Inosine 5 -monophosphate dehydrogenase (IMPDH) is a rate-limiting
enzyme for the synthesis of
GTP and
dGTP. Two
isoforms of IMPDH have been identified. IMPDH Type I is ubiquitous and predominantly present in normal cells, whereas IMPDH Type II is predominant in malignant cells. IMPDH plays an important role in the expression of cellular genes, such as p53, c-myc and Ki-ras. IMPDH activity is transformation and progression linked in
cancer cells. IMPDH inhibitors,
tiazofurin,
selenazofurin, and
benzamide riboside share similar mechanism of action and are metabolized to their respective
NAD analogues to exert antitumor activity.
Tiazofurin exhibits clinical responses in patients with
acute myeloid leukemia and
chronic myeloid leukemia in
blast crisis. These responses relate to the level of the
NAD analogue formed in the leukemic cells. Resistance to
tiazofurin and related IMPDH inhibitors relate mainly to a decrease in
NMN adenylyltransferase activity. IMPDH inhbitors induce apoptosis. IMPDH inhitors are valuable probes for examining biochemical functions of
GTP as they selectively reduce guanylate concentration. Incomplete depletion of cellular
GTP level seems to down-regulate
G-protein function, thereby inhibit cell growth or induce apoptosis.
Inosine 5'-monophosphate
dehydrogenase (IMPDH, EC 1.1.1.205) catalyzes the dehydrogenation of
IMP to
XMP utilizing
NAD as the
proton acceptor. Studies have demonstrated that IMPDH is a rate-limiting step in the de novo synthesis of guanylates, including
GTP and
dGTP. The importance of IMPDH is central because
dGTP is required for the
DNA synthesis and
GTP plays a major role not only for the cellular activity but also for cellular regulation. Two
isoforms of IMPDH have been demonstrated. IMPDH Type I is ubiquitous and predominately present in normal cells, whereas the IMPDH Type II
enzyme is predominant in malignant cells. Although guanylates could be salvaged from
guanine by the
enzyme hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8), the level of circulating
guanine is low in dividing cells and this route is probably insufficient to satisfy the needs of guanylates in the cells.