Pathway Map Details

HETE and HPETE biosynthesis and metabolism

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14,15-DHET, 11,12-EET, CYP2E1,,,, 14(R),15(S)-diETE, CYP4A11, EPHX2,, 12(S),20-diHETE,, ALOX15B, 5(S),20-diETE,,,,,,, 5(S)-HETE, COX-1 (PTGS1), 8,9-EET, 15(S)-HETE, 8,9-DHET,, COX-2 (PTGS2), 5(S),12(S)-diHPETE,,,,, 14,15-EET, CYP2C9, Arachidonic acid, 12(S)-HPETE, PGH2, 19-HETE, 12(R)-HETE, 15(S)-HPETE,,, 5(S),15(S)-diHPETE, GPX4 (PHGPx),, 14(R),15(S) -diHPETE,,, 8(S),15(S)-diETE,,,, 12(R)-HPETE, CYP4F3,, 5,6-EET, ALOX5, 11,12-DHET, 20-HETE, CYP4F2, 14,15-LTA4, ALOX12, PTGIS, 5(S)-HPETE, ALOX12B,,,, GPX1,, ALOX15, 1.13.11.-,, CYP2C8,, MGST3, 5(S),15(S)-diETE, 12(S)-HETE, MGST2, THAS,,, 15-OxoETE, CYP2J2


HETE and HPETE biosynthesis and metabolism

Besides Prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase) ( COX-1) and Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) ( COX-2) that catalyze the first step of Arachidonic acid metabolic pathway leading to prostaglandin formation, there is another family of lipoxygenase enzymes in mammalian cells that catalyze the conversion of Arachidonic acid to hydroperoxyeicosatetraenoic acids (HPETEs) that can be further enzymatically reduced to the hydroxylated form (HETE).

Arachidonic acid is converted to 12(R)-HPETE by Arachidonate 12-lipoxygenase, 12R type ( ALOX12B ) [1], [2] and to 12(S)-HPETE by Arachidonate 12-lipoxygenase, 12S type ( ALOX12 ) [3], [4]. Both 12(R)-HPETE and 12(S)-HPETE further may be reduced to 12(R)-HETE and 12(S)-HETE, respectively, by Glutathione peroxidase 1 ( GPX1 ) [5], [2] or by Glutathione peroxidase 4 (phospholipid hydroperoxidase) ( GPX4 (PHGPx) ) [5]. 12(S)-HETE can be further oxidized to 12(S),20-DihydroxyETE ( 12(S),20-diHETE ) by specific cytochrome P450 enzyme, isoforms leukotriene-B4 20-monooxygenase: Cytochrome P450, family 4, subfamily F, polypeptide 2 ( CYP4F2) [6] and Cytochrome P450, family 4, subfamily F, polypeptide 3 ( CYP4F3) [7], [8].

Arachidonate 5-lipoxygenase ( ALOX5 ) converts Arachidonic acid to 5(S)-HPETE [9], [10], [11] that is further reduced to 5(S)-HETE by Microsomal glutathione S-transferases 2 and 3 ( MGST2 and MGST3) accordingly [12]. CYP4F2 [6] and CYP4F3 [13], [8] oxidize 5(S)-HETE to 5(S),20-DihydroxyETE ( 5(S),20-diHETE ).

5(S),12(S)-DihydroperoxyETE ( 5(S),12(S)-diHPETE ) is formed from either 12(S)-HPETE or 5(S)-HPETE by action of ALOX5 [14] or Arachidonate 15-lipoxygenase ( ALOX15) [15], respectively.

ALOX15 [16], [17], [18], [19] and Arachidonate 15-lipoxygenase, type B ( ALOX15B ) [20] convert 15(S)-HydroperoxyETE ( 15(S)-HPETE ) to Arachidonic acid. GPX1 can reduce 15(S)-HPETE to hydroxyl form 15(S)-HETE [21]. ALOX5 converts 15(S)-HPETE to 5(S),15(S)-DihydroperoxyETE ( 5(S),15(S)-DiHPETE ) [22], [23], [19]. Moreover, ALOX15 can convert 5(S)-HPETE to the same product 5(S),15(S)-diHPETE [24] that can be further reduced to 5(S),15(S)-DihydroxyETE ( 5(S),15(S)-diHETE ) by GPX1 [25].

