Catecholamines Are Synthesized in Final Form & Stored in Secretion Granules
المؤلف:
Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil
المصدر:
Harpers Illustrated Biochemistry
الجزء والصفحة:
32nd edition.p499-500
2025-11-12
43
Three amines—dopamine, norepinephrine, and epinephrine— are synthesized from tyrosine in the chromaffin cells of the adrenal medulla. The major product of the adrenal medulla is epinephrine. This compound constitutes about 80% of the cat echolamines in the medulla, and it is not made in extramedullary tissue. In contrast, most of the norepinephrine present in organs innervated by sympathetic nerves is made in situ (about 80% of the total), and most of the rest is made in other nerve endings and reaches the target sites via the circulation. Epinephrine and norepinephrine may be produced and stored in different cells in the adrenal medulla and other chromaffin tissues.
The conversion of tyrosine to epinephrine requires four sequential steps: (1) ring hydroxylation; (2) decarboxylation; (3) side chain hydroxylation to form norepinephrine; and (4) N-methylation to form epinephrine. The biosynthetic path way and the enzymes involved are illustrated in Figure 1.
Fig1. Biosynthesis of catecholamines. (PNMT, phenylethanolamine-N-methyltransferase.)
Tyrosine Hydroxylase Is Rate-Limiting for Catecholamine Biosynthesis
Tyrosine is the immediate precursor of catecholamines, and tyrosine hydroxylase is the rate-limiting enzyme in catechol amine biosynthesis. Tyrosine hydroxylase is found in both soluble and particle-bound forms only in tissues that synthesize catecholamines; it functions as an oxidoreductase, with tetrahydropteridine as a cofactor, to convert l-tyrosine to l-dihydroxyphenylalanine (l-dopa). As the rate-limiting enzyme, tyrosine hydroxylase is regulated in a variety of ways. The most important mechanism involves feedback inhibition by the catecholamines, which compete with the enzyme for the pteridine cofactor. Catecholamines cannot cross the blood–brain barrier; hence, in the brain they must be synthesized locally. In certain central nervous system diseases (eg, Parkinson disease), there is a local deficiency of dopamine synthesis. l-Dopa, the precursor of dopamine, readily crosses the blood–brain barrier and so is an important agent in the treatment of Parkinson disease.
Dopa Decarboxylase Is Present in All Tissues
This soluble enzyme requires pyridoxal phosphate for the conversion of l-dopa to 3,4-dihydroxyphenylethylamine (dopamine). Compounds that resemble l-dopa, such as α-methyldopa, are competitive inhibitors of this reaction. α-Methyldopa is effective in treating some kinds of hypertension.
Dopamine β-Hydroxylase (DBH) Catalyzes the Conversion of Dopamine to Norepinephrine
DBH is a monooxygenase and uses ascorbate as an electron donor, copper at the active site, and fumarate as modulator. DBH is in the particulate fraction of the medullary cells, probably in the secretion granule; thus, the conversion of dopamine to norepinephrine occurs in this organelle.
Phenylethanolamine-N-Methyltransferase (PNMT) Catalyzes the Production of Epinephrine
PNMT catalyzes the N-methylation of norepinephrine to form epinephrine in the epinephrine-forming cells of the adrenal medulla. Since PNMT is soluble, it is assumed that norepinephrine-to-epinephrine conversion occurs in the cytoplasm. The synthesis of PNMT is induced by glucocorticoid hormones that reach the medulla via the intra-adrenal portal system. This special system provides for a 100-fold steroid concentration gradient over systemic arterial blood, and this high intra-adrenal concentration appears to be necessary for the induction of PNMT.
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