Chem*4520 Metabolic Processes Fall Semester 2000 Modified October 2000
schematic view of the enzyme citrate synthase, with bound acetyl-CoA analog in green	Department of Chemistry and Biochemistry Home Page Back to Chem*4520 Home Page

Prostaglandin H synthase attacks arachidonate with two moles of O₂

Most of the work is done by a single enzyme, prostaglandin PGH2 synthase, which contains two catalytic centers, a cyclo-oxygenase and a peroxidase. The reaction is initiated by the cyclo-oxygenase. A first molecule of O2, which is a diradical, attacks the allylic system from C-11 to C-15 at the C-11 double bond, with loss of H. at C-13. Then follows a two pronged attack by the other end of the O-O at C-9 concomitantly with attack by a second O2 diradical at C-15. This results in cyclization across the gap from C-8 to C-12, forming a five member ring. The end product of cyclo-oxygenase reaction is the the unstable peroxide, prostaglandin G2, PGG2. Finally, the peroxidase component reduces the peroxide at C-15 to a stable hydroxyl group in prostaglandin H2.

Prostaglandin H is the starting point for synthesis of other prostaglandins

A simple rearrangement (induced by proton shift) to give ketone at C-9 and hydroxyl at C-11 gives prostaglandin E, e.g. PGE2. (Prostaglandin D is the product with hydroxyl at C-9 and ketone at C-11; however its significance is less certain.) Reductive opening of the endoperoxide, using NADPH to act as a hydride (H-) donor gives prostaglandin F, e.g. PGF2 The indicates the stereochemistry of O-9. The subscript 2 indicates the number of double bonds in the final prostaglandin. In prostaglandins derived from arachidonate, 5 remains untouched (cis-geometry) while 13 trans arises from allylic shift of the original 14 cis. The other two double bonds have disappeared into the ring and its oxygen functional groups.

Prostaglandins may also derive from eicosatrienoate ^8,11,14, in which case ⁵ is missing, e.g. PGH₁ and derived prostaglandins lacking ⁵.

Fatty acids lacking ¹⁴ can't form prostaglandins, hence the dietary requirement for at least linoleate, 18:2^9,12, which can be converted to arachidonate with mammalian enzymes.

Prostaglandins derived from eicosapentaenoate 20:5^5,8,11,14,17 end up with an additional unshifted double bond ^{17 cis}, e.g. PGH₃ and derivatives.

There is a whole alphabet soup of prostaglandin types, but many of these derive from non-biological modifications during isolation. Only two other products of PGH2 rearrangement are known to be physiologically significant: PGI2 or prostacyclin and TXA2 or thromboxane, in which a ring rearrangement has inserted -O- into the carbon backbone of arachidonate.

Function of prostaglandins

Many functions are associated with control over contraction of smooth muscle or the intracellular non-muscle actomyosin system. For PGE and PGI, actions appear to be mediated through activation of adenylate cyclase and elevated intracellular levels of cyclic AMP. PGF and TXA seem to oppose the increase in cyclic AMP.

PGE2	stimulates	vascular dilation bronchiodilation gastrointestinal and uterine contraction inflammatory response
	mimics	hormones that act through cyclic AMP
	inhibits	platelet aggregation
PGF2	stimulates	vascular constriction bronchioconstriction smooth muscle contraction, e.g. intestinal tract, uterus intrauterine injection induces expulsion of uterine contents breakdown of corpus luteum
PGI2	inhibits	platelet aggregation (increases cAMP) vascular constriction bronchioconstriction gastrointestinal and uterine contraction
TXA2	stimulates	platelet aggregation (decreases cAMP) vascular constriction bronchioconstriction

In particular, PGI₂ and TXA₂ appear to act as a mutually opposed pair. TXA₂ is produced by platelets, and stimulates their activation, a positive feedback loop that gives a rapid thrombotic response when triggered. TXA₂ action is kept in check by PGI₂ secreted by vascular epithelium. If vascular epithelium is intact, PGI prevents clotting, but on vascular damage, loss of PGI synthesis shifts the balance in favour of TXA, and platelet aggregation occurs.

Non-steroidal anti-inflammatory drugs (NSAIDS), including acetylsalicylate (Aspirin®), acetaminophen (Tylenol® ) and ibuprofen are inhibitors of prostaglandin synthase. The effect on the PGI/TXA pair results in an anti-thrombotic effect, protective against stroke and heart attack (but promoting a risk from bleeding ulcers). Vasodilation reduces headache. Inhibition of PGE reduces inflammation.

Department of Chemistry and Biochemistry Home Page

Web-related comments can be sent to Uwe Oehler at DrIguana@chembio.uoguelph.ca