Guanosine monophosphate synthase

Mycophenolic acid has anti-fungal, anti-bacterial and anti-viral activity. It is a potent inhibitor of inositol monophosphate dehydrogenase and guanosine monophosphate synthase and hence of nucleotide biosynthesis. Mycophenolic acid has a powerful immunosuppressive activity and the morpholine amide (CellCept ) is used to prevent rejection of organ transplants and has been recommended for the treatment of psoriasis. 

Fig. 173. Interconversion of inosine, adenosine and guanosine monophosphates 1 Inosine monophosphate dehydrogenase 2 guanosine monophosphate synthase 3 guanosine monophosphate reductase 4 adenylosuccinate synthetase 5 adenylosuccinate lyase 6 adenosine (phosphate) deaminase...

Fig. 3. Mechanisms of vasocontraction and vasorelaxation in endothelial and smooth muscle cells. COX cyclooxygenase, eNOS endothelial nitric oxide synthase, HO-1 heme oxygenase-1, EET epoxyeicosatrienoic acid, EDHF endothelium-derived hyperpolariz-ing factor, PGI2 prostaglandin I2, NO nitric oxide, CO carbon monoxide, PLC phospholipase C, IP3 inositol 1,4,5-trisphosphate, DAG diacylglycerol, ER/SR endo-plasmic/sarcoplasmic reticulum, AC adenylyl cyclase, cAMP cyclic adenosine monophosphate, sGC soluble guanylyl cyclase, cGMP cyclic guanosine monophosphate.

Figure 3. Compartmentalization of the purine salvage pathway of Leishmania. Abbreviations are as follows AAH, adenine aminohydrolase XPRT, xanthine phosphoribosyltransferase HGPRT, hypoxanthine-guaninephosphoribosyltransferase ADSS, adenylosuccinate synthetase ASL, adenylosuccinate lyase IMPDH, inosine monophosphate dehydrogenase GMPS, gua-nosine monophosphate synthase GDA, guanine deaminase AMPDA, adenosine monophosphate deaminase GMPR, guanosine monophosphate reductase APRT, adenine phosphoribosyltransferase AK, adenosine kinase. Enzymes that have been localized are shown in black and those that are predicted to be in the denoted locations are depicted in gray.

The purine synthase inhibitor mizoribine is phosphorylated to the active form mizoribine 5 -monophosphate, which selectively inhibits inosine monophosphate dehydrogenase and guanosine monophosphate synthetase. Mizoribine has been used to treat systemic lupus erythematosus, lupus nephritis, nephrotic syndrome, and other childhood diseases. 

Desmethyl tirilazad reduced brain nitric oxide synthase activity and cyclic guanosine monophosphate during cerebral global ischaemia in rats (Fernandez et al. 1997). 

Fig. 76.2 Polyphenols and polyphenol-rich sources induce endothelial-dependent NO- and EDH-mediated relaxations. Polyphenols are potent inducers of the oidothelial formation of nitric oxide (NO) and endothelium-derived hyperpolarizatitm (EDH) via a redox-soisitive mechanism. SKca small conductance calcium-activated potassium channels, IKca intermediate conductance calcium-activated potassium channels, Src Src family kinase, PI3K phosphatidylinositol 3-kinase, eNOS endothelial NO synthase, L-Arg L-arginine, sGC soluble guanylyl cyclase, GTP guanosine triphosphate, cGMP cyclic guanosine monophosphate, AA arachidonic acid, COX cyclooxygenase, ATP adenosine triphosphate, cAMP cyclic adenosine monophosphate...

Laychock, S. G., Modica, M. E., and Cavanaugh, C. T. (1991). L-arginine stimulates cyclic guanosine 3, 5 -monophosphate formation in rat islets of Langerhans and RlNm5F insulinoma cells Evidence for L-arginine Nitric oxide synthase. Endocrinology (Baltimore) 129, 3043-3052. 

The conversion of IMP to AMP requires amination at C-6 of the purine system, and the nitrogen for this process is derived from aspartate (Asp, D) (adenylosuccinate synthase, EC 6.3.4.4). It appears that the driving force for the loss of water in this process that yields N -l, 2-dicarboxyl adenosine monophosphate (adenosine 5 -phosphate, AMP) is the conversion of guanosine triphosphate (GTP) to guano-sine diphosphate (GDP). Adenosine monophosphate (adenosine 5 -phosphate, AMP) is formed from the N -derivative by loss of fumarate (catalyzed by adenylosuccinate lyase, EC 4.3.2.2). 

It was shown in Scheme 12.97 (which is partially repeated here as Scheme 14.2) that inosine 5 -phosphate (IMP) underwent amination by the addition of aspartate (Asp, D) to the carbon of the carbonyl to produce N -(5)-l,2-dicarboxyethyl adenosine monophosphate. The reaction was aided by adenylosuccinate synthase (EC 6.3.4.4).The phosphate was derived from guanosine triphosphate (GTP).Then, after the elimination of fumarate (adenylosuccinate lyase, EC 4.3.2.2), AMP resulted. 

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