition of H(2)O(2) with a catalytic activity of 190.0 Ug-1. The entire epoxidation process was carried out within 12 h using a conventional water bath shaker.

Matched MeSH terms: Epoxy Compounds/metabolism*
Radiochemical assay of glutathione S-epoxide transferase and its enhancement by phenobarbital in rat liver in vivo

Marniemi J, Parkki MG

Biochem Pharmacol, 1975 Sep 01;24(17):1569-72.
PMID: 9
Matched MeSH terms: Epoxy Compounds/metabolism
Fulltext Acrylamide and glycidamide hemoglobin adduct levels and endometrial cancer risk: A nested case-control study in nonsmoking postmenopausal women from the EPIC cohort

Obón-Santacana M, Freisling H, Peeters PH, Lujan-Barroso L, Ferrari P, Boutron-Ruault MC, et al.

Int J Cancer, 2016 Mar 01;138(5):1129-38.
PMID: 26376083 DOI: 10.1002/ijc.29853

Acrylamide, classified in 1994 by IARC as "probably carcinogenic to humans," was discovered in 2002 in some heat-treated, carbohydrate-rich foods. Four prospective studies have evaluated the association between dietary acrylamide intake and endometrial cancer (EC) risk with inconsistent results. The purpose of this nested case-control study, based on the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, was to evaluate, for the first time, the association between hemoglobin adducts of acrylamide (HbAA) and glycidamide (HbGA) and the risk of developing EC in non-smoking postmenopausal women. Hemoglobin adducts were measured in red blood cells by HPLC/MS/MS. Four exposure variables were evaluated: HbAA, HbGA, their sum (HbAA+HbGA), and their ratio (HbGA/HbAA). The association between hemoglobin adducts and EC was evaluated using unconditional multivariable logistic regression models, and included 383 EC cases (171 were type-I EC), and 385 controls. Exposure variables were analyzed in quintiles based on control distributions. None of the biomarker variables had an effect on overall EC (HRHbAA;Q5vsQ1 : 0.84, 95%CI: 0.49-1.48; HRHbGA;Q5vsQ1 : 0.94, 95%CI: 0.54-1.63) or type-I EC risk. Additionally, none of the subgroups investigated (BMI

Matched MeSH terms: Epoxy Compounds/metabolism*
Dual modification of starch via partial enzymatic hydrolysis in the granular state and subsequent hydroxypropylation

Karim AA, Sufha EH, Zaidul IS

J Agric Food Chem, 2008 Nov 26;56(22):10901-7.
PMID: 18975963 DOI: 10.1021/jf8015442

The effect of enzymatic pretreatment on the degree of corn and mung bean starch derivatization by propylene oxide was investigated. The starch was enzymatically treated in the granular state with a mixture of fungal alpha-amylase and glucoamylase at 35 degrees C for 16 h and then chemically modified to produce enzyme-hydrolyzed-hydroxypropyl (HP) starch. Partial enzyme hydrolysis of starch in the granular state appeared to enhance the subsequent hydroxypropylation, as judged from the significant increase in the molar substitution. A variable degree of granule modification was obtained after enzyme hydrolysis, and one of the determinants of the modification degree appeared to be the presence of natural pores in the granules. Enzyme-hydrolyzed-HP starch exhibited significantly different functional properties compared to hydroxypropyl starch prepared from untreated (native) starch. It is evident that the dual modification of starch using this approach provides a range of functional properties that can be customized for specific applications.

Matched MeSH terms: Epoxy Compounds/metabolism
Fulltext Acrylamide and Glycidamide Hemoglobin Adducts and Epithelial Ovarian Cancer: A Nested Case-Control Study in Nonsmoking Postmenopausal Women from the EPIC Cohort

Obón-Santacana M, Lujan-Barroso L, Travis RC, Freisling H, Ferrari P, Severi G, et al.

Cancer Epidemiol Biomarkers Prev, 2016 Jan;25(1):127-34.
PMID: 26598536 DOI: 10.1158/1055-9965.EPI-15-0822

BACKGROUND: Acrylamide was classified as "probably carcinogenic to humans (group 2A)" by the International Agency for Research on Cancer. Epithelial ovarian cancer (EOC) is the fourth cause of cancer mortality in women. Five epidemiological studies have evaluated the association between EOC risk and dietary acrylamide intake assessed using food frequency questionnaires, and one nested case-control study evaluated hemoglobin adducts of acrylamide (HbAA) and its metabolite glycidamide (HbGA) and EOC risk; the results of these studies were inconsistent.
METHODS: A nested case-control study in nonsmoking postmenopausal women (334 cases, 417 controls) was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Unconditional logistic regression models were used to estimate ORs and 95% confidence intervals (CI) for the association between HbAA, HbGA, HbAA+HbGA, and HbGA/HbAA and EOC and invasive serous EOC risk.
RESULTS: No overall associations were observed between biomarkers of acrylamide exposure analyzed in quintiles and EOC risk; however, positive associations were observed between some middle quintiles of HbGA and HbAA+HbGA. Elevated but nonstatistically significant ORs for serous EOC were observed for HbGA and HbAA+HbGA (ORQ5vsQ1, 1.91; 95% CI, 0.96-3.81 and ORQ5vsQ1, 1.90; 95% CI, 0.94-3.83, respectively); however, no linear dose-response trends were observed.
CONCLUSION: This EPIC nested case-control study failed to observe a clear association between biomarkers of acrylamide exposure and the risk of EOC or invasive serous EOC.
IMPACT: It is unlikely that dietary acrylamide exposure increases ovarian cancer risk; however, additional studies with larger sample size should be performed to exclude any possible association with EOC risk.

Matched MeSH terms: Epoxy Compounds/metabolism*