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8R-Lipoxygenase-catalyzed synthesis of a prominent cis-epoxyalcohol from dihomo-?-linolenic acid: a distinctive transformation compared with S-lipoxygenases.

ABSTRACT: Conversion of fatty acid hydroperoxides to epoxyalcohols is a well known secondary reaction of lipoxygenases, described for S-specific lipoxygenases forming epoxyalcohols with a trans-epoxide configuration. Here we report on R-specific lipoxygenase synthesis of a cis-epoxyalcohol. Although arachidonic and dihomo-?-linolenic acids are metabolized by extracts of the Caribbean coral Plexaura homomalla via 8R-lipoxygenase and allene oxide synthase activities, 20:3?6 forms an additional prominent product, identified using UV, GC-MS, and NMR in comparison to synthetic standards as 8R,9S-cis-epoxy-10S-erythro-hydroxy-eicosa-11Z,14Z-dienoic acid. Both oxygens of (18)O-labeled 8R-hydroperoxide are retained in the product, indicating a hydroperoxide isomerase activity. Recombinant allene oxide synthase formed only allene epoxide from 8R-hydroperoxy-20:3?6, whereas two different 8R-lipoxygenases selectively produced the epoxyalcohol.A biosynthetic scheme is proposed in which a partial rotation of the reacting intermediate is required to give the observed erythro epoxyalcohol product. This characteristic and the synthesis of cis-epoxy epoxyalcohol may be a feature of R-specific lipoxygenases.

SUBMITTER: Jin J

PROVIDER: S-EPMC3269157 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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8R-Lipoxygenase-catalyzed synthesis of a prominent cis-epoxyalcohol from dihomo-γ-linolenic acid: a distinctive transformation compared with S-lipoxygenases.

Jin Jing J Boeglin William E WE Cha Jin K JK Brash Alan R AR

Journal of lipid research 20111210 2

Conversion of fatty acid hydroperoxides to epoxyalcohols is a well known secondary reaction of lipoxygenases, described for S-specific lipoxygenases forming epoxyalcohols with a trans-epoxide configuration. Here we report on R-specific lipoxygenase synthesis of a cis-epoxyalcohol. Although arachidonic and dihomo-γ-linolenic acids are metabolized by extracts of the Caribbean coral Plexaura homomalla via 8R-lipoxygenase and allene oxide synthase activities, 20:3ω6 forms an additional prominent pro ...[more]

PMID: 22158855

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Project description:BackgroundLipoxygenases (LOX) play pivotal roles in the biosynthesis of leukotrienes and other biologically active potent signalling compounds. Developing inhibitors for LOX is of high interest to researchers. Modelling the interactions between LOX and its substrate arachidonic acid is critical for developing LOX specific inhibitors. Currently, there are no LOX-substrate structures. Recently, the structure of a coral LOX, 8R-LOX, which is 41% sequence identical to the human 5-LOX was solved to 1.85Å resolution. This structure provides a foundation for modelling enzyme-substrate interactions.MethodsIn this research, we applied a computational method, Internal Coordinate Mechanics (ICM), to model the interactions between 8R-LOX and its substrate arachidonic acid. Docking arachidonic acid to 8R-LOX was performed. The most favoured docked ligand conformations were retained. We compared the results of our simulation with a proposed model and concluded that the binding pocket identified in this study agrees with the proposed model partially.ResultsThe results showed that the conformation of arachidonic acid docked into the ICM-identified docking site has less energy than that docked into the manually defined docking site for pseudo wild type 8R-LOX. The mutation at I805 resulted in no docking pocket found near Fe atom. The energy of the arachidonic acid conformation docked into the manually defined docking site is higher in mutant 8R-LOX than in wild type 8R-LOX. The arachidonic acid conformations are not productive conformations.ConclusionsWe concluded that, for the wild type 8R-LOX, the conformation of arachidonic acid docked into the ICM-identified docking site is more stable than that docked into the manually defined docking site. Mutation affects the structure of the putative active site pocket of 8R-LOX, and leads no docking pockets around the catalytic Fe atom. The docking simulation in a mutant 8R-LOX demonstrated that the structural change due to the mutation impacts the enzyme activity. Further research and analysis is required to obtain the 8R-LOX-substrate model.

Project description:Background: The impact of abdominal obesity (AO) on plasma fatty acid changes and cardiometabolic risk in children who are obese and overweight has rarely been investigated. This study determined whether plasma fatty acid composition differed between children with AO and those without AO and its relationship with metabolic risk, particularly in the obese and overweight groups. Methods: A total of 181 schoolchildren (aged 7-18 years) were included. Anthropometric and biochemical data and plasma fatty acid profiles were analyzed, and the indices of desaturase activity were estimated. Children were categorized based on their body weight and AO status. A continuous metabolic risk score was calculated using the sum of the z-scores of metabolic variables. A one-way analysis of variance test was used to compare the composition ratio of fatty acids between children with and without AO in the obese and overweight groups and normal-weight controls. Pearson analysis was also used to explore significant fatty acid and desaturase indicators associated with metabolic abnormalities. Results: Children who were obese and overweight (N = 126) displayed higher dihomo-γ-linolenic acid (20:3n-6) and γ-linolenic acid (18:3n-6) proportions than normal-weight controls (N = 55), but lower heptadecanoic acid (17:0) proportion, regardless of the AO status of each individual. Obese and overweight children with AO (N = 89), but not their non-AO counterparts (N = 37), exhibited a significantly higher proportion of palmitoleic acid (16:1n-7) than the remaining study groups. Pearson analysis showed that high proportions of palmitoleic acid and dihomo-γ-linolenic acid, as well as increased stearoyl-coenzyme A desaturase-1(16) and delta-6 desaturase and decreased delta-5 desaturase activities, are strongly correlated with weight-height ratio, homeostasis model of assessment values for insulin resistance, hypertriglyceridemia, and continuous metabolic risk scores. Conclusion: Higher palmitoleic acid and dihomo-γ-linolenic acid proportions, as well as increased stearoyl-coenzyme A desaturase-1(16) and delta-6 desaturase and decreased delta-5 desaturase activities are associated with AO and increased metabolic risk in children who are obese and overweight.

Dataset Information

8R-Lipoxygenase-catalyzed synthesis of a prominent cis-epoxyalcohol from dihomo-?-linolenic acid: a distinctive transformation compared with S-lipoxygenases.

Publications

8R-Lipoxygenase-catalyzed synthesis of a prominent cis-epoxyalcohol from dihomo-γ-linolenic acid: a distinctive transformation compared with S-lipoxygenases.

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