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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Biosynthesis of Catecholamines

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Correspondence to Michael J. Kuhar, Division of Neuroscience, Yerkes Regional Primate Research Center of Emory University, Atlanta, Georgia 30322.

The enzymatic processes involved in the formation of catecholamines have been characterized. The component enzymes in the pathway have been purified to homogeneity, which has allowed for detailed analysis of their kinetics, substrate specificity and cofactor requirements and for the development of inhibitors (Fig. 12-1). Studies with knockout mice clearly indicate the importance of these enzymes since absence of at least some of them results in loss of viability (Table 12-1).

Figure 12-1. Biosynthetic pathway for catecholamines.

Figure 12-1

Biosynthetic pathway for catecholamines.

Table 12-1. Studies with Knockout Mice.

Table 12-1

Studies with Knockout Mice.

Tyrosine hydroxylase is the rate-limiting enzyme for the biosynthesis of catecholamines

Tyrosine hydroxylase (TH) is found in all cells that synthesize catecholamines and is a mixed-function oxidase that uses molecular oxygen and tyrosine as its substrates and biopterin as its cofactor [3]. TH is a homotetramer, each subunit of which has a molecular weight of approximately 60,000. It catalyzes the addition of a hydroxyl group to the meta position of tyrosine, thus forming 3,4-dihydroxy-l-phenylalanine (l-DOPA). TH can also hydroxylate phenylalanine to form tyrosine, which is then converted to l-DOPA; this alternative synthetic route may be of significance in patients affected with phenylketonuria, a condition in which phenylalanine hydroxylase activity is depressed (see Chap. 44). TH has a Km for tyrosine in the micromolar range. As a result, it is virtually saturated by the high tissue concentrations of endogenous tyrosine. The cofactor, biopterin, may be at subsaturating concentrations within catecholamine-containing neurons and, thus, may play an important role in regulating NE biosynthesis. TH is primarily a soluble enzyme; however, interactions with membrane constituents, such as phosphatidylserine, or with polyanions, such as heparin sulfate, have been shown to alter its kinetic characteristics. Analogs of tyrosine, such as α-methyl-p-tyrosine (AMPT), are competitive inhibitors of TH. Sequence analysis [4] reveals consensus sequences for phosphorylation primarily in the N-terminal portion of the molecule. The gene reveals considerable sequence homology with phenylalanine hydroxylase and tryptophan hydroxylase.

DOPA decarboxylase catalyzes the removal of the carboxyl group from DOPA to form dopamine

DOPA decarboxylase (DDC) is a pyridoxine-dependent enzyme that has a low Km and a high Vmax with respect to l-DOPA; thus, endogenous l-DOPA is efficiently converted to DA [5]. DDC can also decarboxylate 5-hydroxytryptophan, the precursor of serotonin, as well as other aromatic amino acids; accordingly, it has also been called aromatic amino acid decarboxylase (AADC). DDC is widely distributed throughout the body, where it is found both in catecholamine- and serotonin-containing neurons and in non-neuronal tissues, such as kidney and blood vessels. In DA-containing neurons, this enzyme is the final step in the pathway. α-Methyldopa inhibits DDC in vitro and leads to a reduction in blood pressure after being converted to the false transmitter α-methylnorepinephrine in vivo.

For neurons that synthesize epinephrine or norepinephrine, dopamine β-hydroxylase is the next step in the biosynthetic pathway

Like TH, dopamine β-hydroxylase (DBH) is a mixed-function oxidase that uses molecular oxygen to form the hydroxyl group added to the β carbon on the side chain of DA [6]. Ascorbate, reduced to dihydroascorbate during the reaction, provides a source of electrons. DBH contains Cu2+, which is involved in electron transfer in the reaction; accordingly, copper chelators, such as diethyldithiocarbamate, are potent inhibitors of the enzyme. DBH is a tetrameric glycoprotein containing subunits of 77 and 73 kDa, as determined by sodium dodecyl sulfate (SDS) gel electrophoresis. A full-length clone encodes a polypeptide chain of 578 amino acids [7]. The enzyme is concentrated within the vesicles that store catecholamines; most of the DBH is bound to the inner vesicular membrane, but some is free within the vesicles. DBH is released along with catecholamines from nerves and from the adrenal gland and is found in plasma.

In cells that synthesize epinephrine, the final step in the pathway is catalyzed by the enzyme phenylethanolamine N-methyltransferase

This enzyme is found in a small group of neurons in the brainstem that utilize epinephrine as their neurotransmitter and in the adrenal medullary cells, for which epinephrine is the primary neurohormone. Phenylethanolamine N-methyltransferase (PNMT) transfers a methyl group from S-adenosylmethionine to the nitrogen of NE, forming a secondary amine [8]. The coding sequence of bovine PNMT is contained in a single open reading frame encoding a protein of 284 amino acids [9]. PNMT activity is regulated by corticosteroids.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK27988

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