7.8- Dihydropteridine

There is no easy understanding of the spectral properties of these compounds in general, which may or may not have a built-in chromophoric system responsible for a long-wavelength absorption like 7,8-dihydropteridin-4-one or a blue-shifted excitation like its 5,6-dihydro isomer. More important than the simple dihydropteridine model substances are the dihydropterins and dihydrolumazines, which are naturally occurring pteridine derivatives and reactive intermediates in redox reactions. 

Little information is available about 5,6-dihydropteridines, of which various 6,7-diphenyl-5,6-dihydropterins (65HCA764, 69HCA306) and -lumazines (68HCA1029, 70HCA789) have been synthesized and characterized. As noticed already (51BSF521), this type of compound isomer-izes in an acid-catalyzed reaction to the 7,8-dihydro derivative (77HCA922) or oxidizes to... 

Another approach uses the reaction of 6-chloro-5-nitropyrimidines with a-phenyl-substituted amidines followed by base-catalyzed cyclization to pteridine 5-oxides, which can be reduced further by sodium dithionite to the heteroaromatic analogues (equation 97) (79JOC1700). Acylation of 6-amino-5-nitropyrimidines with cyanoacetyl chloride yields 6-(2-cyanoacetamino)-5-nitropyrimidines (276), which can be cyclized by base to 5-hydroxypteridine-6,7-diones (27S) or 6-cyano-7-oxo-7,8-dihydropteridine 5-oxides (277), precursors of pteridine-6,7-diones (278 equation 98) (75CC819). 

A novel type of ring closure is the reaction of 6-amino-5-dichloroacetylaminopyrimidines (285) with sulfur and morpholine under the conditions of a Kindler reaction (B-64MI21605). 7-Morpholinopteridin-6-ones (287) are formed, either via thiooxamide derivatives (286) or via corresponding 7,8-dihydropteridines (284 equation 102). Chloral hydrate also reacts with 2-substituted 5,6-diaminopyrimidin-4-ones to form pteridin-6-ones (56JCS3311, 64JCS565) by a so far unknown mechanism. 

The water molecule was found to add across the 7,8-positions in 6-hjr-droxypteridine by Brown and Mason. These authors showed that the neutral species of 6-hydroxypteridine exists mainly as 6,7-dihydroxy-7,8-dihydropteridine (4) in equilibrium with a little of 3. The stable cation is largely derived from 4 and the stable anion largely from 3. 

FIGURE 40-2 The phenylalanine hydroxylase (PAH) pathway. Phenylketonuria usually is caused by a congenital deficiency of PAH (reaction 1), but it also can result from defects in the metabolism of biopterin, which is a cofactor for the hydroxylase. Enzymes (1) Phenylalanine hydroxylase (2) Dihydropteridine reductase (3) GTP cyclohydrolase (4) 6-pyruvoyltetrahydrobiopterin synthase. BH4, tetrahydrobiopterin DEDT, o-erythro-dihydroneopterin triphosphate QH2, dihydrobiopterin. 

Rarely, phenylketonuria results from a defect in the metabolism of biopterin, a cofactor for the phenylalanine hydroxylase pathway. The electron donor for phenylalanine hydroxylase is tetrahydrobiopterin (BH4), which transfers electrons to molecular oxygen to form tyrosine and dihydrobiopterin (QH2 Fig. 40-2 reaction 2). BH4 is regenerated from QH2 in an NADH-dependent reaction that is catalyzed by dihydropteridine reductase (DHPR), which is widely distributed. In the brain, this... 

DHPR dihydropteridine reductase GIRK G-protein-coupled inwardly rectifying K+ channel... 

K., Wachter, H., Werner-Felmayer, G., Mayer, B., Identification of the 4-amino analogue of tetrahydrobiopterin as a dihydropteridine reductase inhibitor and a potent pteridine antagonist of rat neuronal nitric oxide synthase, Biochem. J. 320 (1996), p. 193-196... 

Extensive NMR investigation of the formation of adducts between pteri-dine and liquid ammonia has shown that two different species are obtained the covalent 1 1 a-adduct 4-amino-3,4-dihydropteridine, and the thermodynamically more favored 2 1 a-adduct 6,7-diamino-5,6,7,8-tetrahy-dropteridine (Scheme 11.42) (75RTC45 76OMR607). This adduct is also formed in ammonia [71JCS(C)2357]. 

This enzyme [EC 4.1.2.25] catalyzes the conversion of 2-amino-4-hydroxy-6-(D-eryi/iro-l,2,3-trihydroxypro-pyl)-7,8-dihydropteridine to 2-amino-4-hydroxy-6-hy-droxymethyl-7,8-dihydropteridine and glycolaldehyde. 

This enzyme [EC 1.6.99.7] catalyzes the reaction of NAD(P)H with 6,7-dihydropteridine (that is, the quinoid form of dihydropteridine) to produce NAD(P)+ and 5,6,7,8-tetrahydropteridine. The enzyme is not identical with dihydrofolate reductase. 

This enzyme [EC 3.5.4.16] catalyzes the reaction of GTP with two water molecules to produce formate and 2-amino - 4 - hydroxy - 6 - erythro -1,2,3- trihydroxypropyl) -dihydropteridine triphosphate. The reaction involves hydrolysis of two C-N bonds and isomerization of the pentose unit. The recyclization step may be nonenzy-matic. 

DIHYDROOROTATE DEHYDROGENASE DIHYDROOROTATE OXIDASE DIHYDROPTERIDINE REDUCTASE DIHYDROPTEROATE SYNTHASE DIHYDROPYRIMIDINASE DIHYDROURACIL DEHYDROGENASE Dihydroxyacetone kinase,... 

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