Biological Significance of Guanylate Synthesis and IMP Dehydrogenase Isoforms

摘要

IMP dehydrogenase (IMPDH) is the rate-limiting enzyme for de novo guanine nucleotide synthesis and a potential target for anticancer and immunosuppressive chemotherapy. Human IMPDH was regarded as a single molecular species until the discovery in 1989 of two isoforms derived from different genes. The two isoforms showed striking differences in expression during neoplastic transformation and proliferation, lymphocytic activation and cell maturation. The type II IMPDH expression is stringently linked with immature characteristics and type Ⅰ appears to be expressed constitutively. Selective inhibition of the inducible type Ⅱ IMPDH may mitigate toxicity caused by inhibition of the type I isoform. Although mycophenolic acid has a slight selectivity to type Ⅱ in its inhibition, the selectivity may not be sufficient. Further studies will be required to elucidate biological, biochemical and structural differences between type Ⅰ and type Ⅱ IMPDHs and to better understand the selective inhibition of these two isoforms in anticancer and immunosuppressive chemotherapy.