The Dopamine Hypothesis of Schizophrenia: A Review*

▪ Abstract Phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase constitute a small family of monooxygenases that utilize tetrahydropterins as substrates. When from eukaryotic sources, these enzymes are composed of a homologous catalytic domain to which are attached discrete N-terminal regulatory domains and short C-terminal tetramerization domains, whereas the bacterial enzymes lack the N-terminal and C-terminal domains. Each enzyme contains a single ferrous iron atom bound to two histidines and a glutamate. Recent mechanistic studies have begun to provide insights into the mechanisms of oxygen activation and hydroxylation. Although the hydroxylating intermediate in these enzymes has not been identified, the iron is likely to be involved. Reversible phosphorylation of serine residues in the regulatory domains affects the activities of all three enzymes. In addition, phenylalanine hydroxylase is allosterically regulated by its substrates, phenylalanine and tetrahydrobiopterin.

Tetrahydropterin-dependent amino acid hydroxylases.

✓ In this review of spinal cord injury research, the author has selected contributions which in his opinion best represent modern experimental concepts regarding the mechanism and management of spinal cord injuries. He has placed special emphasis on the controversial issues appropriate to a new, stimulating, and competitive area of research.

The pathophysiological response to spinal cord injury. The current status of related research.

Dopamine has been implicated as a potential mediating factor in a variety of neurodegenerative disorders. Dopamine can be oxidized to form a reactive dopamine quinone that can covalently modify cellular macromolecules including protein and DNA. This oxidation can be enhanced through various enzymes including tyrosinase and/or prostaglandin H synthase. One of the potential targets in brain for dopamine quinone damage is tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis. The present studies demonstrated that dopamine quinone, the formation of which was enhanced through the activity of the melanin biosynthetic enzyme, tyrosinase, covalently modified and inactivated tyrosine hydroxylase. Dihydroxyphenylalanine (DOPA; the catechol-containing precursor of dopamine) also inactivated tyrosine hydroxylase under these conditions. Catecholamine-mediated inactivation occurred with both purified tyrosine hydroxylase as well as enzyme present in crude pheochromocytoma homogenates. Inactivation was associated with covalent incorporation of radiolabelled dopamine into the enzyme as assessed by immunoprecipitation, size exclusion chromatography, and denaturing sodium dodecylsulfate (SDS)-polyacrylamide gel electrophoresis. Furthermore, the covalent modification and inactivation of tyrosine hydroxylase was blocked by antioxidant compounds (dithiothreitol, reduced glutathione, or NADH). In addition to kinetic feedback inhibition and the formation of an inhibitory dopamine/Fe+3 complex, these findings suggest that a third mechanism exists by which dopamine (or DOPA) can inhibit tyrosine hydroxylase, adding further complexity to the regulation of catecholamine biosynthesis.

Dopamine, in the presence of tyrosinase, covalently modifies and inactivates tyrosine hydroxylase

Phosphorylation and activation of tyrosine hydroxylase mediate the acetylcholine-induced increase in catecholamine biosynthesis in adrenal chromaffin cells.

Nagatsu Toshiharu

Papers

Inhibition of dopamine β-hydroxylase by fusaric acid (5-butylpicolinic acid) in vitro and in vivo

Pteridines as cofactor or inhibitor of tyrosine hydroxylase.

Lysyl oxidase activity in human normal skins and postburn scars

Effect of oudenone on adrenal tyrosine hydroxylase activity in vivo and on tissue catecholamine concentrations.

Monoamine oxidase activity of the thyroid glands in thyroid disease.