ALOX12 converts 15(S)-HPETE to 8(S),15(S)-DihydroperoxyETE ( 8(S),15(S)-diHPETE ) [26], [27], 14(R),15(S)-DihydroperoxyETE ( 14(R),15(S)-diHPETE ) [26], [27], or 14,15-Leukotriene A4 ( 14,15-LTA4 ) [27], [28]. Same double oxygenation products were identified for recombinant ALOX15 [18]. 14,15-LTA4 is hydrolyzed to 14(R),15(S)-DihydroxyETE ( 14(R),15(S)-DiHETE ) by Epoxide hydrolase 2, cytoplasmic ( EPHX2 ) [29].

Thromboxane A synthase 1 (platelet) ( THAS ) and Prostaglandin I2 (prostacyclin) synthase ( PTGIS ) convert 15(S)-HPETE to 15-OxoETE [30].

Arachidonic acid can be oxidized to active metabolites by certain specific cytochrome P450 enzymes (CYPs). 19-HydroxyETE ( 19-HETE ) and 20-HydroxyETE ( 20-HETE ) are formed by Cytochrome P450, family 2, subfamily J, polypeptide 2 ( CYP2J2) [31], Cytochrome P450, family 2, subfamily E, polypeptide 1 ( CYP2E1) [32], Cytochrome P450, family 4, subfamily A, polypeptide 11 ( CYP4A11 ) [33], CYP4F2 [33] or CYP4F3 [34], respectively.

CYP2J2 metabolizes Arachidonic acid to Epoxyeicosatrienoic acids (EETs): 5,6-EET, 8,9-EET, 11,12-EET and 14,15-EET [35], [31]. CYP2C9 and CYP2C8 also was shown to catalyze formation of 11,12-EET and 14,15-EET. EETs are rapidly metabolized via soluble epoxide hydrolase EPHX2 to corresponding dihydroxyeicosatrienoic acids (DHETs): 8,9-DHET, 11,12-DHET and 14,15-DHET [36], [37].


