Inhibition of tyrosine hydroxylase by R and S enantiomers of salsolinol, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline.
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 cofactor of tyrosine hydroxylase, L-erythro-5,6,7,8-tetrahydrobiopterin, 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.
Department of Neurology, Nagoya University School of Medicine, Japan.
M
M
Minami
T
T
Takahashi
W
W
Maruyama
A
A
Takahashi
P
P
Dostert
T
T
Nagatsu
M
M
Naoi
D000310:Adrenal Gland Neoplasms / Q000201:enzymology* / Q000473:pathology*; D000818:Animals; D001708:Biopterins / Q000378:metabolism / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology*; D010673:Pheochromocytoma / Q000201:enzymology* / Q000473:pathology*; D051381:Rats; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured / Q000201:enzymology / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors*
D007546:Isoquinolines; D001708:Biopterins; C036617:salsolinol; D014446:Tyrosine 3-Monooxygenase