Evidence already available is used to demonstrate
that although prostaglandin G/H 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 1ε 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 and/or 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 PGG2
production and protect the enzyme from oxidative destruction.