4- Hydroxy-3,4-dihydropteridine

Equilibria in aqueous solutions of pteridine have been investigated. When pteridine was added to acid, the cation of 4-hydroxy-3,4-dihydropteridine was rapidly formed and this slowly underwent ring fission to the cation of 2-amino-methyleneamino-3-formylpyrazine. Both 2- and 7-methylpteridine behaved similarly 4-methylpteridine gave 3-acetyl-2-aminomethyleneaminopyrazine, but production of 44iydroxy-4-methyl-3,4-dihydropteridine could not be demonstrated (1167). 

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 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. 

Intracellular protozoa of the phylum Apicomplexa such as plasmodium, toxoplasma, and eimeria have long been known to respond to sulfonamides and sulfones. This has led to the assumption that Apicomplexa must synthesize their own folate in order to survive. The reaction of 2-amino-4-hydroxy-6-hydroxymethyl-dihydropteridine diphosphate with />aminobenzoate to form 7,8-dihydropteroate has been demonstrated in cell-free extracts of the human malaria parasite Plasmodium falciparum. 2-Amino-4-hydroxy-6-hydroxymethyl-dihydropteridine pyrophosphokinase and 7,8-dihydropteroate synthase have also been identified. Sulfathiazole, sulfaguanidine, and sulfanilamide act as competitive inhibitors of p-aminobenzoate. It has not been possible to demonstrate dihydrofolate synthase activity in the parasites, which raises the possibility that 7,8-dihydropteroate may have substituted for dihydrofolate in malaria parasites. Similar lack of recognition of folate as substrate was also observed in the dihydrofolate reductase of Eimeria tenella, a parasite of chickens. 

Amino-4-hydroxy-6-(o-erythro-1,2,3-trihydroxypropyl)-7,8-dihydropteridine L-aspartate 4-semiaidehyde L-aspartyl-4-phosphate... 

H2, 3-Dimethylphenyl)-4-hydroxy-2-oxo-l,2-dihydropteridine with sodium hydroxide in refluxing ethanol gave 2-carboxy-3-(2, 3 -dimethylphenylamino)pyrazine (Laboratories Hermes,... 

Various bicyclic heterocycles have been prepared from carbamoylpyrazine V-oxides 2-amino-5-chloro-3-7V-methyIcarbamoylpyrazine 1-oxide refluxed with triethyl orthoformate and acetic anhydride gave 6-chloro-3-methyl-4-oxo-3,4-dihydropteridine 8-oxide (1222) 2-amino-3-carbamoyl-5-methyl(or phenyl)pyrazine 1-oxide with triethyl orthoformate, or with ethyl chloroformate followed by cyclization of the intermediate urethane, gave 6-methyl(or phenyl)-4-hydroxy-pteridine 8-oxide (537). 

Guanine (A) is converted in several steps to the pteridyl alcohol 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine (B). A two-step phosphorylation results in the pyrophosphate (D). The amine function of PABA is now in position to displace nucle-... 

Bacteria use/ -aminobenzoic acid only for conversion to 7.8-dihydrofolic acid (Griffin and Brown, 1964). Thus, E, coli condenses j -aminobenzoic acid (and, alternatively, -aminobenzoylglutamic acid) with 2-amino-4-oxo-6-hydroxy-methyl-7,8-dihydropteridine 9.21) (as the 6-pyrophosphate) to give dihydro-pteroic acid (and alternatively, dihydrofolic acid) (Jaenicke and Chan, 1960). The sulfonamides competitively inhibit the isolated enzyme dihydrofolate the-tase which catalyses these steps (G. Brown, 1962). From Lactobacillus plantamm two enzymes responsible for this synthesis have been isolated in a pure state (Shiota et al., 1969a). The first of these catalyses the esterification of the pteridine 9.21) to its pyrophosphoryl derivative. The second is Brown s dihydrofolate synthetase. This second enzyme has also been isolated from several strains of Pneumococcus, found to have a mol. wt. of 90000, and to need ATP and Mg " as coenzymes (Ortiz, 1970). 

Several papers have been published on the synthesis and properties of fused-ring systems incorporating the 1,4-thiazine structure, mainly pyrido-[2,3-6]-l,4-thiazines, pyrazino[2,3-6]-1,4-thiazines, and pyrimido-[4,5-Z)]-l,4-thiazines, including some sulphur isosteres of dihydropteridines [e.g. (112)]. A detailed account of ring-chain tautomerism in 6-hydroxy-... 

Taylor and Loux (9Bb) have synthesized two compounds related in structure, 2-amino-4-hydroxy-8-(D-l -ribityl)-7,8-dihydropteridine-6-carboxylio acid and 2-amino-4-hydroxy-7-kcto-8-(D-r-ribityl)-7,8-dihydropteridine-6-oarboxylic acid. 

The antagonism of bactericidal sulfanilamides by p-aminobenzoic acid (PABA), a precursor of the vitamin folic acid, has been well documented in the pharmacological literature. More recently, it was shown that the phytotoxic activity of asulam, a herbicidal sulfanilamide derivative, also results from an inhibition of the biosynthesis of the vitamin folic acid. " In particular, asulam inhibits competitively the enzyme 7,8-dihydropteroate synthase, which catalyzes the conversion of 2-amino-4-hydroxy-6-hydroxy-methyl-7,8-dihydropteridine and PABA to dihydropteroic acid, leading to folate depletion. A consequence of the depletion of folic acid derivatives is the buildup of intermediates of the de novo synthesis of purine nucleo-tides. ° Such intermediates include 5 -phosphoribosyl glycineamide (GAR) or 5 -phosphoribosyl-5-amino-4-imidazole (AICAR). The accumulation of GAR and AICAR in asulam-treated pea seedlings has been reported. 

Since the oxidized pteridine proved to be too unstable to isolate from reaction mixtures containing the complete phenylalanine hydroxy-lation system, attempts were made to demonstrate its formation in a simplified system. It seemed possible that the same intermediate which is formed during the enzymic hydroxylation of phenylalanine might be formed during nonenzymic oxidations of tetrahydropteridines. To detect its formation under these conditions, a rapid assay was employed which is based on the fact that the intermediate, in contrast to the 7,8-dihydropteridine, is capable of oxidizing TPNH even in the absence of enzymes. 

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