Mycophenolate mofetil: Molecular mechanisms of action

Abstract

Mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid (MPA), is investigated in clinical trials for the prevention of organ and tissue rejection in transplantation. Esterification of MPA to the prodrug MMF improves its bioavailability. MMF prolongs allograft survival and reverses ongoing rejection in animal studies, and has shown preliminary efficacy in human clinical trials in combination with established therapies for transplantation. The immunosuppressive activity of MPA results from the potent reversible inhibition of IMP dehydrogenase (IMPDH). Inhibition of IMPDH by MPA causes the depletion of intracellular GTP pools and inhibits proliferation of lymphocytes. IMPDH is the first enzyme in the committed pathway of de novo synthesis of guanine nucleotides. Two isoforms of human IMPDH are known. The type I enzyme is constitutively expressed, while the type II isozyme is induced in activated lymphocytes and other proliferating cells. MPA inhibits the type II enzyme with fivefold greater affinity than the type I enzyme (Ki=7 nM against type II IMPDH). Against the human enzymes, the kinetics of inhibition by MPA are uncompetitive with respect to both substrates IMP and NAD. Uncompetitive inhibition indicates that MPA preferentially binds to the enzyme after substrates, perhaps to an enzyme-IMP-NAD ternary complex or to an enzyme-XMP binary complex in the product side of the reaction. Uncompetitive inhibition by MPA cannot be overcome by increases in intracellular concentrations of the substrates. The immunosuppressive mechanisms of MPA are discussed in relation to lymphocyte proliferation, alterations of pools of other nucleotides coincident with GTP depletion, and inhibition of other GTP-dependent biochemical events.