Cyclooxygenase Allosterism, Fatty Acid-mediated Cross-talk between Monomers of Cyclooxygenase Homodimers.
Prostaglandin endoperoxide H synthases (PGHSs) 1 and 2, also known as cyclooxygenases (COXs), catalyze the oxygenation of arachidonic acid (AA) in the committed step in prostaglandin (PG) biosynthesis. PGHSs are homodimers that display half of sites COX activity with AA; thus, PGHSs function as conformational heterodimers. Here we show that, during catalysis, fatty acids (FAs) are bound at both COX sites of a PGHS-2 dimer. Initially, an FA binds with high affinity to one COX site of an unoccupied homodimer. This monomer becomes an allosteric monomer, and it causes the partner monomer to become the catalytic monomer that oxygenates AA. A variety of FAs can bind with high affinity to the COX site of the monomer that becomes the allosteric monomer. Importantly, the efficiency of AA oxygenation is determined by the nature of the FA bound to the allosteric monomer. When tested with low concentrations of saturated and monounsaturated FAs (e.g. oleic acid), the rates of AA oxygenation are typically 1.5-2 times higher with PGHS-2 than with PGHS-1. These different kinetic behaviors of PGHSs may account for the ability of PGHS-2 but not PGHS-1 to efficiently oxygenate AA in intact cells when AA is a small fraction of the FA pool such as during "late phase" PG synthesis.
Yuan
Chong
C
Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
Sidhu
Ranjinder S
RS
Kuklev
Dmitry V
DV
Kado
Yuji
Y
Wada
Masayuki
M
Song
Inseok
I
Smith
William L
WL
D002384:Catalysis; D020134:Catalytic Domain; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008823:Micelles; D008954:Models, Biological; D008956:Models, Chemical; D019301:Oleic Acid / Q000737:chemistry; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary
D005227:Fatty Acids; D008823:Micelles; D019301:Oleic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; D011451:Prostaglandin-Endoperoxide Synthases