Prostaglandin 2 biosynthesis and metabolism

Prostaglandin 2 biosynthesis and metabolism

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 [22], [32]. 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 [18], [20], [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.

References:

1. O'Neill GP, Mancini JA, Kargman S, Yergey J, Kwan MY, Falgueyret JP, Abramovitz M, Kennedy BP, Ouellet M, Cromlish W
   Overexpression of human prostaglandin G/H synthase-1 and -2 by recombinant vaccinia virus: inhibition by nonsteroidal anti-inflammatory drugs and biosynthesis of 15-hydroxyeicosatetraenoic acid. Molecular pharmacology 1994 Feb;45(2):245-54
2. Miller DB, Munster D, Wasvary JS, Simke JP, Peppard JV, Bowen BR, Marshall PJ
   The heterologous expression and characterization of human prostaglandin G/H synthase-2 (COX-2). Biochemical and biophysical research communications 1994 May 30;201(1):356-62
3. Kargman S, Wong E, Greig GM, Falgueyret JP, Cromlish W, Ethier D, Yergey JA, Riendeau D, Evans JF, Kennedy B, Tagari P, Francis DA, O'Neill GP
   Mechanism of selective inhibition of human prostaglandin G/H synthase-1 and -2 in intact cells. Biochemical pharmacology 1996 Oct 11;52(7):1113-25
4. Marnett LJ, Rowlinson SW, Goodwin DC, Kalgutkar AS, Lanzo CA
   Arachidonic acid oxygenation by COX-1 and COX-2. Mechanisms of catalysis and inhibition. The Journal of biological chemistry 1999 Aug 13;274(33):22903-6
5. Johnson FM, Yang P, Newman RA, Donato NJ
   Cyclooxygenase-2 induction and prostaglandin E2 accumulation in squamous cell carcinoma as a consequence of epidermal growth factor receptor activation by imatinib mesylate. Journal of experimental therapeutics & oncology 2004 Dec;4(4):317-25
6. Garavito RM, Malkowski MG, DeWitt DL
   The structures of prostaglandin endoperoxide H synthases-1 and -2. Prostaglandins & other lipid mediators 2002 Aug;68-69:129-52
7. Chubb AJ, Fitzgerald DJ, Nolan KB, Moman E
   The productive conformation of prostaglandin G2 at the peroxidase site of prostaglandin endoperoxide H synthase: docking, molecular dynamics, and site-directed mutagenesis studies. Biochemistry 2006 Jan 24;45(3):811-20
8. Hla T, Neilson K
   Human cyclooxygenase-2 cDNA. Proceedings of the National Academy of Sciences of the United States of America 1992 Aug 15;89(16):7384-8
9. Barnett J, Chow J, Ives D, Chiou M, Mackenzie R, Osen E, Nguyen B, Tsing S, Bach C, Freire J
   Purification, characterization and selective inhibition of human prostaglandin G/H synthase 1 and 2 expressed in the baculovirus system. Biochimica et biophysica acta 1994 Nov 16;1209(1):130-9
10. Eckl KM, Krieg P, Kuster W, Traupe H, Andre F, Wittstruck N, Furstenberger G, Hennies HC
    Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis. Human mutation 2005 Oct;26(4):351-61
11. Yu Z, Schneider C, Boeglin WE, Brash AR
    Human and mouse eLOX3 have distinct substrate specificities: implications for their linkage with lipoxygenases in skin. Archives of biochemistry and biophysics 2006 Nov 15;455(2):188-96
12. Smith WL, Garavito RM, DeWitt DL
    Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2. The Journal of biological chemistry 1996 Dec 27;271(52):33157-60
13. Ruan KH, Deng H, So SP
    Engineering of a protein with cyclooxygenase and prostacyclin synthase activities that converts arachidonic acid to prostacyclin. Biochemistry 2006 Nov 28;45(47):14003-11
14. Fujii J, Ikeda Y
    Advances in our understanding of peroxiredoxin, a multifunctional, mammalian redox protein. Redox report : communications in free radical research 2002;7(3):123-30
15. Arner ES, Holmgren A
    Physiological functions of thioredoxin and thioredoxin reductase. European journal of biochemistry / FEBS 2000 Oct;267(20):6102-9
16. Maher P
    Redox control of neural function: background, mechanisms, and significance. Antioxidants & redox signaling 2006 Nov-Dec;8(11-12):1941-70
