Inosine monophosphate dehydrogenase: A target for immunosuppression.

Guanine nucleotides are essential for many cellular functions. Therefore inosine monophosphate dehydrogenase (IMPDH), the rate limiting enzyme for the de novo synthesis of guanine nucleotides, has been a target for the development of anti-viral, anti-bacterial, anti-fungal and immunosuppressive agents. These studies were undertaken to examine the importance of guanine nucleotides and IMPDH activity for T cell activation. Mizoribine and mycophenolic acid are two IMPDH inhibitors that inhibit T cell activation by causing a dose-dependent depletion of guanine nucleotides. Mizoribine does not interfere with early gene expression but causes a block in the transition of cells from G1 to S phase of the cell cycle. 6-mercaptopurine causes depletion of both guanine and adenine nucleotides, but the effect on adenine nucleotides appears to be more important for inhibitory activity. In contrast, azathioprine inhibits T lymphocyte proliferation by a mechanism independent of the depletion of guanine nucleotides. The activation of T cells results in a 6-fold elevation in total cellular guanine ribonucleotide pools and a concomitant 15-fold increase in specific IMPDH enzymatic activity. IMPDH activity in human cells is the result of two different proteins, type I and type II. The expression of both type I (3 kb) and type II (2 kb) IMPDH mRNA is induced approximately 10-fold by 24 to 48 hours following stimulation of purified T lymphocytes. In addition a second, 4 kb, IMPDH type I mRNA is expressed in stimulated T cells as a result of alternate splicing of the 5$\sp\prime$ and/or 3$\sp\prime$ untranslated regions. Southern blot analysis of human genomic DNA demonstrates that type I IMPDH has multiple processed pseudogenes, whereas type II is a single-copy gene. Rat, mouse, dog, cow, and chicken have single copy genes for both type I and type II IMPDH. Therefore, IMPDH I and II are highly conserved and IMPDH activity is the result of the expression of both genes in mammals. IMPDH activity is essential for T cell activation and consequently is a promising target for new immunosuppressive agents.PhDPharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/103742/1/9409671.pdfDescription of 9409671.pdf : Restricted to UM users only