3,4-dihydroxystyrene, a novel microbial inhibitor for phenylalanine hydroxylase and other pteridine-dependent monooxygenases

• Published in: Biochimica et biophysica acta Vol. 789; no. 2; pp. 111 - 118
• Main Authors: Koizumi, Shinichi, Matsushima, Yuko, Nagatsu, Toshiharu, Iinuma, Hironobu, Takeuchi, Tomio, Umezawa, Hamao
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 11.09.1984
• Subjects: 3,4-Dihydroxystyrene; Animals; Basidiomycota - analysis; Binding, Competitive; Enzyme inhibitor; Liver - enzymology; Monooxygenase; Phenylalanine - pharmacology; Phenylalanine hydroxylase; Phenylalanine Hydroxylase - antagonists & inhibitors; Pteridine; Pteridines - pharmacology; Rats; Structure-Activity Relationship; Styrenes - pharmacology; Time Factors; Tryptophan Hydroxylase - antagonists & inhibitors; Tyrosine 3-Monooxygenase - antagonists & inhibitors; DMPH; Phenylalanine hydroxylase; 3,4-Dihydroxystyrene; Enzyme inhibitor; Pteridine; 6MPH 4; DOPA; Monooxygenase
• ISSN: 0167-4838; 0006-3002; 1879-2588
• DOI: 10.1016/0167-4838(84)90194-8

A new microbial inhibitor for rat-liver phenylalanine hydroxylase ( l-phenylalanine, tetrahydropetridine: oxygen oxidoreductase (4-hydroxylating), EC 1.14.16.1) was isolated from a culture medium of Fomes tasmanicus, and its structure was determined as 3,4-dihydroxystyrene. This compound inhibited the enzyme by 50% at a concentration of 5 · 10 −6 M and 5 · 10 −7 M, respectively, without or with preincubation at 25°C for 15 min. Without preincubation, dihydroxystyrene inhibited phenylalanine hydroxylase noncompetitively with phenylalanine and a pteridine cofactor, 6,7-dimethyltetrahydropterin, and uncompetitively with oxygen. A change in kinetic properties of the inhibition was observed when the enzyme was preincubated with dihydroxystyrene; the degree of inhibition was increased, and the purely noncompetitive-type inhibition with phenylalanine changed to a mixed-type inhibition. A study concerning the structure-inhibitory activity relationship using several compounds similar to dihydroxystyrene, indicated that the catechol structure is essential and that the structure of the aliphatic side-chain affects the inhibitory potency. A similar degree of inhibition was observed using 6,7-dimethyl- or 6-methyltetrahydropterin or tetrahydrobiopterin as a cofactor. Dihydroxystyrene also inhibited other pteridine-dependent monooxygenases, tyrosine hydroxylase (EC 1.14.16.2) and tryptophan hydroxylase (EC 1.14.16.4), indicating that dihydroxystyrene is a general inhibitor for pteridine-dependent monooxygenases.