Pathway Map Details

Prostaglandin 2 biosynthesis and metabolism FM

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PGI2,,,, DHRS4,,, HPGD,, COX-2 (PTGS2), None, 12-13,14-Dihydro-PGJ2 delta,, PGH2,, 15-Hydroperoxyprostacyclin,, Arachidonic acid,, ALOX12B, 15-hydroperoxy-PGE1, PRDX5,, 13,14-dihydro-PGF2alpha, THAS,, 15-oxo-Prostaglandin H2, None, 6-Keto-prostaglandin E1, PGHD,, CYP4F12,, 5.3.3.-, ALDX,,, None, 15-oxo-Prostaglandin I2,, spontaneous,,, PRDX4,, None,, PTGIS, Prostaglandin B2,,, PGG2, 20-Hydroxy-prostaglandin H1,,, 15-Keto-PGF2alpha,, 12-hydroxyheptadeca-5,8,10-trienoic acid,, Prostaglandin J2, Prostaglandin F2 alpha, COX-1 (PTGS1),,, Thromboxane A2 , PGE2 , 1.13.11.-,, None,, PRDX1, 15-Hydroperoxy-PGE2, CBR2, PGD2, 13,14-Dihydro-15-keto-PGF2alpha,, Thromboxane B2 , Prostaglandin C2, AKR1C3, 5,6-Dihydro-15-keto-prostaglandin E2, LTB4DH, Prostaglandin A2, 13,14-dihydro-15-keto-PGE2, 15-hydroperoxy-5,8,10-heptadecatrienoic acid,, LOXE3, PGES, PRDX3, None, 6-Keto-prostaglandin F1alpha, Carbonyl reductase [NADPH] 3, PRDX2, CBR1, 15-keto-prostaglandin E2,, PGES2, 15-Hydroperoxy-PGD2, 11-epi-PGF2alpha, 9-Oxo-PGF2alpha, 15-Hydroperoxythromboxane B2,, PGDS


Prostaglandin 2 biosynthesis and metabolism FM

Prostaglandin biosynthesis starts with arachidonic acid that is oxidized to Prostaglandin 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]. An alternative reaction involves oxidation of arachidonic acid resulting in formation of Prostaglandin G2 ( PGG2 ) catalyzed either by COX-1 (PTGS1) [6], [7] and COX-2 (PTGS2) [8], [9], or by Epidermis-type lipoxygenase 3 ( LOXE3 ) [10], [11] and Arachidonate 12-lipoxygenase, 12R type ( ALOX12B ) [10], [11]. COX-1 (PTGS1) and COX-2 (PTGS2) [9], [12], [13] can oxidize PGH2 directly to PGG2, whereas PGG2 can be reduced directly to PGH2 by a number of enzymes, e.g., Peroxiredoxin-1 ( PRDX1 ), Peroxiredoxin-2 ( PRDX2 ), Thioredoxin-dependent peroxide reductase, mitochondrial precursor ( PRDX3 ), Peroxiredoxin-4 ( PRDX4 ) [14], Peroxiredoxin-5, mitochondrial precursor ( PRDX5 ) [15], [16] ). This reduction is coupled with the oxidation of reduced glutathione.

PGH2 can be directly transformed to Prostaglandin E2 ( PGE2 ) by the Prostaglandin E synthase ( PGES ) [17], [18] and Prostaglandin 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 reductase family 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 way is 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 PGD2 in the reaction catalyzed by ALDX and AKR1C3 [32], [22]. Another way involves transformation of PGH2 also catalyzed by AKR1C3 [33]. PGE2 can also be reduced to 15-oxo-PGE2 either by 15-hydroxyprostaglandin dehydrogenase [NAD+] ( HPGD ) [34], [35] or CBR1. The latter subsequently catalyzes the reduction of 15-oxo-PGE2 to 15-ketoprostaglandin F2 alpha ( 15-Keto-PGF2alpha ) that is in turn reduced by CBR1 to PGF2 alpha.

PGE2 loses water moiety and transforms to Prostaglandin A2 ( PGA2 ). The latter is further transformed to Prostaglandin C2 ( PGC2 ). PGC2 can be also transformed to Prostaglandin B2 ( PGB2 ) [36]. PGD2 can be transformed 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 malonic dialdehyde as a byproduct, Thromboxane A(,2 ) [38], [39] and Thromboxane B2. Thromboxane A2 in its turn can spontaneously convert to Thromboxane B2. Prostaglandin E synthase ( PGES) and Prostaglandin E synthase 2 ( PGES2) catalyze the transformation of PGH2 to 15-hydroperoxy-PGE1 [20], [18], [21]. Cytochrome P450, family 4, subfamily F, polypeptide ( CYP4F12 ) reduces PGH2 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 by HPGD [42], [43].

PGE2 metabolite 15-oxo-PGE2 is reduced to 13,14-dihydro-15-keto-PGE2 by Prostaglandin reductase 1 ( LTB4DH ), while another metabolite 15-keto-PGF2alpha is also reduced by the same enzyme to 13,14-dihydro-15-keto-PGF2alpha. The latter product is subsequently transformed by CBR1 to 13,14-dihydro-PGF2alpha. 15-Keto-PGF2 alpha can also be formed 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 to 15-hydroperoxy-5,8,10-heptadecatrienoic acid with Malonic dialdehyde as a byproduct, or to 15-hydroperoxythromboxane B2. PGES and PGES2 transform PGG2 to 15-hydroperoxy-PGE2 [18], [21]. Prostaglandin D2 synthase (brain) ( PGHD ) and Prostaglandin D2 synthase 2 hematopoietic ( PGDS ) can also catalyze formation of 15-hydroperoxy-PGD2 [46], [47], [48]. PTGIS hydroxylates PGG2 to 15-hydroperoxyprostacyclin.

PGI2 also undergoes significant metabolic transformation. It can be hydrolyzed to form 6-keto-prostaglandin F1alpha that is subsequently oxidized to 6-keto-prostaglandin E1 [49]. Another pathway involves PGI2 oxidation to 15-oxo-prostaglandin I2 [50] that is finally transformed by PTGIS to 15-oxo-prostaglandin H2.


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