Prostaglandin terminal synthases as novel therapeutic targets

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) exert their anti-inflammatory and anti-tumor effects by reducing prostaglandin (PG) production via the inhibition of cyclooxygenase (COX). However, the gastrointestinal, renal and cardiovascular side effects associated with the pharmacological inhibition of the COX enzymes have focused renewed attention onto other potential targets for NSAIDs. PGH₂, a COX metabolite, is converted to each PG species by species-specific PG terminal synthases. Because of their potential for more selective modulation of PG production, PG terminal synthases are now being investigated as a novel target for NSAIDs. In this review, I summarize the current understanding of PG terminal synthases, with a focus on microsomal PGE synthase-1 (mPGES-1) and PGI synthase (PGIS). mPGES-1 and PGIS cooperatively exacerbate inflammatory reactions but have opposing effects on carcinogenesis. mPGES-1 and PGIS are expected to be attractive alternatives to COX as therapeutic targets for several diseases, including inflammatory diseases and cancer.

Keywords: NSAIDs; carcinogenesis; inflammatory reaction; prostacyclin; prostaglandin.

Figure 1.

Biosynthetic pathways of prostanoids. Arachidonic acid released from membrane phospholipids by the action of phospholipase A₂ (PLA₂) is converted to PGH₂ by cyclooxygenase (COX), and PGH₂ is then isomerized to prostanoids by each PG-specific terminal enzyme. Of the two COX enzymes, COX-1 is expressed constitutively in most tissues, and COX-2 is induced in response to various types of stimuli. NSAIDs exert both beneficial and adverse effects by reducing prostanoid production via the inhibition of COX. PGDS: PGD synthase; PGES: PGE synthase; PGFS: PGF synthase; PGIS: PGI synthase; TXS: thromboxane synthase.

Figure 2.

Structure of mPGES-1. (A) Overall structure of the human PGES-1 trimer (PDB4AL0).¹⁹⁾ (B) Schematic model structure of the human mPGES-1 monomer. The red letters show the residues critical for mPGES-1 enzymatic activity,^14,20) and the blue letters show the residues that account for the species discrepancy in the human-specific mPGES-1 inhibitor.⁵⁷⁾ I, II, III, and IV indicate transmembrane helix 1, 2, 3, and 4, respectively.

Figure 3.

Two suggested chemical mechanisms of GSH-dependent isomerization of PGH₂ to PGE₂ by mPGES-1.²⁰⁾ (A) The thiolate of GSH could be stabilized by Arg¹²⁶ and could attack on the endoperoxide oxygen atom at the C-9 carbon of PGH₂ to produce an unstable reaction intermediate. The subsequent proton abstraction at C-9 followed by S-O bond cleavages is mediated by Asp⁴⁹, and then a carbonyl forms and the oxygen sulfur bond is broken to form PGE₂. (B) The reaction starts by proton abstraction at C-9 via Asp⁴⁹, and then a carbonyl forms and the endoperoxide is broken. The thiol of GSH functions as a proton donor to the developing C-11 oxyanion.

Figure 4.

Structural formulae of mPGES-1 inhibitors.

Figure 5.

Mechanism of PGI₂ and TXA₂ biosynthesis by PGIS and TXS, respectively.⁶⁸⁾ For PGI₂ biosynthesis, PGH₂ is bound to the active site of PGIS with its C-11 oxygen oriented close to the heme iron. The homolytic scission of the endoperoxide bond followed by the immediate formation of an [S⁻⋯Fe^IV⋯O-R] species leads to an alkoxyradical. Subsequent cyclization to the carbon radical, Fe(IV) oxidation to the carbocation, and loss of the C-6 proton yield the vinyl ether, PGI₂. In contrast, for TXA₂ biosynthesis, PGH₂ is bound to the active site of TXS with its C-9 oxygen at the heme iron. In addition to TXA₂, almost the same amounts of malondialdehyde (MDA) and 12-HHT are produced by the TXS reaction.

Figure 6.

Crosstalk between PGIS-derived PGI₂ and mPGES-1-derived PGE₂ in inflammatory reactions (A) and carcinogenesis (B). A: Crosstalk between PGIS and mPGES-1 in inflammatory reactions. Both COX-2/PGIS-derived PGI₂ and COX-2/mPGES-1-derived PGE₂ function as proinflammatory agents. They cooperatively exacerbate inflammatory reactions. As shown in the lower panel, the LPS-primed acetic acid-induced writhing reaction was reduced in both the PGIS KO and mPGES-1 KO mice, and it was suppressed more effectively in the PGIS/mPGES-1 DKO mice compared with the PGIS KO and mPGES-1 KO mice (^*p < 0.05 and ^**p < 0.01 vs control mice).⁸⁵⁾ B: Crosstalk between PGIS and mPGES-1 in carcinogenesis. COX-2/PGIS-derived PGI₂ functions as an anticarcinogenic agent in contrast to COX-2/mPGES-1-derived PGE₂ in various tissues. When mPGES-1-derived PGE₂ increases and then exceeds the anticarcinogenic actions of PGIS-derived PGI₂, a tumor might progress. As shown in the lower panel, in an AOM-induced colon cancer model, mPGES-1 deficiency decreased the number of polyps, whereas PGIS deficiency tended to increase the polyp numbers and significantly increased the number of large polyps (^*p < 0.05 and ^**p < 0.01 vs control mice).⁸⁵⁾