PGG2/H2 synthase stands for ProstaGlandin G2/H2 synthase. As the name suggests it is an enzyme that belongs to the family of myeloperoxidases1 involved in synthesising biochemical precursors. Those precursors belong to a group of eicosanoids: prostaglandin G2 (PGG2) and its reduced form prostaglandin H2 (PGH2) (Fig.1). The second of these two precursors is necessary for the production of prostanoids: prostaglandins (PGs - E2, F2, D2), tromboxane A2 (TXA2) and prostacyclins (PGI2). PGG2/H2 synthase stands also for an enzyme traditionally called cyclooxygenase (COX); the main target for pharmacological agents - COX inhibitors in the treatment of human diseases.
A heme-containing COX enzyme is a bifunctional biocatalyst with two interconnected cellular activities: cyclooxygenase for endogenous substrate arachidonic acid (AA) and peroxidase for hydroperoxy endoperoxide (PGG2); for final product of hydroxy endoperoxide (PGH2) (Fig.1). COX is a dimmer i.e. it has two identical subunits within the structure (a homodimer) therefore for the enzyme to carry out both reactions with dependency of one to another, the structure possesses two pairs of active sites: cyclooxygenase (COX) and peroxidase (POX) per subunit. The peroxidase active site activates the heme groups (two per enzyme) located in the cyclooxygenase active site before the reactions take place. Although these active sites are distinct biocatalysis of both of them is feasible.
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The first function involves utilisation of molecular oxygen with hydroperoxide acting as a source of it and hence initiator of cyclooxygenase activity. At C11 of AA attraction of hydrogen by Tyr385 forms pentadienyl radical that allows forming reactive species upon attachment of molecular oxygen which then forms cyclic peroxide with C9 followed by second formation of the bridge between C8 - C12 (formation of bicyclic peroxide). C15 peroxyl formed (pre-PGG2) using next available molecule of oxygen (acyclic peroxide formation) is then reduced using the same hydrogen that was attracted by Tyr385 at the start of catalysis thus regenerating enzyme's activity for the next cycle in prostanoids biosynthesis. As a result formation of hydroperoxy endoperoxide - PGG2 (cyclooxygenation or COX reaction) is achieved (Fig. 2). The next step then involves reduction of 2 electrons from the PGG2 formed producing PGH2 (hydroxy endoperoxide), an alcohol with a hydroxyl group created at carbon 15 (peroxidase or POX reaction).
Reaction with molecular oxygen is a very unusual case since in casualty it yields very reactive species i.e. radicals. Since each biosynthesis of PGs occurs in each nucleated cell, except lymphocyte (Tyrrell lecture), involvement of molecular O2 is very extreme. In order to determine origin of each oxygen atom in the structure of PGG2 an experiment using an isotopic mixture of molecular oxygen was used (O216 and O218). Such atom labelling allowed tracing the presence of it and determining its steps in the formation of free radicals. As a consequence either isotopic molecule did not dissociate during cyclooxygenation and/or instead was preserved prior to cyclisation. The remaining isotopic molecular oxygen took part peroxidising the C15. The double diooxygenation therefore allowed for investigation of hydroperoxy endoperoxide (PGG2) formation followed by the reduction of it to hydroxy endoperoxide (PGH2) respectively. Finally, PGH2 formed gets then converted to the number of its enzymatic derivatives (isomerases, synthases, reductases) required for consequent production of biologically active second messengers: I2, E2, F2, D2 and tromboxane A2 6.
Mammalian cell possesses two isoforms of COX: 1 and 2. COX 1 and COX 2 are of the same type of enzyme in regard to mechanism of action, protein folding, structural characteristics and function. However attention must be paid when taking closer look at them since chemical ways of structural characterisation revealed several similarities and differences with some having more importance than the others. To such chemical ways EPR spectroscopy (detection of unpaired electrons), crystallography, steady-state kinetic assays just to name a few, were taken into consideration. The full assessment is provided in the table shown below (Fig.3.) - for more in depth details please refer to the references used denoted by numbers at each subheading under "property".
The nature of cyclooxygenase inhibition in the human body
Mammalian cell possesses two isoforms of PGG2/H2 synthase: 1 and 2. First subtype is referred to as "the good one" whereas the second as "the bad one" 3. Such general and rather simplistic characterisation is due to the function of prostaglandins formed by COX-1 and 2 respectively. Both isozymes have protective and invasive properties. To protective ones we could rank gastro-intestinal epithelial integrity, renal sodium balance, regulation and development of kidneys, angiogenesis and myocardial protection. The invasive however include platelet synthesis and thrombus formation, atherosclerosis, fever, inflammation and its symptoms, and pain 3. Although the last two are of not desired effects nevertheless they do constitute protective function as well as they allow for recognition of something that requires our attention and hence medical intervention. Inhibition of either action would allow an upstream or downstream shift of functions performed by each isoform.
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Inhibition of cyclooxygenase action is desired in the treatment of human diseases. Not only because it suppresses the inflammatory production of prostaglandins in the conditions such as: dysmenorrhoea, rheumatoid arthritis, osteoarthritis but also because it prevents platelet aggregation, suppresses tumour growth and supports bone healing.
Current developments in field of COX inhibition involves several agents with ability to control action of isozymes however recent limitation of their use due to several reports of undesired side effects they cause an approach to identification their targeting is limited.
The types of cyclooxygenase inhibitors in the treatment of human diseases
NSAIDs act by interfering with cyclooxygenase pathway which mediates production of chemicals responsible for various responses within the body such as inflammation, gastric protection and cardiovascular effects 5. Since COXes exist in two isoforms nsaids can interfere with either first, second or both actions simultaneously.
FUTURE APPLICATIONS OF COX INHIBITORS IN THE TREATMENT OF HUMAN DISEASES
The era of nsaids begun at the end of xix century. It was not know until 74 years after the mechanism of action of cox inhibitor, aspirin, was appreciated.
- Comparison of the properties of prostaglandin Hsynthase-1 and -2. R.J. Kulmacz, W.A. van der Donk and A.-.L. Tsai, Progress in Lipid Research. 42 (2003), pp. 377-404.
- Structural and functional differences between cyclooxygenases: Fatty acid oxygenases with a critical role in cell signalling Carol A. Rouzer, Lawrence J. Marnett Biochemical and Biophysical Research Communications 338 (2005) 34-44
- Advances in the pathophysiology of constitutive and inducible cyclooxygenases: two enzymes in the spotlight Luca Parente and Mauro Perretti Biochemical Pharmacology Volume 65, Issue 2, 15 January 2003, Pages 153-159
- Prostaglandin H synthase: Resolved and unresolved mechanistic issues. Ah-Lim Tsai and Richard J. Kulmacz Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA Received 8 July 2009; revised 25 August 2009. Available online 1 September 2009.
- The Cyclooxygenase: Past, present and future. A tribute to John R. Vane (1927-2004). Regina M. Botting Journal of Thermal Biology 31 (2006) 208-219
- J Pharm Pharmaceut Sci (www. cspsCanada.org) 11 (2): 81s-110s, 2008 81s Evolution of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Cyclooxygenase (COX) Inhibition and Beyond P. N. Praveen Rao1 and Edward E. Knaus2.