Disease relevance of tetrahydropterin

• Phenylalanine hydroxylase from Chromobacterium violaceum. Uncoupled oxidation of tetrahydropterin and the role of iron in hyroxylation [1].
• Enzymatic activity of quinonoid dihydropterin reductase and tetrahydropterin content in human ocular tissues and senile cataracts [2].
• The structure of the major tetrahydropterin in Escherichia coli was determined as (6R)-5,6,7,8-tetrahydro-L-monapterin, i. e [3].
• Here we report on the purification of two methylene tetrahydropterin dehydrogenases from the methylotroph Hyphomicrobium zavarzinii ZV580 [4].

High impact information on tetrahydropterin

• Urate oxidase may be the archetype of an expanding new family of tunnel-shaped proteins that now has three members; tetrahydropterin synthase, GTP cyclohydrolase I and urate oxidase [5].
• Kinetic analysis of TH extracted from the caudoputamen of normal and HPRT- mice demonstrated a 45% decrease in Vmax with an increased affinity for the tetrahydropterin cofactor in the mutants [6].
• Human tyrosine hydroxylase isoforms. Inhibition by excess tetrahydropterin and unusual behavior of isoform 3 after camp-dependent protein kinase phosphorylation [7].
• Tyrosine 3-monooxygenase (tyrosine hydroxylase) is a non-heme iron, tetrahydropterin-dependent enzyme which catalyzes the rate-limiting step in the biosynthesis of catecholamines [8].
• With erythro-phenylserine, the hydroxylation reaction is tightly coupled (i.e. 1 mol of hydroxyphenylserine is formed for every mole of tetrahydropterin cofactor consumed), while with threo-phenylserine and tryptophan the reaction is largely uncoupled (i.e. more cofactor consumed than product formed) [9].

Biological context of tetrahydropterin

• The substrate binding sites of F(420) and methylenetetrahydromethanopterin are most likely embedded into a crevice between the domains of one subunit, their isoalloxazine and tetrahydropterin rings being placed inside a pocket formed by this crevice and a loop segment of the adjacent monomer of the dimer [10].
• Mutagenesis of residues in the center of the loop resulted in alterations in the KM values for substrates, the Vmax value for dihydroxyphenylalanine (DOPA) synthesis, and the coupling of tetrahydropterin oxidation to tyrosine hydroxylation [11].
• Oxygen consumption during PAH reduction by tetrahydropterin in the absence of phenylalanine but not in its presence explains the different reduction stoichiometries (tetrahydropterin:enzyme) that have been observed [12].

Anatomical context of tetrahydropterin

• The activity of pyruvoyl tetrahydropterin synthase in the erythrophores is nearly the same as that in rat kidney and pineal gland [13].
• The distribution of GTP-cyclohydrolase I, pyruvoyl tetrahydropterin (dysopropterin) synthase, and pyruvoyl tetrahydropterin reductase in goldfish erythrophores, melanophores, and erythrophoroma cells in vitro has been revealed by specific biochemical assays [13].
• The assay utilizes the tetrahydropterin-dependent reduction of ferri-cytochrome C in the presence of NADH and requires a smaller number of cells than assays described for cultured skin fibroblasts [14].
• Higher doses of pterins given orally (20 mg kg-1) raise the levels of tetrahydropterin in cerebrospinal fluid (CSF) to normal in patients with defective biopterin synthesis in whom initial concentration of biopterin species are low [15].

Associations of tetrahydropterin with other chemical compounds

• Methylenetetrahydrofolate reductase can also suppor phenylalanine hydroxylation in vitro by regeneration of the tetrahydropterin cofactor [16].
• Alanine substitution in positions 182-186 resulted in lowered ratios of tyrosine hydroxylation to tetrahydropterin oxidation [11].
• This could be modeled as a decrease in the cone angle for the indole ring of about 12 degrees . The data are consistent with a model in which binding of a tetrahydropterin results in a change in the conformation of the surface loop required for proper formation of the amino acid binding site [17].
• Arginine hydroxylation requires the presence of a bound, redox-active tetrahydropterin; pterin-free iNOS(heme) or iNOS(heme) reconstituted with a redox-inactive analogue, 6(R,S)-methyl-5-deaza-5,6,7,8-tetrahydropterin, did not form NHA under these conditions [18].
• We have examined the interaction of phenylalanine hydroxylase with phenylalanine, tetrahydropterin cofactors, and an activating phospholipid, lysophosphatidylcholine [19].

Gene context of tetrahydropterin

• These results indicate that the tetrahydropterin intermediates are natural substrates of the human AKR family enzymes and suggest a novel alternative pathway from PPH(4) to BH(4), in which 3 alpha-hydroxysteroid dehydrogenase type 2 and aldose reductase work in concert [20].
• Neurochemical effects following peripheral administration of tetrahydropterin derivatives to the hph-1 mouse [21].
• A new type of dihydropteridine reductase [EC 1.6.99.10], which is specific for NADPH as the substrate in the reduction of quinonoid-dihydropterin to tetrahydropterin, was purified to homogeneity from bovine liver and human liver [22].
• A flexible loop in tyrosine hydroxylase controls coupling of amino acid hydroxylation to tetrahydropterin oxidation [11].
• Since H2O2 can be produced by autooxidation of the tetrahydropterin cofactor required for the hydroxylation reaction, in vitro assays are usually carried out in the presence of added catalase [23].

Analytical, diagnostic and therapeutic context of tetrahydropterin

• Liquid chromatography/electrochemistry is employed to follow the oxidation of the tetrahydropterin cofactor to the dihydropterin and to follow the formation of tyrosine [24].
• The results of kinetic experiments give validity to both our affinity chromatography of the reductase and to an ordered mechanism for the formation of tetrahydropterin [25].

References