17. Ouellet M, Falgueyret JP, Ear PH, Pen A, Mancini JA, Riendeau D, Percival MD
    Purification and characterization of recombinant microsomal prostaglandin E synthase-1. Protein expression and purification 2002 Dec;26(3):489-95
18. Thoren S, Weinander R, Saha S, Jegerschold C, Pettersson PL, Samuelsson B, Hebert H, Hamberg M, Morgenstern R, Jakobsson PJ
    Human microsomal prostaglandin E synthase-1: purification, functional characterization, and projection structure determination. The Journal of biological chemistry 2003 Jun 20;278(25):22199-209
19. Murakami M, Naraba H, Tanioka T, Semmyo N, Nakatani Y, Kojima F, Ikeda T, Fueki M, Ueno A, Oh S, Kudo I
    Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. The Journal of biological chemistry 2000 Oct 20;275(42):32783-92
20. Tanikawa N, Ohmiya Y, Ohkubo H, Hashimoto K, Kangawa K, Kojima M, Ito S, Watanabe K
    Identification and characterization of a novel type of membrane-associated prostaglandin E synthase. Biochemical and biophysical research communications 2002 Mar 8;291(4):884-9
21. Murakami M, Nakashima K, Kamei D, Masuda S, Ishikawa Y, Ishii T, Ohmiya Y, Watanabe K, Kudo I
    Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2. The Journal of biological chemistry 2003 Sep 26;278(39):37937-47
22. Hayashi H, Fujii Y, Watanabe K, Urade Y, Hayaishi O
    Enzymatic conversion of prostaglandin H2 to prostaglandin F2 alpha by aldehyde reductase from human liver: comparison to the prostaglandin F synthetase from bovine lung. The Journal of biological chemistry 1989 Jan 15;264(2):1036-40
23. Suzuki-Yamamoto T, Nishizawa M, Fukui M, Okuda-Ashitaka E, Nakajima T, Ito S, Watanabe K
    cDNA cloning, expression and characterization of human prostaglandin F synthase. FEBS letters 1999 Dec 3;462(3):335-40
24. Komoto J, Yamada T, Watanabe K, Takusagawa F
    Crystal structure of human prostaglandin F synthase (AKR1C3). Biochemistry 2004 Mar 2;43(8):2188-98
25. Inazu N, Ruepp B, Wirth H, Wermuth B
    Carbonyl reductase from human testis: purification and comparison with carbonyl reductase from human brain and rat testis. Biochimica et biophysica acta 1992 Mar 5;1116(1):50-6
26. Tinguely JN, Wermuth B
    Identification of the reactive cysteine residue (Cys227) in human carbonyl reductase. European journal of biochemistry / FEBS 1999 Feb;260(1):9-14
27. Nakayama T, Yashiro K, Inoue Y, Matsuura K, Ichikawa H, Hara A, Sawada H
    Characterization of pulmonary carbonyl reductase of mouse and guinea pig. Biochimica et biophysica acta 1986 Jun 19;882(2):220-7
28. Nakanishi M, Kakumoto M, Matsuura K, Deyashiki Y, Tanaka N, Nonaka T, Mitsui Y, Hara A
    Involvement of two basic residues (Lys-17 and Arg-39) of mouse lung carbonyl reductase in NADP(H)-binding and fatty acid activation: site-directed mutagenesis and kinetic analyses. Journal of biochemistry 1996 Aug;120(2):257-63
29. Wermuth B
    Purification and properties of an NADPH-dependent carbonyl reductase from human brain. Relationship to prostaglandin 9-ketoreductase and xenobiotic ketone reductase. The Journal of biological chemistry 1981 Feb 10;256(3):1206-13
30. Cho H, Hamza A, Zhan CG, Tai HH
    Key NAD+-binding residues in human 15-hydroxyprostaglandin dehydrogenase. Archives of biochemistry and biophysics 2005 Jan 15;433(2):447-53
31. Matsunaga T, Shintani S, Hara A
    Multiplicity of mammalian reductases for xenobiotic carbonyl compounds. Drug metabolism and pharmacokinetics 2006 Feb;21(1):1-18
32. Watanabe K, Fujii Y, Nakayama K, Ohkubo H, Kuramitsu S, Kagamiyama H, Nakanishi S, Hayaishi O
    Structural similarity of bovine lung prostaglandin F synthase to lens epsilon-crystallin of the European common frog. Proceedings of the National Academy of Sciences of the United States of America 1988 Jan;85(1):11-5
33. Matsuura K, Shiraishi H, Hara A, Sato K, Deyashiki Y, Ninomiya M, Sakai S
