Carbocations in the synthesis of prostaglandins by the cyclooxygenase of pgh synthase? a radical departure!

Abstract

Evidence already available is used to demonstrate that although prostaglandin G0H synthase hydroxylates arachidonic acid through radical intermediates, it effects cyclizations through a carbocation center at C-10. This is produced following migration of H to the initial radical at C-13 and a 1E oxidation. Under orbital symmetry control, the cyclizations can give only the ring size and trans stereochemistry actually observed. After cyclization, the H-shift reverses to take the sequence back into current radical theory for hydroxylation at C-15. Thus 10,10-difluoroarachidonic acid cannot be cyclized, although it can be hydroxylated. Acetylation of Ser516 in the isoform synthase-2 is considered to oppose carbocation formation and0or H-migration and so prevent cyclizations while permitting hydroxylations; the associated inversion of chirality at C-15 can then readily be accommodated without the change in conformation required by other schemes. Suicide inhibition occurs when carbocations form stable bonds upon~thermal! contact with adjacent heteroatoms, etc. Because the cyclooxygenase and peroxidase functions operate simultaneously through the same heme, phenol acts as reducing cosubstrate for the cyclooxygenase, thus enabling it to promote PGG 2 production and protect the enzyme from oxidative destruction.

Synthesis and Applications of Stereospecifically 3H-Labeled Arachidonic Acids as Mechanistic Probes for Lipoxygenase and Cyclooxygenase Catalysis1

“…As considered later under Discussion, the results of an incubation of psoriatic scales with [5,6,8,9,11,12,14,15]octadeuterated arachidonic acid can help in understanding the mechanism of 12S-HETE synthesis. Of the eight deuterium atoms on the double bonds of arachidonate, the deuterium at C-12 is diagnostic for isomerizations involving 12-keto and 12-hydroxyl groups.…”

“…In 1999, Dean and Dean proposed an alternative mechanism of prostaglandin formation by cyclooxygenase (9). The authors hypothesized that an intermediate carbocation located at C-10 of arachidonic acid promotes carbocyclization to the five-membered prostaglandin ring.…”

“…After cyclization to the prostaglandin ring and reduction back to the radical state, it is postulated that the original hydrogen is transferred back from the 13-pro-R position to its initial configuration at C-10. The cyclooxygenase reaction is then completed by the "normal" 15S oxygenation to yield PGG 2 (9).…”

“…One electron oxidation at C-10 yields the proposed carbocation intermediate. After carbocyclization to the five-membered prostaglandin ring and formation of the endoperoxide, H R migrates back to its initial position at C-10; cyclooxygenase catalysis is completed by oxygenation at C-15 to yield prostaglandin G 2 (9).…”

“…We used the [10-3 H]-labeled arachidonic acids to investigate the mechanism of biosynthesis of 12S-HETE in psoriatic scales, and to test the validity of a recently published hypothesis concerning the mechanism of prostaglandin ring formation by cyclooxygenase (9).…”