Reduced 6,6,8‐Trimethylpterins

Abstract

The substrates of dihydropteridine reductase (EC 1.6.99.7), quinonoid 7,8‐dihydro(6H)pterins, are unstable and decompose in various ways. In attempting to prepare a more stable substrate, 6,6,8‐trimethyl‐5,6,7,8‐tetrahydro(3H)pterin was synthesised and the quinonoid 6,6,8‐trimethyl‐7,8‐dihydro(6H)pterin derived from it is extremely stable with a half‐life in 0.1 M Tris/HCl (pH 7.6, 25°C) of 33 h. Quinonoid 6,6,8‐trimethyl‐7,8‐dihydro(6H)pterin is not a substrate for dihydropteridine reductase but it is reduced non‐enzymically by NADH at a significant rate and it is a weak inhibitor of the enzyme: I50 200 μM, pH 7.6, 25°C when using quinonoid 6‐methyl‐7,8‐dihydro(6H)pterin as substrate. 6,6,8‐Trimethyl‐5,6,7,8‐tetrahydropterin is a cofactor for phenylalanine hydroxylase (EC 1.14.16.1) with an apparent Km of 0.33 mM, but no cofactor activity could be detected with tyrosine hydroxylase (EC 1.14.16.2). Its phenylalanine hydroxylase activity, together with the enhanced stability of quinonoid 6,6,8‐trimethyl‐7,8‐dihydro(6H)pterin, suggest that it may have potential for the treatment of variant forms of phenylketonuria.

Enzymic properties of a new mechanism-based substrate for dihydrofolate reductase

“…5,8-Dihydrpterins have been observed only transiently during electrochemical reductions and have not been characterized (Kwee & Lund, 1973). As for 8-substituted quinonoid-dihydropterins (Randles & Armarego, 1985;Armarego et al, 1986), 8-methyl-5,8-dihydropterin would be expected to rearrange rapidly (Kwee & Lund, 1973) to the 7.8-dihydro tautomer: our previous theoretical calculations suggested that 5,8-dihydropterin would be ~11 kcal mol™1 less stable than 7,8-dihydropterin (Gready, 1985b). On mecha-Thibault et al…”

Pterin chemistry and its relationship to the molybdenum cofactor

“…Tetrahydropterins are generally unstable in air towards oxidation to a dihydro state followed by rapid rearrangement to the stable 7,8-dihydro tautomer. It has been observed that the rearrangement is blocked by disubstitution at the 6 position permitting isolation of a quinonoid tautomer of dihydropterin [64,65]. …”

Pterin-Dependent Amino Acid Hydroxylases

“…In general terms, the pyrimidine portion of the pterin ring is most essential. However, several deviations in this part of the pterin nucleus do not abrogate PAH activity, including monomethylation of the exocyclic N 2 group, replacement of the C 4 carbonyl by an amino group, and monomethylation of N 8 (6,6,8-trimethyl-PH 4 is nonfunctional with TyrH, however) …”