Inosine Monophosphate Dehydrogenase and Its Inhibitors: An Overview

Introduction Inosine 5'-monophosphate dehydrogenase (IMPDH, E.C.1.1.1.205), the NADdependent enzyme that controls de novo synthesis of purine nucleotides, catalyzes the oxidation of inosine 5'-monophosphate (IMP) to xanthosine 5'-monophosphate (XMP), which is then converted to guanosine 5'-monophosphate (GMP) by GMP synthase (Fig.1). IMP also serves as a substrate for the biosynthesis of adenosine 5'-monophosphate (AMP). An adequate pool of purine nucleotides is essential for cell proliferation, cell signaling, and as an energy source. Consequently, inhibition of IMPDH causes a variety of biological responses, and it is not surprising that this enzyme has emerged as a major target for antiviral, antileukemic and immunosuppressive therapies. The inhibition of IMPDH is accompanied by a reduction in guanine nucleotide pools. This results in an interruption of DNA and RNA synthesis (1), a decline in intracellular signaling (2-6), and down-regulation of c-myc and Ki-ras oncogenes in vitro (7-9) and in leukemic cells of patients treated with