Biopterin inhibition

Several imidazoles have been found to inhibit NOS, including 1-phenylimidazole, 2-phenylimidazole, and 4-phenylimidazole. These imidazoles bind heme in NOS and other enzymes. A search for isoform-specific inhibitors based on an imidazole structure has led to the discovery of l-(trifluoromethylphenyl) imidazole, N-(4-nitrophenacyl) imidazole, and N-(4-nitrophenyIacyl)-2-methyI-imidazole, below (54). The nitrophenylacylimidazoles are selective for nNOS rather than eNOS inhibition. They appear to bind to the tetrahydro-biopterin site and are competitive inhibitors of tetrahydrobiopterin binding. They are noncompetitive inhibitors of arginine binding. It appears that electron-withdrawing N-1 substituents enhance activity and nNOS selectivity. 

Treatment of biopterin and biopterin reductase deficiency consists not only of regulating the blood levels of phenylalanine but of supplying the missing form of coenzyme and the precursors of neurotransmitters, namely, dihydroxyphenylalanine and 5-hydroxytryptophan, along with a compound that inhibits peripheral aromatic decarboxylation. This compound is necessary because the amine products do not cross the blood-brain barrier. 

Methylbiopterin and 2 -deoxybiopterin are two naturally occurring pterin-6-yl acyclo C-nucleosides related to biopterin. The former was isolated from methanol extracts of the marine anthozoan Asteroides calycularis Pallas and found to inhibit growth of mouse and chick fibroblasts in culture (87E950), whereas the latter was isolated from urine of patients with malignant lymphoma (95MI2). 

Another group of diseases with perturbed BH4 metaholism in human epidermis are skin disorders, including vitiligo and the Hermansky—Pudlak syndrome. Although the etiology for these disorders is not yet known, both involve lowered PCD/DCoH activities concomitant with 6- and 7-biopterin and H2O2 accumulation in skin, tyrosinase inhibition, and abnormal melanin biosynthesis. ... 

Tyrosine is converted to dopa by the rate-limiting enzyme, tyrosine hydroxylase, which reqnires tetrahydro-biopterin and is inhibited by alpha-methyltyrosine. Dopa is decarboxylated to dopamine by L-aromatic amino acid decarboxylase, which reqnires pyridoxal phosphate (vitamin Bg) as a coenzyme. Carbidopa, which is used with l-dopa in the treatment of parkinsonism, inhibits this enzyme (see Figure 37). Dopamine is converted to norepinephrine by dopamine beta-hydroxylase, which requires ascorbic acid (vitamin C), and is inhibited by diethyldithiocarbamate. Norepinephrine is converted to epinephrine by phenyletha-nolamineN-melhyltransferase (PNMT), requiring S-adenosyl-methionine. The activity of PNMT is stimulated by corticosteroids. 

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