Premium
Inhibition of Tyrosine Hydroxylase by R and S Enantiomers of Salsolinol, 1‐Methyl‐6,7‐Dihydroxy‐1,2,3,4‐ Tetrahydroisoquinoline
Author(s) -
Minami Midori,
Takahashi Tsutomu,
Maruyama Wakako,
Takahashi Akira,
Dostert Philippe,
Nagatsu Toshiharu,
Naoi Makoto
Publication year - 1992
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1992.tb10951.x
Subject(s) - biopterin , tyrosine hydroxylase , tetrahydrobiopterin , tyrosine 3 monooxygenase , chemistry , tyrosine , allosteric regulation , dopamine , biochemistry , cofactor , enzyme , stereochemistry , biology , endocrinology
Salsolinol is one of the dopamine‐derived tetrahydroisoquinolines and is synthesized from pyruvate or acetaldehyde and dopamine. As it cannot cross the blood‐brain barrier, salsolinol as the R enantiomer in the brain is considered to be synthesized in situ in dopaminergic neurons. Effects of R and S enantiomers of salsolinol on kinetic properties of tyrosine hydroxylase [tyrosine, tetrahydrobiopterin:oxygen oxidoreductase (3‐hydroxylating); EC 1.14.16.2], the rate‐limiting enzyme of catecholamine biosynthesis, were examined. The naturally occurring co‐factor of tyrosine hydroxylase, l ‐ erythro ‐5,6,7,8‐tetra‐hydrobioptein, was found to induce allostery to the enzyme polymers and to change the affinity to the biopterin itself. Using l ‐ erythro ‐5,6,7,8‐tetrahydrobiopterin, tyrosine hydroxylase recognized the stereochemical structures of the salsolinols differently. The asymmetric center of salsolinol at C‐1 played an important role in changing the affinity to l ‐tyrosine. The allostery of tyrosine hydroxylase toward biopterin cofactors disappeared, and at low concentrations of biopterin such as in brain tissue, the affinity to the cofactor changed markedly. A new type of inhibition of tyrosine hydroxylase, by depleting the allosteric effect of the endogenous biopterin, was found. It is suggested that under physiological conditions, such a conformational change may alter the regulation of DOPA biosynthesis in the brain.