Hepoxilin

Hepoxilin A3
Names
IUPAC name
(5E,9E)-8-hydroxy-10-[3-[(E)-oct-2-enyl] -2-oxiranyl]deca-5,9-dienoic acid
Other names
HXA3
Identifiers
94161-11-2 YesY
Jmol 3D model Interactive image
PubChem 5353666
Properties
C20H32O4
Molar mass 336.47 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
YesY verify (what is YesYN ?)
Infobox references

Hepoxilins (Hx) A3 (i.e. HxA3) and B3 (i.e. HxB3), and their non-enzymatically formed isomers are nonclassic eicosanoid derivatives of the polyunsaturated fatty acid (PUFA), arachidonic acid. A second group of less well studied hepoxilins, HxA4, HXB4, and their non-enzymatically formed isomers are nonclassical eicosanoid deriviatives of the PUFA,eicosapentaenoic acid. More recently,14,15-HXA3 and 14,15-HXB3 have been defined as arachidonic acid derivatives that are produced by a different metabolic pathway than HxA3, HXB3, HXA4, or HXB4. Finally, hepoxilin-like products of two other PUFAs, docosahexaenoic acid and linoleic acid, have been described. Some of the hepoxilins have been found to have a range of biological activities in animal models and/or cultured mammalian (including human) tissues. It has been proposed that these activity studies indicate the these hepoxilins function in human physiology and pathology such as the stimulation of insulin secretion and inflammation responses.

History

HxA3 and HxB3 were first identified, named, shown to have biological activity in stimulating insulin secretion in cultured rat pancreatic islets of Langerhans in Canada in 1984 by CR Pace-Asciak and JM Martin.[1] Shortly thereafter, Pace-Asciak identified, named, and showed to have insulin secretagogue activity HxA4 and HXB4.[2]

Nomenclature

Hepoxilins are distinguished from most other eicosanoids (i.e. signaling molecules made by oxidation of 20-carbon fatty acids) in that they contain both epoxide and hydroxyl residues: they are alkylepoxy 20-carbon fatty acids. HxA3 and HxB3 are structurally differentiated in particular from two other classes of arachidonic acid-derived eicosanoids, the leukotrienes and lipoxins, in that HxA3 and HxB3 have no conjugated double bonds. HxA4 and HxB4 are distinguished from HxA3 and HxB3 in that they possess four rather than three double bonds. The 14,15-HXA3 and 14,15-HXB3 non-classical eicosanoids are distinguished from the aforementioned hepoxilins in that they are formed by a different metabolic pathway and differ in the positioning of their epoxide and hydroxyl residues. Two other classes of alkylepoxy fatty acids, those derived from the 22-carbon polyunsaturated fatty acid, docosahexaenoic acid, and the 18-carbon fatty acid, linoleic acid, are distinguished from the aforementioned hepoxilins by their carbon chain length; they are termed hepoxilin-like rather than hepoxilins.[3][4] A hepoxilin-like derivative of linoleic acid is formed on linoleic acid that is esterified to a sphingosine in a complex lipid termed esterified omega-hydroxylacyl-sphingosin (EOS) that is critical for the possess of developing and maintaining the skin's water barrier function in mammals including humans; genetically-based deficiency in forming this hepoxilin-like linoleic acid derivative is one of the causes for congenital Ichthyosis in humans.[4]

Biochemistry

Human HxA3 and HxB3 are formed in a two-step reaction. First, molecular oxygen (O2) is added to carbon 12 of arachidonic acid (i.e. 5Z,8Z,11Z,14Z-eicosatetraenoic acid) and concurrently the 8Z double bond in this arachidonate moves to the 9E position to form the intermediate product, 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (i.e. 12S-hydroperoxyeicosatetraenoic acid or 12S-HpETE). Second, 12S-HpETE is converted to the two hepoxilin products, HxA3 (i.e. 8R/S-hydroxy-11,12-oxido-5Z,9E,14Z-eicosatrienoic acid) and HxB3 (i.e. 10R/S-hydroxy-11,12-oxido-5Z,8Z,14Z-eicosatrienoic acid).[3] This two-step metabolic reaction is illustrated below:

5Z,8Z,11Z,14Z-eicosatetraenoic acid + O2 → 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid → 8R/S-hydroxy-11,12-oxido-5Z,9E,14Z-eicosatrienoic acid + 10R/S-hydroxy-11,12-oxido-5Z,8Z,14Z-eicosatrienoic acid


Recent studies suggest that certain hepoxilins may form as 1) the non-enzymatic decomposition of the S or R stereoisomers of 12-hydroperoxeicosatetraenoic acid) (12-HpETE) (see 12-Hydroxyeicosatetraenoic acid) and 2) the metabolism by ALOXE3 of the R stereoisomer of 12-HpETE which is made by ALOX12B.[5][6] The ALOX12B/ALOXE3 pathway may be critical to the maintenance of water impermeability in the skin; inactivating mutations of either of the latter two lipoxygenases are associated with the human disease Congenital ichthyosiform erythroderma (see also Ichthyosis#Types#Genetic simple ichthyoses table listing of Lamellar ichthyosis, type 5); this disease appears to result primarily from a failure of ALOX12B or ALOXE3 to metabolize the linoleic acid moiety in a complex sphinganine (see lipoxygenase#Biological function and classification#Human lipoxygenases) that is involved in rendering the squamous epithelium water impermeable rather than to any deficiency in hepoxilins.[5][6][7][8][9]

