Guanosine triphosphate, oxidation

Receptors linked to guanylyl cyclase and which catalyze the formation of guanosine triphosphate (GMP) to guanosine-3A -cychc monophosphate (cychc GMP) include those for atrial natriuretic factor (ANF) and endothehal-derived relaxing factor (EDRF), mediating vasodilatation, and nitric oxide [10102 3-9], NO, or a clearly related derivative. 

Synthesized by soluble guanylyl cyclase and particulate guanylyl cyclase from guanosine triphosphate (GTP). Nitric oxide activates soluble guanylyl cyclase to enhance cyclic GMP production that contributes to various NO actions. Cyclic GMP is hydrolyzed by phosphodiesterases. Cyclic GMP binds to and activates cGMP-dependent protein kinase, phosphodiesterases, and Cyclic Nucleotide-regulated Cation Channels. 

Guanylyl cyclases (GC) are a family of enzymes (EC 4.6.1.2) that catalyse the formation of the second messenger cyclic GMP (cGMP) from guanosine triphosphate (GTP). GCs are subdivided in soluble GCs and GCs that are membrane-bound and linked to a receptor. Activation occurs by nitric oxide (NO) and pqrtide hormones, respectively [1,2]. 

The primary function of the dtric acid cycle is oxidation of acetyl CoA to carbon dioxide. The energy released from this oxidation is saved as NADH, FADHj, and guanosine triphosphate (GTP). The overall result of the cyde is represented by the following reaction ... 

Note that this overall reaction requires three coenzymes that we encountered as metabolites of vitamins in chapter 15 NAD+, derived from lucotiiuc acid or nicotinamide FAD, derived from riboflavin and coenzyme A(CoASH), derived from pantothenic acid. In the overall process, acetyl-SCoA is oxidized to two molecules of carbon dioxide with the release of CoASH. Both NAD+ and FAD are reduced to, respectively, NADH and FADH2. Note that one molecule of guanosine triphosphate, GTP, functionally equivalent to ATP, is generated in the process. 

Nitric oxide is a molecule with pleiotropic effects on the cardiovascular system. Figure 15. Nitric oxide (NO) is produced when NO synthase (NOS) converts L-ar-ginine to citrulline. The major target of NO in the cardiovascular system is the NO sensitive soluble guanyl cyclase that converts guanosine triphosphate (GTP) to c-GMP. 

Tabraue, C., Penate, R.D., Gallardo, G., Hernandez, I., Quintana, J., Blanco, F.L., Reyes, J.G., Fanjul, L.F., and Ruiz De Galarreta, C.M. (1997). Induction of guanosine triphosphate-cyclohydrolase by follicle-stimulating hormone enhances interleukin-1 P-stimulated nitric oxide synthase activity in granulosa cells. Endocrinology 738 162-168. 

FMN, flavin mononucleotide GMP, guanosine monophosphate GTP, guanosine triphosphate NAD, nicotinamide-adenine dinucleotide (NAD+, oxidized form NADH, reduced form). 

Guanosine triphosphate and ribulose-5-phosphate are recruited in a 1 2 stoichiometric ratio by GTP cyclohydrolase II and DHBP synthase, respectively, for riboflavin biosynthesis. Since at substrate saturation the activity of B. subtilis DHBP is twice the activity of B. suhtilis cyclohydrolase II (DSM, unpublished observations) and since both enzymatic activities are associated with the same bifunctional protein encoded by rihA, the balanced formation of the pyrimidinedione and the dihydroxybutanone intermediates is ensured. However, the ifg.s constant of DHBP synthase ( 1 mmol is about 100-fold higher than the ifg.s constant of GTP cyclohydrolase II imposing the risk of excessive synthesis of the pyrimidinone and pyrimidinedione intermediates in case of reduced intracellular concentrations of pentose phosphate pathway intermediates. This can be expected, for instance, in glucose-limited fed-batch fermentations, which are frequentiy used in industrial applications. The pyrimidinone and pyrimidinedione intermediates are highly reactive, oxidative compounds, which can do serious damage on the bacteria. 

Other nucleoside triphosphates, which are energetically equivalent to ATP, are important in some metabolic reactions cytidine triphosphate in phospholipid biosynthesis, guanosine triphosphate in protein biosynthesis and oxidative decarboxylation of 2-oxoacids (see Thcarboxylic acid cycle), inosine triphosphate in certain carboxylations, uridine triphosphate in polysaccharide biosythesis. 

These oxidation reactions require oxygen (O2) and tetrahydrobiopterin as a cofactor. Thus, as shown in Scheme 13.39, 7,8-dihydroneopterin 3 -triphosphate (generated from guanosine triphosphate [GTP] as seen in Scheme 12.118) is converted to 6-pyruvoyl-5,6,7,8-tetrahydropterin by an elimination reaction and two keto-enol isomerizations. The process is catalyzed by the enzyme 6-pyruvoyltetra-hydropterin synthase (EC 4.2.3.12). Then, via an intermediate, written as an equilibrium between a-hydroxyketones (named dihydrosepiapterin) linked by a common enol, reduction to tetrahydrobiopterin is effected (in two separate steps) by 2 equivalents of NADPH used by the enzyme sepiapterin reductase (EC 1.1.1.153). Tetrahydrobiopterin is the cofactor involved in the National Institutes of Health (NIH) shift (cf. Chapter 6) pathway used by the iron-containing enzyme phenylalanine 4-monooxygenase (EC 1.14.16.1) to convert phenylalanine (Phe, F) to tyrosine (Tyr, Y) and is converted to (6i )-6-(L-erythro-l,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4a-hydroxypterin in the process. 

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...

---