Structure, biochemistry and biology of hepoxilins

摘要: Hepoxilins are biologically relevant epoxy-hydroxy eicosanoids synthesized through the 12S-lipoxygenase (12S-LOX) pathway of arachidonic acid (AA) metabolism. The is bifurcated at level 12S-hydroperoxy-eicosatetraenoic (12S-HpETE), which can either be reduced to 12S-hydro-eicosatetraenoic (12S-HETE) or converted hepoxilins. present review gives an update on biochemistry, biology and clinical aspects hepoxilin-based drug development. isolation, cloning characterization a rat leukocyte-type 12S-LOX from insulinoma RINm5F cells revealed possessing intrinsic 8S/R-hydroxy-11,12-epoxyeicosa-5Z,9E,14Z-trienoic (HXA3) synthase activity. Site-directed mutagenesis studies showed that HXA3 activity was impaired when positional specificity AA altered. Interestingly, amino Leu353, not conventional sequence determinants Met419 Ile418, found crucial determinant for oxygenation. regulation formation dependent cellular overall peroxide tone. Cellular glutathione peroxidases (cGPxs) compete with 12S-HpETE as substrate reduce 12S-HETE convert HXA3, respectively. Therefore, cells, devoid GPxs, capable converting under basal conditions, whereas overexpressing cGPx unable do so. exhibits myriad biological effects, most associated stimulation intracellular calcium transport across membrane. activation HXA3–G-protein-coupled receptors explains many extracellular effects including AA- diacylglycerol (DAG) release in human neutrophils, insulin secretion pancreatic β-cells islets, synaptic actions brain. availability stable analogs termed 10-hydroxy-11,12-cyclopropyl-eicosa-5Z,8Z,14Z-trienoic derivatives (PBTs), recently made several animal possible explored role therapeutic treatment diseases. Thus, PBT-3 induced apoptosis K562 tumour inhibited growth CML solid tumours nude mice. bleomycin-evoked lung fibrosis inflammation mice raised circulation rats. At low glucose concentrations (0–3 mm), also stimulated IRE1α, endoplasmic reticulum-resident kinase. latter regulates protein folding biosynthesis. In conclusion, HXA3-mediated signaling may involved normal physiological functions, drugs serve therapeutics diseases such type II diabetes idiopathic fibrosis.