Inosine-5′-monophosphate dehydrogenase
Inosine-5′-monophosphate dehydrogenase (IMPDH) is an essential cytoplasmic purine metabolic enzyme that catalyzes the NAD-dependent oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP), the first and rate-limiting step towards the synthesis of guanosine triphosphate (GTP) from IMP. IMPDH has an essential role in providing precursors for DNA and RNA bioysynthesis. IMPDH also plays a role in signal transduction pathways that mediate cell differentiation. As purine metabolism is largely conserved across all known organisms, so is the structure and function of IMPDH. IMPDH from pathogenic bacterium Streptococcus pyogenes to human crystallizes as a tetramer.[1]
Within the binding pocket of IMPDH, a cysteine residue attacks the hydrogen atom on the 2' carbon of IMP. Then, in the presence of a nearby acidic residue within the active site, NAD + is oxidized into NADH and an E-XMP intermediate is formed. The final XMP is produced after a solvent water molecule hydrolyzes the E-XMP intermediate at the 2' carbon and regenerates the catalytic enzyme.[2] Enzyme assays are conducted to calculate the Michaelis-Menten parameters for the Asp338Ala mutation and a 600-fold decrease in the rate constant ka is reported.[3] Therefore, it is suggested that Asp338 acts as the catalytic charged residue during the reaction between IMPDH and IMP. However, crystal structure of Tritrichomonas foetus shows that Asp338 has a water-meditated hydrogen bonding network, which would prevent the residue to perform its catalytic function.[4]
IMPDH expression is found to be upregulated in tumor tissues and tumor cell lines.[5][6] Accordingly, human IMPDH is a target of clinical anti-cancer drugs, in particular mycophenolic acid,[7] which is also a widely used immuno-depressor. In murine cells, p53-dependent growth suppression requires down-regulation of IMPDH.[8]
See also
- Ribonucleoside monophosphate
- Xanthosine
References
- ↑ Zhang, Rong-Guang; Evans, Gwyndaf; Rotella, Frank J.; Westbrook, Edwin M.; Beno, Don; Huberman, Eliezer; Joachimiak, Andrzej; Collart, Frank R. (1999). "Characteristics and Crystal Structure of Bacterial Inosine-5'-monophosphate Dehydrogenase". Biochemistry 38 (15): 4691–700. doi:10.1021/bi982858v. PMID 10200156.
- ↑ Sintchak, M.D.; Nimmesgern, E. The structure of inosine 5'-monophosphate dehydrogenase and the design of novel inhibitors. Immunopharmacology 2000, 40, 163-163.
- ↑ Kerr, K.M.; Hedstrom, L. The roles of conserved carboxylate residues to IMP dehydrogenase and identification of a transition state analog. Biochemistry 1997, 36, 13365-13373.
- ↑ Whitby, F.G.; Luecke, H.; Kuhn, P.; Somoza, J.R.; Huete-Prez, J.A.; Phillips, J.D.; Hill, C.P.; Fletterick, R.J.; Wang, C.C. Crystal structure of Tritrichomonas foetus inosine 5'-monophosphate dehydrogenase and the enzyme-product complex. Biochemistry 1997, 36, 10666-10674.
- ↑ Collart, FR; Chubb, CB; Mirkin, BL; Huberman, E (1992). "Increased inosine-5'-phosphate dehydrogenase gene expression in solid tumor tissues and tumor cell lines". Cancer Research 52 (20): 5826–8. PMID 1356621.
- ↑ Zimmermann, Albert G.; Gu, Jing-Jin; Laliberte, Josée; Mitchell, Beverly S. (1998). "Inosine-5′-Monophosphate Dehydrogenase: Regulation of Expression and Role in Cellular Proliferation and T Lymphocyte Activation". Progress in Nucleic Acid Research and Molecular Biology 61: 181–209. doi:10.1016/S0079-6603(08)60827-2. ISBN 978-0-12-540061-9. PMID 9752721.
- ↑ Liu, Y; Bohn, SA; Sherley, JL (1998). "Inosine-5'-monophosphate dehydrogenase is a rate-determining factor for p53-dependent growth regulation". Molecular Biology of the Cell 9 (1): 15–28. PMC 25212. PMID 9436988.
- ↑ Weber, G (1983). "Biochemical strategy of cancer cells and the design of chemotherapy: G. H. A. Clowes Memorial Lecture". Cancer Research 43 (8): 3466–92. PMID 6305486.
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