Corresponding trioxlins A4 and B4 are formed by the same pathway from EPA [10] Two, more recently described hepoxins, 11(S)-hydroxy-14(S),15(S)-epoxy-5(Z),8(Z),12(E)-eicosatrienoic acid and 13(R)-hydroxy-14(S),15(S)-epoxy-5(Z),8(Z),11(Z)-eicosatrienoic acid, termed respectively 14,15-HXA3 and 14,15-HXB3 are made by 15-lipoxygenase-1 with 15(S)-hydroperoxy-eicosatetraenoic acid as an intermediate; 14,15-HXA3 may then be further metabolized by glutathione transferases to 11(S),15(S)-dihydroxy-14(R)-glutathionyl-(5Z),8(Z),12(E)eicosatrienoic acid (14,15-HXA3C) which is then further metabolized to 11(S),15(S)-dihydroxy-14(R)-cysteinyl-glycyl-(5Z),8(Z),12(E)eicosatrienoic acid (14,15-HXA3D).[11] The latter two hepoxilins are analogous to eoxins and leukotrienes and presumed to share the same glutatione transferase and peptidase pathways in their formation (see 15-Hydroxyicosatetraenoic acid).


Physiological effect

In the skin, Hx are pro-inflammatory, but in neutrophils they are anti-inflammatory.[12] Hx are potent insulin secretagogues.[10] One hepoxilin, HepA3, mediates neutrophil migration across the intestines.[13] Hepoxilins are also produced in the brain.[14] Cells under oxidative stress secrete HX3, which in turn upregulates peroxidase, decreasing oxidative stress. This is proposed to constitute a compensatory defense response to protect the vitality and functionality of the cell.[15]

References

  1. ↑ Pace-Asciak CR, Martin JM (1984). "Hepoxilin, a new family of insulin secretagogues formed by intact rat pancreatic islets". Prostaglandins, leukotrienes, and medicine 16 (2): 173–80. doi:10.1016/0262-1746(84)90069-6. PMID 6396652.
  2. ↑ Pace-Asciak CR. Prostaglandins Leukot Med. 1986 Apr;22(1):1-9
  3. 1 2 Biochim Biophys Acta. 2015 Apr;1851(4):383-96. doi: 10.1016/j.bbalip.2014.09.007. Epub 2014 Sep 19. Review.PMID 25240838
  4. 1 2 Biochim Biophys Acta. 2014 Mar;1841(3):401-8. doi: 10.1016/j.bbalip.2013.08.020. Epub 2013 Sep 7. Review.PMID 24021977
  5. 1 2 Biochim Biophys Acta. 2014 Mar;1841(3):401-8. doi:10.1016/j.bbalip.2013.08.020 Epub 2013 Sep 7. Review. PMID 24021977
  6. 1 2 Biochim Biophys Acta. 2014 Mar;1841(3):390-400. doi:10.1016/j.bbalip.2013.08.005 Epub 2013 Aug 16. Review. Erratum in: Biochim Biophys Acta. 2014 Dec;1841(12):1767. PMID 23954555
  7. ↑ J Biol Chem. 2011 Jul 8;286(27):24046-56. doi:10.1074/jbc.M111.251496 Epub 2011 May 10. PMID 21558561
  8. ↑ https://www.wikigenes.org/e/gene/e/242.html
  9. ↑ https://www.wikigenes.org/e/gene/e/59344.html
  10. 1 2 Pace-Asciak CR (1986). "Formation of hepoxilin A4, B4 and the corresponding trioxilins from 12(S)-hydroperoxy-5,8,10,14,17-icosapentaenoic acid". Prostaglandins, leukotrienes, and medicine 22 (1): 1–9. doi:10.1016/0262-1746(86)90017-X. PMID 3012585.
  11. ↑ Lipids 4:69-79, 2011
  12. ↑ Christie, William W. (2006). "LEUKOTRIENES AND LIPOXINS: Chemistry and Biology". Retrieved January 4, 2007.
  13. ↑ Randall J. Mrsny, Andrew T. Gewirtz, Dario Siccardi, Tor Savidge , Bryan P. Hurley , James L. Madara, and Beth A. McCormick (2004). "Identification of hepoxilin A3 in inflammatory events: A required role in neutrophil migration across intestinal epithelia". Proceedings of the National Academy of Sciences of the United States of America 101 (19): 7421–6. doi:10.1073/pnas.0400832101. PMC 409934. PMID 15123795. Retrieved January 4, 2007.
  14. ↑ Piomelli, Daniele (2000). "Arachidonic Acid". Neuropsychopharmacology: The Fifth Generation of Progress (New York: Chapman & Hall). ISBN 0-412-10951-4. Retrieved 2006-03-03.
  15. ↑ M.P. Zafiriou; et al. (October–November 2007). "Prostaglandins, Leukotrienes and Essential Fatty Acids : Biological role of hepoxilins: Upregulation of phospholipid hydroperoxide glutathione peroxidase as a cellular response to oxidative stress?". Prostaglandins, Leukotrienes and Essential Fatty Acids 77 (3–4): 209–215. doi:10.1016/j.plefa.2007.08.007. PMID 17997296. Retrieved 2007-12-04.
This article is issued from Wikipedia - version of the Thursday, May 05, 2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.