INTRICATE REGULATION OF TYROSINE-HYDROXYLASE ACTIVITY AND GENE-EXPRESSION

Tyrosine hydroxylase catalyzes the rate-limiting step in the biosynthe sis of the catecholamines dopamine, norepinephrine, and epinephrine. T herefore, the regulation of tyrosine hydroxylase enzyme number and int rinsic enzyme activity represents the central means for controlling th e synthesis of these important biogenic amines. An intricate scheme ha s evolved whereby tyrosine hydroxylase activity is modulated by nearly every documented form of regulation. Beginning with the genomic DNA, evidence exists for the transcriptional regulation of tyrosine hydroxy lase mRNA levels, alternative RNA processing, and the regulation of RN A stability. There is also experimental support for the role of both t ranslational control and enzyme stability in establishing steady-state levels of active tyrosine hydroxylase protein, Finally, mechanisms ha ve been proposed for feedback inhibition of the enzyme by catecholamin e products, allosteric modulation of enzyme activity, and phosphorylat ion-dependent activation of the enzyme by various different kinase sys tems. Given the growing literature suggesting that different tissues r egulate tyrosine hydroxylase mRNA levels and activity in different way s, regulatory mechanisms provide not only redundancy but also diversit y in the control of catecholamine biosynthesis.