Prostaglandin H2

Picot, D., Loll, P.J., Garavito, R.M. The x-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature 367 243-249, 1994. 

Following the initial abstraction of a hydrogen atom, the carbon radical then reacts with 02 to give an oxygen radical, which reacts with aC C bond within the same molecule in an addition reaction. Several further transformations ultimately yield prostaglandin H2. 

Problem 5.3 Using a curved fishhook arrow, propose a mechanism for formation of the cvclopen-tane ring of prostaglandin H2- What kind of reaction is occurring ... 

Fu JY, Masferrer JL, Seibert K et al (1990) The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. J Biol Chem 265 16737-16740... 

Free radicals are by-products of prostaglandin metabolism and may even regulate the activity of the arachidonate pathway. Arachidonic acid, released from lipids as a result of activation of phospholipases by tissue injury or by hormones, may be metabolized by the prostaglandin or leu-kotriene pathways. The peroxidase-catalysed conversion of prostaglandin G2 to prostaglandin H2 (unstable prostanoids) and the mechanism of hydroperoxy fatty acid to the hydroxy fatty acid conversion both yield oxygen radicals, which can be detected by e.s.r. (Rice-Evans et al., 1991). 

Loll P. J., Picot D., Garavito M. The structured basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. Nature Struct Biol 1995 2,637-43. 

Cyclooxygenase- lisa constitutive enzyme that converts arachidonic acid to prostaglandin H2 581... 

The enzyme prostaglandin H2 synthase-1 (PGHS-1) manufactures prostaglandin H2, which is converted to prostaglandin E2 and causes fever and inflammation. PGHS-1 contains two protein subunits with long channels. 

Studies in the 1970s revealed that an enzyme, cyclooxygenase (COX), converts arachidonic acid (4) to an intermediate, prostaglandin H2 (5), as shown below ... 

Arachidonic acid Hydroperoxy endoperoxide prostaglandin G2 (PGG2) Prostaglandin H2 (PGH2)... 

Another enzyme converts prostaglandin H2 to prostaglandin E2 (PGE2) ... 

Two different pathways lead from arachidonate to prostaglandins, prostacyclins, and thromboxanes, on the one hand, or leuko-trienes on the other. The key enzyme for the first pathway is prostaglandin synthase [2]. Using up O2, it catalyzes in a two-step reaction the cyclization of arachidonate to prostaglandin H2, the parent substance for the prostaglandins, prostacyclins, and thromboxanes. Acetylsalicylic acid (aspirin) irreversibly ace-tylates a serine residue near the active center of prostaglandin synthase, so that access for substrates is blocked (see below). 

This heme thiolate-dependent enzyme [EC 5.3.99.4] catalyzes the interconversion of prostaglandin H2 and prostaglandin I2 (prostacyclin). 

By acting both as a dioxygenase and as a peroxidase, this enzyme [EC 1.14.99.1] catalyzes the reaction of ara-chidonate with reduced acceptor AH2 and two dioxygen molecules to produce prostaglandin H2, oxidized acceptor A, and water. 

This glutathione-dependent enzyme [EC 5.3.99.3], also known as prostaglandin E synthase, prostaglandin H2 E isomerase, and endoperoxide isomerase, catalyzes the... 

This heme-thiolate-dependent enzyme [EC 5.3.99.5] catalyzes the conversion of (5Z,13E)-(155 )-9a ,lla -epidi-oxy-15-hydroxyprosta-5,13-dienoate to (5Z,13 )-(155)-9o ,llQ -epoxy-15-hydroxythromba-5,13-dienoate. Thus, it converts prostaglandin H2 into thromboxane A2. 

F. Ushikubi, M. Nakajima, M. Hirata, M. Okuma, M. Fujiwara, S. Narumiya, Purification of the thromboxane A2/prostaglandin H2 receptor from human blood platelets, J. Biol. Chem. 264(1989) 16496. 

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