IMPDH2

Related Reading

Introductions

IMP dehydrogenase 2 is the rate-limiting enzyme in the de novo guanine nucleotide biosynthesis. It is thus involved in maintaining cellular guanine deoxy- and ribonucleotide pools needed for DNA and RNA synthesis. IMPDH2 catalyzes the NAD-dependent oxidation of inosine-5'-monophosphate into xanthine-5'-monophosphate, which is then converted into guanosine-5'-monophosphate. IMPDH2 has been identified as an intracellular target of the natural product sanglifehrin A.

Figure 1. Structure of IMPDH2.

Structure and function

IMPDH is a tetrameric enzyme consisting of a monomeric subunit with a molecular weight of approximately 55 kDa [5], usually composed of 400-500 residues. A visual representation of the active site with IMP and NAD binding. The key residues of the protein (white) and the catalytic cysteine (cyan) are shown. The dashed lines indicate polar contacts. Most IMPDH monomers contain two structural domains: a catalytic (β/α) 8-barrel structural domain with the active site located in a loop at the C-terminal end of the barrel, and a sub-structural domain consisting of two repeating cystathionine β-synthase (CBS) structural domains inserted into the dehydrogenase sequence

As a Tumor Target

IMPDH2 catalyzes the rate-limiting reaction of de novo GTP biosynthesis at the IMP metabolic branch point. The activity of IMPDH in-creased in all rat hepatomas examined above that in normal liver, and the rise correlated positively with the increase in tumor growth rates. By measuring the metabolic fluxes, the expression of the proliferative program of intact cancer cells has been shown to be linked with the preferential channeling of IMP into guanylate biosynthesis. The inhibition of IMPDH by tiazofurin and the decline of the GTP pool in K562 human leukemic cells resulted in the down-regulation of c-Ki-ras and c-myc protooncogenes and induced erythroid differentiation. Tiazofurin showed a therapeutic effect in vivo in rats bearing hepatoma 3924A and in clinical trials in patients with refractory leukemia. In these studies, tiazofurin provided selective toxicity against neoplastic cells compared to normal tissues. Thus，IMPDH is a sensitive target for cancer chemotherapy.

Catalytic mechanism

The mechanism of IMP dehydrogenase involves a series of two distinct chemical reactions as follows:
(1) a rapid redox reaction involving the transfer of hydride to NAD+ to produce NADH and an enzyme-bound XMP intermediate (E-XMP*).
(2) a hydrolysis step to release XMP from the enzyme. IMP binds to the active site and a conserved cysteine residue attacks the 2-position of the purine ring. The hydrogen anion is then transferred from the C2 position to NAD+ and the E-XMP* intermediate is formed.

Clinical significance

This gene is up-regulated in some neoplasms, suggesting it may play a role in malignant transformation. Guanine nucleotide synthesis is essential for maintaining normal cell function and growth, and is also important for the maintenance of cell proliferation and immune responses. IMPDH expression is found to be upregulated in some tumor tissues and cell lines. B and T lymphocytes display a dependence on IMPDH for normal activation and function, and demonstrate upregulated IMPDH expression. Therefore, IMPDH has been addressed as a drug target for immunosuppressive and cancer chemotherapy.