    Identification of a principal mRNA species for human 3alpha-hydroxysteroid dehydrogenase isoform (AKR1C3) that exhibits high prostaglandin D2 11-ketoreductase activity. Journal of biochemistry 1998 Nov;124(5):940-6
34. Jarabak J, Braithwaite SS
    Kinetic studies on a 15-hydroxyprostaglandin dehydrogenase from human placenta. Archives of biochemistry and biophysics 1976 Nov;177(1):245-54
35. Cho H, Huang L, Hamza A, Gao D, Zhan CG, Tai HH
    Role of glutamine 148 of human 15-hydroxyprostaglandin dehydrogenase in catalytic oxidation of prostaglandin E2. Bioorganic & medicinal chemistry 2006 Oct 1;14(19):6486-91
36. Polet H, Levine L
    Metabolism of prostaglandins E, A, and C in serum. The Journal of biological chemistry 1975 Jan 25;250(2):351-7
37. Lim H, Dey SK
    PPAR delta functions as a prostacyclin receptor in blastocyst implantation. Trends in endocrinology and metabolism: TEM 2000 May-Jun;11(4):137-42
38. Haurand M, Ullrich V
    Isolation and characterization of thromboxane synthase from human platelets as a cytochrome P-450 enzyme. The Journal of biological chemistry 1985 Dec 5;260(28):15059-67
39. Tanaka K, Ogawa K, Sugamura K, Nakamura M, Takano S, Nagata K
    Cutting edge: differential production of prostaglandin D2 by human helper T cell subsets. Journal of immunology (Baltimore, Md. : 1950) 2000 Mar 1;164(5):2277-80
40. Stark K, Schauer L, Sahlen GE, Ronquist G, Oliw EH
    Expression of CYP4F12 in gastrointestinal and urogenital epithelia. Basic & clinical pharmacology & toxicology 2004 Apr;94(4):177-83
41. Stark K, Wongsud B, Burman R, Oliw EH
    Oxygenation of polyunsaturated long chain fatty acids by recombinant CYP4F8 and CYP4F12 and catalytic importance of Tyr-125 and Gly-328 of CYP4F8. Archives of biochemistry and biophysics 2005 Sep 15;441(2):174-81
42. Schlegel W, Greep RO
    Kinetic studies on 15-hydroxyprostaglandin dehydrogenase from human placenta. Advances in prostaglandin and thromboxane research 1976;1:159-62
43. Thaler-Dao H, Saintot M, Baudin G, Descomps B, Crastes de Paulet A
    Purification of the human placental 15 hydroxy prostaglandin dehydrogenase: properties of the purified enzyme. FEBS letters 1974 Nov 15;48(2):204-8
44. Okazaki T, Casey ML, Okita JR, MacDonald PC, Johnston JM
    Initiation of human parturition. XII. Biosynthesis and metabolism of prostaglandins in human fetal membranes and uterine decidua. American journal of obstetrics and gynecology 1981 Feb 15;139(4):373-81
45. Backlund MG, Mann JR, Holla VR, Buchanan FG, Tai HH, Musiek ES, Milne GL, Katkuri S, DuBois RN
    15-Hydroxyprostaglandin dehydrogenase is down-regulated in colorectal cancer. The Journal of biological chemistry 2005 Feb 4;280(5):3217-23
46. Kanaoka Y, Fujimori K, Kikuno R, Sakaguchi Y, Urade Y, Hayaishi O
    Structure and chromosomal localization of human and mouse genes for hematopoietic prostaglandin D synthase. Conservation of the ancestral genomic structure of sigma-class glutathione S-transferase. European journal of biochemistry / FEBS 2000 Jun;267(11):3315-22
47. Kozak KR, Crews BC, Morrow JD, Wang LH, Ma YH, Weinander R, Jakobsson PJ, Marnett LJ
    Metabolism of the endocannabinoids, 2-arachidonylglycerol and anandamide, into prostaglandin, thromboxane, and prostacyclin glycerol esters and ethanolamides. The Journal of biological chemistry 2002 Nov 22;277(47):44877-85
48. Quinkler M, Bujalska IJ, Tomlinson JW, Smith DM, Stewart PM
    Depot-specific prostaglandin synthesis in human adipose tissue: a novel possible mechanism of adipogenesis. Gene 2006 Oct 1;380(2):137-43
49. Wong PY, Lee WH, Chao PH, Reiss RF, McGiff JC
    Metabolism of prostacyclin by 9-hydroxyprostaglandin dehydrogenase in human platelets. Formation of a potent inhibitor of platelet aggregation and enzyme purification. The Journal of biological chemistry 1980 Oct 10;255(19):9021-4
50. Jarabak J, Berkowitz D, Sun FF
    Oxidation of prostacyclin and its analogs by three 15-hydroxyprostaglandin dehydrogenases. Prostaglandins 1984 Oct;28(4):509-16