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Amino Acid Hydroxylase Inhibitors CHAPTER 2 Amino Acid Hydroxylase Inhibitors Edith G. McGeer and Patrick L. McGeer I. Introduction 45 II. Properties of the Enzymes 46 A. Tyrosine Hydroxylase 46 B. Tryptophan Hydroxylase 50 C. Phenylalanine Hydroxylase 54 III. In Vitro Inhibitors of the Hydroxylases 56 A. Catechols 57 B. Iron-Complexing Agents 63 C. Compounds Capable of Easy Oxidation/Reduction 63 D. Amino Acid Analogs 65 IV. In Vivo Inhibitors of the Hydroxylases 71 A. Catechols 71 B. Iron-Complexing Agents 73 C. Compounds Capable of Easy Oxidation/Reduction 74 D. Amino Acid Analogs 74 E. Miscellaneous in Vivo Inhibitors 83 V. Indirect Mechanisms of Inhibition 84 A. Direct Feedback (Product) Inhibition 84 B. Substrate Availability 85 C. Hormonal Influences 86 D. Indirect Feedback (Interneuronal) Inhibition 88 VI. Conclusion 89 References 90 I. INTRODUCTION There are three principal reactions occurring in animals which involve the introduction of a hydroxyl group into the aromatic ring of an amino acid. These reactions are the hydroxylations of tryptophan to 5-hydroxy- tryptophan (5-HTP), of phenylalanine to tyrosine, and of tyrosine to 3,4-dihydroxyphenylalanine (DOPA). There are certain similarities in 45 46 E. G. MCGEER AND P. L. MCGEER these reactions but important differences as well. An understanding of these similarities and differences is needed for an interpretation of the various actions of different types of inhibitors. In each hydroxylation molecular oxygen is required (1) as well as the same, or a highly similar, pteridine cofactor. The general reaction is presumed to be hydroxylase XH4 + ArH + 02 > ArOH + H20 + XH2 where X is a pteridine and ArH represents the amino acid substrate. The reaction is in each case irreversible. Ferrous ion may be involved in all three hydroxylations, although the evidence in most cases rests mainly on the inhibitory action of some iron-chelating agents. Some nonenzymic oxidation o2+f tryptophan (2) and phenylalanine (3) occurs in the presence of 02, Fe , and a tetrahydropteridine. Each hydroxylase is highly concentrated in a particular, and different, functional area of the body. Phenylalanine hydroxylase is highly specific to the parenchymal cells of the liver. Tyrosine hydroxylase is localized in chromaffin cells of the adrenal medulla, postganglionic nerve cells of the sympathetic nervous system, and dopaminergic and noradrenergic nerve cells of the brain. Tryptophan hydroxylase is found principally in the melatonin-producing parenchymal cells of the pineal gland, the serotonergic neurons of the raphe system of the brain, the argentaffin cells of the gut, and mouse mast cells. Melanin formation also involves hydroxylation of tyrosine. The reac­ tion takes place in melanocytes, which are originally derived from the neural crest. The enzyme involved, tyrosinase, is a copper-containing enzyme and is different from the tyrosine hydroxylase of the adrenal medulla or nerve cells. It may carry3 the reaction sequenc3 e further than DOPA (4), although conversion of [ H]tyrosine to [ H]DOPA in mouse melanoma in vivo has been taken as support for the postulate that DOPA is the physiological intermediate in melanin formation (5). II. PROPERTIES OF THE ENZYMES A. Tyrosine Hydroxylase 1. ASSAY The most convenient methods of assay for tyrosine hydroxylase are radiometric, although one fluorescent method has been published (6). One widely used technique is to measure the tritiated water released following conversion of 3,5-tritio-L-tyrosine to 5-tritio-DOPA (7, 8). 2. AMINO ACID HYDROXYLASE INHIBITORS 47 One mole of singly tritiated water is formed for each mole of tyrosine that is converted to DOPA, and the water is separated by freeze-drying it into a counting vial or by passage through an ion-exchange column, which absorbs the tritiated amino acids.14 Another metho14 d is to measure the [ C]DOPA formed during incuba­ tion with [ C]L-tyrosine. A DOPA decarboxylase inhibitor such as NSD-1034 (JV-methyl-Af-3-hydroxyphenylhydrazine14 ) is employed to prevent further metabolism of DOPA. The [ C]DOPA is isolated on an alumina column, eluted, and counted (4, 9). Both methods are rapid and simple and employ tyrosine concentrations below saturation14. Experi­ ments with brain homogenates incubated with a mixture of [ C] tyrosine and tritiated tyrosine indicate that the two methods give entirely com­ parable results (10). The tritiated tyrosine metho14 d gives higher blanks (and lower test to blank ratios) than the C method, presumably be­ cause of exchange of tritium between tyrosine and water molecules during the incubation and isolation procedures (10a). 