Consequences of IMP Dehydrogenase Inhibition, and its Relationship to Cancer and Apoptosis

Abstract

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 [1]. IMPDH Type I is ubiquitous and predominately present in normal cells, whereas the IMPDH Type II enzyme is predominant in malignant cells [2]. 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 [3].

Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs

“…It is an important factor in maintaining guanine nucleoside pools, and a virus is highly dependent on this process. IMPDH Type I is ubiquitously expressed in normal cells, whereas a high level of IMPDH Type II is also associated with many hematological cancers . In addition, ribavirin 40 has a negative impact on eukaryotic translation initiation factor eIF4E activity, which is dysfunctional in 30% of cancers. − High levels of eIF4E have been correlated with clinical progression, increased angiogenesis, and poor prognosis in breast cancer, , and ribavirin 40 was shown to suppress growth in breast cell lines …”

Metabolomic analysis characterizes tissue specific indomethacin-induced metabolic perturbations of rats

“…smaller than adenine nucleotide in most mammalian cells. 34,35 Therefore, the guanine nucleotide is believed to be the limiting factor for DNA and RNA synthesis. 36,37 The depletion of guanine nucleotides has been implicated in the induction of cellular apoptosis, [38][39][40] the mechanism being largely attributed to inhibited DNA and pre-ribosomal RNA synthesis, which results in cells arrest.…”

Isobaric Peptide Termini Labeling for MS/MS-Based Quantitative Proteomics

“…A straightforward, conceptually simple semiquantitative way of evaluating IPTL data is provided using Mascot score ratio values. Finally, we show that IPTL can be used for the quantification of complex proteomic changes by providing data replicating the well-documented changes of apoptotic cells upon incubation with STLC or other inducers of apoptosis. − …”