Prostaglandin 2 biosynthesis and metabolism FM
Prostaglandin 2 biosynthesis and metabolism FM
Prostaglandin biosynthesis starts with arachidonic acid that is oxidized toProstaglandin H2 ( PGH2 ) by Prostaglandin G/H synthase 1 precursor ( COX-1(PTGS1) ) or by Prostaglandin G/H synthase 2 precursor ( COX-2 (PTGS2) )[1], [2], [3], [4], [5]. Analternative reaction involves oxidation of arachidonic acid resulting in formationof Prostaglandin G2 ( PGG2 ) catalyzed either by COX-1 (PTGS1) [6], [7] and COX-2 (PTGS2) [8], [9], orby Epidermis-type lipoxygenase 3 ( LOXE3 ) [10], [11] andArachidonate 12-lipoxygenase, 12R type ( ALOX12B ) [10], [11]. COX-1 (PTGS1) and COX-2 (PTGS2) [9], [12], [13] can oxidize PGH2 directly to PGG2, whereasPGG2 can be reduced directly to PGH2 by a number of enzymes, e.g.,Peroxiredoxin-1 ( PRDX1 ), Peroxiredoxin-2 ( PRDX2 ), Thioredoxin-dependentperoxide reductase, mitochondrial precursor ( PRDX3 ), Peroxiredoxin-4 (PRDX4 ) [14], Peroxiredoxin-5, mitochondrial precursor ( PRDX5) [15], [16]). This reduction is coupled with the oxidation ofreduced glutathione.
PGH2 can be directly transformed to Prostaglandin E2 ( PGE2 ) by theProstaglandin E synthase ( PGES ) [17], [18] andProstaglandin E synthase 2 ( PGES2 ) [19], [20], [21], and to Prostaglandin D2 ( PGD2 ) by the Alcohol dehydrogenase [NADP+] (ALDX ) [22]. PGD2 can also be formed by Aldo-keto reductasefamily 1 member C3 ( AKR1C3 ) with 11-epi-PGF2alpha as a precursor [23], [24].
There are various ways to form Prostaglandin F2 alpha ( PGF2 alpha ). One wayis by reduction of the PGE2 catalyzed by Carbonyl reductase [NADPH] 1 (CBR1 ) [25], [26], Carbonyl reductase [NADPH] 2 (CBR2 ) [27], [28], Carbonyl reductase [NADPH] 3[29] and Dehydrogenase/reductase SDR family member 4 ( DHRS4 ) [30], [31]. PGF2 alpha can also be synthesized from PGD2in the reaction catalyzed by ALDX and AKR1C3 [32], [22]. Another way involves transformation of PGH2 also catalyzed byAKR1C3 [33]. PGE2 can also be reduced to 15-oxo-PGE2either by 15-hydroxyprostaglandin dehydrogenase [NAD+] ( HPGD ) [34],[35] or CBR1. The latter subsequently catalyzes the reduction of15-oxo-PGE2 to 15-ketoprostaglandin F2 alpha ( 15-Keto-PGF2alpha ) that isin turn reduced by CBR1 to PGF2 alpha.
PGE2 loses water moiety and transforms to Prostaglandin A2 ( PGA2 ). Thelatter is further transformed to Prostaglandin C2 ( PGC2 ). PGC2 can bealso transformed to Prostaglandin B2 ( PGB2 ) [36]. PGD2 can betransformed to Prostaglandin J2 ( PGJ2 ). Prostaglandin I2 (prostacyclin) synthase( PTGIS ) catalyzes dehydration on PGH2 resulting in the formation of Prostaglandin I2 ( PGI2 ) [37].
PGH2 is metabolized by a set of enzymes. Thromboxane A synthase 1 (platelet) (THAS ) forms 12-hydroxyheptadeca-5,8,10-trienoic acid and malonicdialdehyde as a byproduct, Thromboxane A(,2 ) [38], [39] and Thromboxane B2. Thromboxane A2 in its turn can spontaneouslyconvert to Thromboxane B2. Prostaglandin E synthase ( PGES) andProstaglandin E synthase 2 ( PGES2) catalyze the transformation of PGH2 to15-hydroperoxy-PGE1 [20], [18], [21].Cytochrome P450, family 4, subfamily F, polypeptide ( CYP4F12 ) reducesPGH2 to 20-hydroxy-prostaglandin H1 [40], [41].This enzyme also catalyzes the reduction of PGE2 to 9-oxo-PGF2alpha.PGE2 can be transformed to 5,6-dihydro-15-keto-prostaglandin E2 byHPGD [42], [43].
PGE2 metabolite 15-oxo-PGE2 is reduced to13,14-dihydro-15-keto-PGE2 by Prostaglandin reductase 1 ( LTB4DH ), whileanother metabolite 15-keto-PGF2alpha is also reduced by the same enzyme to13,14-dihydro-15-keto-PGF2alpha. The latter product is subsequently transformed byCBR1 to 13,14-dihydro-PGF2alpha. 15-Keto-PGF2 alpha can also beformed from PGF2 alpha via the reaction catalyzed by CBR1 [44]or HPGD [34], [45].
PGJ2 is metabolically transformed to 12-13,14-dihydro-PGJ2 delta.
THAS catalyzes the transformation of PGG2 to15-hydroperoxy-5,8,10-heptadecatrienoic acid with Malonic dialdehyde as abyproduct, or to 15-hydroperoxythromboxane B2. PGES and PGES2transform PGG2 to 15-hydroperoxy-PGE2 [18], [21].Prostaglandin D2 synthase (brain) ( PGHD ) and Prostaglandin D2 synthase 2hematopoietic ( PGDS ) can also catalyze formation of 15-hydroperoxy-PGD2[46], [47], [48]. PTGIS hydroxylatesPGG2 to 15-hydroperoxyprostacyclin.
PGI2 also undergoes significant metabolic transformation. It can be hydrolyzedto form 6-keto-prostaglandin F1alpha that is subsequently oxidized to6-keto-prostaglandin E1 [49]. Another pathway involves PGI2oxidation to 15-oxo-prostaglandin I2 [50] that is finally transformedby PTGIS to 15-oxo-prostaglandin H2.
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