  1. Boeglin WE, Kim RB, Brash AR
    A 12R-lipoxygenase in human skin: mechanistic evidence, molecular cloning, and expression. Proceedings of the National Academy of Sciences of the United States of America 1998 Jun 9;95(12):6744-9
  2. Schneider C, Keeney DS, Boeglin WE, Brash AR
    Detection and cellular localization of 12R-lipoxygenase in human tonsils. Archives of biochemistry and biophysics 2001 Feb 15;386(2):268-74
  3. Hamberg M, Samuelsson B
    Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets. Proceedings of the National Academy of Sciences of the United States of America 1974 Sep;71(9):3400-4
  4. Brger F, Krieg P, Marks F, Frstenberger G
    Positional- and stereo-selectivity of fatty acid oxygenation catalysed by mouse (12S)-lipoxygenase isoenzymes. The Biochemical journal 2000 Jun 1;348 Pt 2:329-35
  5. Sutherland M, Shankaranarayanan P, Schewe T, Nigam S
    Evidence for the presence of phospholipid hydroperoxide glutathione peroxidase in human platelets: implications for its involvement in the regulatory network of the 12-lipoxygenase pathway of arachidonic acid metabolism. The Biochemical journal 2001 Jan 1;353(Pt 1):91-100
  6. Kikuta Y, Kusunose E, Kusunose M
    Characterization of human liver leukotriene B(4) omega-hydroxylase P450 (CYP4F2). Journal of biochemistry 2000 Jun;127(6):1047-52
  7. Marcus AJ, Safier LB, Ullman HL, Broekman MJ, Islam N, Oglesby TD, Gorman RR
    12S,20-dihydroxyicosatetraenoic acid: a new icosanoid synthesized by neutrophils from 12S-hydroxyicosatetraenoic acid produced by thrombin- or collagen-stimulated platelets. Proceedings of the National Academy of Sciences of the United States of America 1984 Feb;81(3):903-7
  8. Kikuta Y, Kusunose E, Sumimoto H, Mizukami Y, Takeshige K, Sakaki T, Yabusaki Y, Kusunose M
    Purification and characterization of recombinant human neutrophil leukotriene B4 omega-hydroxylase (cytochrome P450 4F3). Archives of biochemistry and biophysics 1998 Jul 15;355(2):201-5
  9. Rouzer CA, Matsumoto T, Samuelsson B
    Single protein from human leukocytes possesses 5-lipoxygenase and leukotriene A4 synthase activities. Proceedings of the National Academy of Sciences of the United States of America 1986 Feb;83(4):857-61
  10. Ford-Hutchinson AW, Gresser M, Young RN
    5-Lipoxygenase. Annual review of biochemistry 1994;63:383-417
  11. Silverman ES, Drazen JM
    The biology of 5-lipoxygenase: function, structure, and regulatory mechanisms. Proceedings of the Association of American Physicians 1999 Nov-Dec;111(6):525-36
  12. Jakobsson PJ, Mancini JA, Riendeau D, Ford-Hutchinson AW
    Identification and characterization of a novel microsomal enzyme with glutathione-dependent transferase and peroxidase activities. The Journal of biological chemistry 1997 Sep 5;272(36):22934-9
  13. O'Flaherty JT, Wykle RL, Redman J, Samuel M, Thomas M
    Metabolism of 5-hydroxyicosatetraenoate by human neutrophils: production of a novel omega-oxidized derivative. Journal of immunology (Baltimore, Md. : 1950) 1986 Nov 15;137(10):3277-83
  14. Maclouf J, de Laclos BF, Borgeat P
    Stimulation of leukotriene biosynthesis in human blood leukocytes by platelet-derived 12-hydroperoxy-icosatetraenoic acid. Proceedings of the National Academy of Sciences of the United States of America 1982 Oct;79(19):6042-6
  15. MacMillan DK, Hill E, Sala A, Sigal E, Shuman T, Henson PM, Murphy RC
    Eosinophil 15-lipoxygenase is a leukotriene A4 synthase. The Journal of biological chemistry 1994 Oct 28;269(43):26663-8
  16. Soberman RJ, Harper TW, Betteridge D, Lewis RA, Austen KF
    Characterization and separation of the arachidonic acid 5-lipoxygenase and linoleic acid omega-6 lipoxygenase (arachidonic acid 15-lipoxygenase) of human polymorphonuclear leukocytes. The Journal of biological chemistry 1985 Apr 10;260(7):4508-15
  17. Bryant RW, Bailey JM, Schewe T, Rapoport SM
    Positional specificity of a reticulocyte lipoxygenase. Conversion of arachidonic acid to 15-S-hydroperoxy-eicosatetraenoic acid. The Journal of biological chemistry 1982 Jun 10;257(11):6050-5
  18. K??hn H, Barnett J, Grunberger D, Baecker P, Chow J, Nguyen B, Bursztyn-Pettegrew H, Chan H, Sigal E
    Overexpression, purification and characterization of human recombinant 15-lipoxygenase. Biochimica et biophysica acta 1993 Jul 21;1169(1):80-9
  19. Serhan CN
    Lipoxins and aspirin-triggered 15-epi-lipoxin biosynthesis: an update and role in anti-inflammation and pro-resolution. Prostaglandins & other lipid mediators 2002 Aug;68-69:433-55
