Disease relevance of Tyrosine hydroxylase pteridine cofactor

• At these doses of 6-methyltetrahydropterin, there was an improvement of the patient's neurological symptoms, including a pronounced decrease in eye rolling and drooling and a marked increase in muscle strength, coordination, and physical activity [1].

High impact information on Tyrosine hydroxylase pteridine cofactor

• The model pteridine, 6-methyltetrahydropterin was ten times more efficient than tetrahydrobiopterin in crossing the blood-brain barrier, and striatal concentrations of 6-methyltetrahydropterin remained elevated for 2 hours, declining with a half-life of 3 hours [2].
• Furthermore, the inhibitory effect of catalase on A23187-induced relaxations was abolished when coronary arteries were incubated in the presence of DAHP plus a liposoluble analogue of tetrahydrobiopterin, 6-methyltetrahydropterin (10(-4) mol/L) [3].
• Tetrahydrobiopterin can be replaced by the artificial cofactor, 6-methyltetrahydropterin, in the tyrosine-dependent oxidation at both pH 6.8 and 8 [4].
• Protein phosphorylation activates tyrosine hydroxylase in crude extracts of rat striatum, hypothalamus, and adrenal glands by a reduction in the apparent Km value for 6-methyltetrahydropterin [5].
• Dephosphorylation is accompanied by a corresponding loss in phenylalanine hydroxylase activity when the activity is measured with the natural cofactor, tetrahydrobiopterin, but not when measured with the synthetic cofactor, 6-methyltetrahydropterin [6].

Biological context of Tyrosine hydroxylase pteridine cofactor

• 6-Methyltetrahydropterin reduces the ferric enzyme with a second-order rate constant of 6.1 +/- 0.1 mM(-)(1) s(-)(1) and exhibits saturation kinetics [7].
• 5-Deaza-6-methyltetrahydropterin protects against inactivation and both 5-deaza-6-methyltetrahydropterin and 6-methyltetrahydropterin protect against covalent labeling, indicating that labeling occurs at the pterin binding site [8].

Associations of Tyrosine hydroxylase pteridine cofactor with other chemical compounds

• This finding opens up the possibility of treating phenylketonurics who still possess some residual phenylalanine hydroxylase activity with a tetrahydropterin like 6-methyltetrahydropterin which can give a large increase in rate over that seen with the natural cofactor, tetrahydrobiopterin [9].
• The effects of (6R)- and (6S)-tetrahydrobiopterin (BPH4), tetrahydroneopterin, and 6-methyltetrahydropterin on the activity of tryptophan hydroxylase were investigated in rat raphe slices [10].
• TH had a tendency toward greater affinity for tetrahydrobiopterin (BH4) than for the synthetic cofactor 6-methyltetrahydropterin (6-MPH4), although the maximal velocity of the TH-catalyzed reaction was greater with 6-MPH4 [11].
• Substantial amounts of tetrahydrobiopterin and 6-methyltetrahydropterin can be detected in CSF when these pterins are given peripherally to patients with hyperphenylalaninemia due to defective biopterin synthesis [12].

Gene context of Tyrosine hydroxylase pteridine cofactor

• Rats pretreated with 6-methyltetrahydropterin showed enhanced phenylalanine hydroxylase activity in liver slices demonstrating for the first time that an exogenous tetrahydropterin can interact with the phenylalanine hydroxylase system in vivo [9].
• The analogue 6-methyltetrahydropterin (6M-PH4) is effective in catalysis but does not regulate PAH [13].

Analytical, diagnostic and therapeutic context of Tyrosine hydroxylase pteridine cofactor

• As indicated by its circular dichroism (CD) spectrum, the optical activity of the adduct generated from racemic 6-methyltetrahydropterin requires stereoselectivity of the oxygenation [14].

References