Inosine-5′-monophosphate dehydrogenase

About: Inosine-5′-monophosphate dehydrogenase is a research topic. Over the lifetime, 187 publications have been published within this topic receiving 8450 citations. The topic is also known as: Inosine-5′-monophosphate dehydrogenase & IMPDH.

IMP dehydrogenase, an enzyme linked with proliferation and malignancy

Abstract: PREVIOUS studies conducted in this laboratory demonstrated that in a spectrum of liver tumours with different growth rates there is an imbalance in the activities of key enzymes and competing pathways of carbohydrate, pyrimidine, DNA and ornithine metabolism1–4. Recent investigations on purine metabolism showed that in the hepatomas there was an increased capacity in the de novo pathway of biosynthesis of inosine 5′-monophosphate (IMP), as reflected in the increased activity of glutamine PRPP amidotransferase (EC 2.4.2.14) and a decrease in IMP catabolism5,6. These observations directed our attention to the metabolic fate of IMP because this purine nucleotide is at a strategic position in purine metabolism (Fig. 1). Control at such branching points is exerted primarily by modification of the activity or of the rate of synthesis of the first enzymes of the divergent pathways. In this instance, in normal conditions, a balance is maintained by both positive and negative feedback effects. Thus ATP is required for GMP biosynthesis and GTP for AMP biosynthesis; conversely, GMP and AMP each inhibit their own production7. In normal or malignant proliferation, or in response to a hormone stimulus, changes in control frequently involve reprogramming of gene expression. The theoretical framework and predictive value of generalisations about such biochemical changes (termed the molecular correlation concept) have been elaborated1–3.

The inhibition of nucleic acid synthesis by mycophenolic acid

Abstract: 1 Mycophenolic acid, an antibiotic of some antiquity that more recently has been found to have marked activity against a range of tumours in mice and rats, strongly inhibits DNA synthesis in the L strain of fibroblasts in vitro 2 The extent of the inhibition of DNA synthesis is markedly increased by preincubation of the cells with mycophenolic acid before the addition of [(14)C]thymidine 3 The inhibition of DNA synthesis by mycophenolic acid in L cells in vitro is reversed by guanine in a non-competitive manner, but not by hypoxanthine, xanthine or adenine 4 The reversal of inhibition by guanine can be suppressed by hypoxanthine, 6-mercaptopurine and adenine 5 Mycophenolic acid does not inhibit the incorporation of [(14)C]thymidine into DNA in suspensions of Landschutz and Yoshida ascites cells in vitro 6 Mycophenolic acid inhibits the conversion of [(14)C]hypoxanthine into cold-acid-soluble and -insoluble guanine nucleotides in Landschutz and Yoshida ascites cells and also in L cells in vitro There is some increase in the radioactivity of the adenine fraction in the presence of the antibiotic 7 Mycophenolic acid inhibits the conversion of [(14)C]hypoxanthine into xanthine and guanine fractions in a cell-free system from Landschutz cells capable of converting hypoxanthine into IMP, XMP and GMP 8 Preparations of IMP dehydrogenase from Landschutz ascites cells, calf thymus and LS cells are strongly inhibited by mycophenolic acid The inhibition showed mixed type kinetics with K(i) values of between 303x10(-8) and 45x10(-8)m 9 Evidence was also obtained for a partial, possibly indirect, inhibition by mycophenolic acid of an early stage of biosynthesis of purine nucleotides as indicated by a decrease in the accumulation of formylglycine amide ribonucleotide induced by the antibiotic azaserine in suspensions of Landschutz and Yoshida ascites cells and L cells in vitro