  20. Brash AR, Boeglin WE, Chang MS
    Discovery of a second 15S-lipoxygenase in humans. Proceedings of the National Academy of Sciences of the United States of America 1997 Jun 10;94(12):6148-52
  21. Hill TD, White JG, Rao GH
    Role of glutathione and glutathione peroxidase in human platelet arachidonic acid metabolism. Prostaglandins 1989 Jul;38(1):21-32
  22. Serhan CN, Hamberg M, Samuelsson B, Morris J, Wishka DG
    On the stereochemistry and biosynthesis of lipoxin B. Proceedings of the National Academy of Sciences of the United States of America 1986 Apr;83(7):1983-7
  23. Yamamoto S, Ueda N, Ehara H, Maruyama T, Yokoyama C, Kaneko S, Yoshimoto T, Komatsu N, Watanabe K, Hattori A
    Biochemical studies on mammalian lipoxygenases. Annals of the New York Academy of Sciences 1988;524:12-26
  24. Maas RL, Turk J, Oates JA, Brash AR
    Formation of a novel dihydroxy acid from arachidonic acid by lipoxygenase-catalyzed double oxygenation in rat mononuclear cells and human leukocytes. The Journal of biological chemistry 1982 Jun 25;257(12):7056-67
  25. Chavis C, Vachier I, Chanez P, Bousquet J, Godard P
    5(S),15(S)-dihydroxyeicosatetraenoic acid and lipoxin generation in human polymorphonuclear cells: dual specificity of 5-lipoxygenase towards endogenous and exogenous precursors. The Journal of experimental medicine 1996 Apr 1;183(4):1633-43
  26. Hada T, Ueda N, Takahashi Y, Yamamoto S
    Catalytic properties of human platelet 12-lipoxygenase as compared with the enzymes of other origins. Biochimica et biophysica acta 1991 Apr 24;1083(1):89-93
  27. Brash AR, Yokoyama C, Oates JA, Yamamoto S
    Mechanistic studies of the dioxygenase and leukotriene synthase activities of the porcine leukocyte 12S-lipoxygenase. Archives of biochemistry and biophysics 1989 Sep;273(2):414-22
  28. Maas RL, Brash AR
    Evidence for a lipoxygenase mechanism in the biosynthesis of epoxide and dihydroxy leukotrienes from 15(S)-hydroperoxyicosatetraenoic acid by human platelets and porcine leukocytes. Proceedings of the National Academy of Sciences of the United States of America 1983 May;80(10):2884-8
  29. Wetterholm A, Haeggstr??m J, Hamberg M, Meijer J, R??dmark O
    14,15-Dihydroxy-5,8,10,12-eicosatetraenoic acid. Enzymatic formation from 14,15-leukotriene A4. European journal of biochemistry / FEBS 1988 May 2;173(3):531-6
  30. Yeh HC, Tsai AL, Wang LH
    Reaction mechanisms of 15-hydroperoxyeicosatetraenoic acid catalyzed by human prostacyclin and thromboxane synthases. Archives of biochemistry and biophysics 2007 May 15;461(2):159-68
  31. King LM, Ma J, Srettabunjong S, Graves J, Bradbury JA, Li L, Spiecker M, Liao JK, Mohrenweiser H, Zeldin DC
    Cloning of CYP2J2 gene and identification of functional polymorphisms. Molecular pharmacology 2002 Apr;61(4):840-52
  32. Laethem RM, Balazy M, Falck JR, Laethem CL, Koop DR
    Formation of 19(S)-, 19(R)-, and 18(R)-hydroxyeicosatetraenoic acids by alcohol-inducible cytochrome P450 2E1. The Journal of biological chemistry 1993 Jun 15;268(17):12912-8
  33. Powell PK, Wolf I, Jin R, Lasker JM
    Metabolism of arachidonic acid to 20-hydroxy-5,8,11, 14-eicosatetraenoic acid by P450 enzymes in human liver: involvement of CYP4F2 and CYP4A11. The Journal of pharmacology and experimental therapeutics 1998 Jun;285(3):1327-36
  34. Christmas P, Jones JP, Patten CJ, Rock DA, Zheng Y, Cheng SM, Weber BM, Carlesso N, Scadden DT, Rettie AE, Soberman RJ
    Alternative splicing determines the function of CYP4F3 by switching substrate specificity. The Journal of biological chemistry 2001 Oct 12;276(41):38166-72
  35. Wu S, Moomaw CR, Tomer KB, Falck JR, Zeldin DC
    Molecular cloning and expression of CYP2J2, a human cytochrome P450 arachidonic acid epoxygenase highly expressed in heart. The Journal of biological chemistry 1996 Feb 16;271(7):3460-8
  36. Zeldin DC, Wei S, Falck JR, Hammock BD, Snapper JR, Capdevila JH
    Metabolism of epoxyeicosatrienoic acids by cytosolic epoxide hydrolase: substrate structural determinants of asymmetric catalysis. Archives of biochemistry and biophysics 1995 Jan 10;316(1):443-51
  37. Zeldin DC, Kobayashi J, Falck JR, Winder BS, Hammock BD, Snapper JR, Capdevila JH
    Regio- and enantiofacial selectivity of epoxyeicosatrienoic acid hydration by cytosolic epoxide hydrolase. The Journal of biological chemistry 1993 Mar 25;268(9):6402-7