HETE and HPETE biosynthesis and metabolism

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) [2], [5] 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 [8], [13] 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) [19], [22], [23]. 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 [31], [35]. 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].

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