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Mimicking the lipid peroxidation inhibitory activity of phospholipid hydroperoxide glutathione peroxidase (GPx4) by using fatty acid conjugates of a water-soluble selenolane.

ABSTRACT: A series of fatty acid conjugates of trans-3,4-dihydroxy-1-selenolane (DHS) were synthesized by reacting DHS with appropriate acid chlorides. The obtained monoesters were evaluated for their antioxidant capacities by the lipid peroxidation assay using a lecithin/cholesterol liposome as a model system. The observed antioxidant capacities against accumulation of the lipid hydroperoxide (LOOH) increased with increasing the alkyl chain length and became saturated for dodecanoic acid (C12) or higher fatty acid monoesters, for which the capacities were much greater than those of DHS, its tridecanoic acid (C13) diester, and PhSeSePh. On the other hand, the bacteriostatic activity of myristic acid (C14) monoester, evaluated through the colony formation assay using Bacillus subtilis, indicated that it has higher affinity to bacterial cell membranes than parent DHS. Since DHS-fatty acid conjugates would inhibit lipid peroxidation through glutathione peroxidase (GPx)-like 2e- mechanism, higher fatty acid monoesters of DHS can mimic the function of GPx4, which interacts with LOOH to reduce it to harmless alcohol (LOH). Importance of the balance between hydrophilicity and lipophilicity for the design of effective GPx4 mimics was suggested.

SUBMITTER: Iwaoka M

PROVIDER: S-EPMC6331923 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Exposure to environmental contaminants, including various pesticides and trace metals, can disrupt critical olfactory-driven behaviors of fish such as homing to natal streams, mate selection, and an ability to detect predators and prey. These neurobehavioral injuries have been linked to reduced survival and population declines. Despite the importance of maintaining proper olfactory signaling processes in the presence of chemical exposures, little is known regarding chemical detoxification in the salmon olfactory system, and in particular, the antioxidant defenses that maintain olfactory function. An understudied, yet critical component of cellular antioxidant defense is phospholipid hydroperoxide glutathione peroxidase (PHGPx/GPx4), an isoform within the family of selenium-dependent glutathione peroxidase (GPx) enzymes that can directly reduce lipid peroxides and other membrane-bound complex hydroperoxides. In this study, we cloned two gpx4 isoforms (gpx4a and gpx4b) from Coho salmon olfactory tissues and compared their modulation in olfactory and liver tissues by cadmium, an environmental pollutant and olfactory toxicant that cause oxidative damage as a mechanism of toxicity. Amino acid sequence comparisons of the two gpx4 isoforms shared 71% identity, and also relatively high sequence identities when compared with other fish GPx4 isoforms. Sequence comparisons with human GPx4 indicated conservation of three important active sites at selenocysteine (U46), glutamine (Q81), and tryptophan (W136), suggesting similar catalytic activity between fish and mammalian GPx4 isoforms. Tissue profiling confirmed the expression of gpx4a and gpx4b in all ten Coho tissues examined. The expression of gpx4 mRNAs in the Coho olfactory system was accompanied by comparably high initial rates of GPx4 enzymatic activity in mitochondrial and cytosolic fractions. Exposure to low (3.7 ppb) and high (347 ppb) environmental Cd concentrations for 24-48 h significantly decreased gpx4a expression in Coho olfactory rosettes, whereas olfactory gpx4b mRNA expression was not modulated by exposures at these concentrations. In summary, Coho salmon express two paralogs of gpx4, a key enzyme in the maintenance of signal transduction processes that protect against cellular oxidative damage. The Cd-associated downregulation of salmon olfactory gpx4a expression in particular, may be associated with the loss of olfactory signal transduction that accompanies metal-associated loss of olfaction in salmonids.

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Mimicking the lipid peroxidation inhibitory activity of phospholipid hydroperoxide glutathione peroxidase (GPx4) by using fatty acid conjugates of a water-soluble selenolane.

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