2. LOCATION The most active site of tyrosine hydroxylation in the body is in the adrenal medulla, which has an activity (Vmax) of the order of 1000 nmoles/hour X gm of wet tissue (9). This is about 10 times the activity of the caudate nucleus, the putamen, and the substantia nigra, which have activities at least five times those in any other brain area (11, 12). High activities are found in abnormal chromaffin tissue such as pheochromocytoma and neuroblastoma (13). Considerable activity is also found in tissue having a high concentration of sympathetic nerve endings (14) such as the superior mesenteric artery (15) and the heart. The heart tyrosine hydroxylase activity is greatly reduced in congestive heart failure (16). The high-activity tissue from adrenals, brain, and heart has been used for most inhibitor studies. The tyrosine hydroxylase in the chromaffin cells of the adrenal medulla can be easily solubilized (17-20a). The same is true of the tyrosine hydroxylase of the heart, vas deferens (21), or substantia nigra, but the enzyme in the caudate nucleus and putamen is much more firmly bound to particles (22, 23). Subcellular localization studies of caudate tyrosine hydroxylase have shown it to be highly localized to the nerve ending or synaptosomal fraction (24-27), as would be expected of an enzyme associated with synthesis of a neurotransmitter or neuromodula­ tor. The substantia nigra contains cell bodies of dopaminergic neurons whose axons terminate in the caudate and putamen. Despite the different 48 E. G. MCGEER AND P. L. MCGEER behavior of the enzyme in these different brain locations, it is neverthe­ less associated with the same neuronal system. Presumably the enzyme is soluble in the soma of the cell where it is being synthesized by ribo- somes but becomes membrane bound when it reaches the synaptosomal areas (28). 3. PROPERTIES The adrenal enzyme has been purified 400- to 1000-fold (17, 19, 28). The enzyme purified 400- to 500-fold was reported to require a pteridine cofactor plus a thiol compound, molecular oxygen, and ferrous ions for maximal activity (Table I). Recently, using enzyme purified more than 1000-fold2+ , Shiman et al. (19) have found that catalase can substitute for Fe ions and that either acts to protect the enzyme against inactiva- tion by the H202 generated by nonenzymic oxidation of tetrahydrobiop- terin. A synthetic pteridine, 5,6-dimethyltetrahydropteridine (DMPH4), is generally used for in2+ vitro studies. High concentrations of DMPH4 (>1-10 mM) or of Fe (>2.5 mM) are each inhibitory in some prepa­ rations (29), bu2+t the inhibitory effect of excess DMPH4 may be lessened by adding Fe (8). Highly purified adrenal enzyme is not inhibited by excess cofactor (19). The effects of varying concentrations of 02 depend to some extent on the concentration of cofactor present (30). Structural requirements for cofactor activity apparently include a 2-amino group, a 4-hydroxy group, and an unsubstituted nitrogen in the 5 position (8). As with liver phenylalanine hydroxylase, the order of activity of various pteridines tested is tetrahydrofolate < DMPH4 < 6-methyltetrahydropteridine < tetrahydrobiopterin (19, 31). The natural in vivo cofactor in the adrenal medulla has been reported to be tetrahy­ drobiopterin (31, 32). This compound has been isolated from liver and is believed to be the endogenous cofactor for phenylalanine hydroxylase (33), but its origin in the body is still obscure. Exogenous cofactor does not stimulate the particle-bound tyrosine hy­ droxylase in brain homogenates [cf. Table I (34-36), also 9, 22, 37], This may not, however, reflect a lack of need for cofactor. It could indicate that sufficient cofactor is already contained within the particles or that the exogenous cofactor is not taken up by the particles. Cofactor activity showing the chemical characteristics of tetrahydrobiopterin has been measured in brain and kidney as well as in liver (38), which sug­ gests its ubiquitous nature. The partially purified adrenal enzyme does not hydroxylate D-tyrosine, m-tyrosine, tyramine, or tryptophan. It does convert phenylalanine to 2. AMINO ACID HYDROXYLASE INHIBITORS 49 TABLE I RELATIVE ACTIVITIES OF ADRENAL AND BRAIN TYROSINE HYDROXYLASE PREPARATIONS IN ASSAY SYSTEMS LACKING VARIOUS COMPONENTS Tyrosine hydroxylase source Partially purified enzyme fro m adrenal Crude Crude rat adrenal brain Supernate ParticulatM e homogenatd e homogenatd e System (%Y (%) (%) (7c) e Complete system 100 100 100 100 Minus DMPH4 2.3 0 5 86 Minus DMPH4 and SH 5 109 Minus SH 2+ 38 14.5 107 Minus Fe2+ 22 20 78.5 100 Minus Fe , SH, and DMPH4 109 Minus 02 0.8 5 1 2 Minus enzyme 0 0 0 0 b Data from 3J+. 0 Data from 35. Recent studies (35a) suggest that the trypsin treatment used in the purification of particulate enzyme produces a tyrosine hydroxylase that is only a fragment of the nativd e form. e Data from 36. 2+ Complete system contains DMPH4, 2-mercaptoethanol (SH), Fe , O2 of air, and enzyme. tyrosine, suggesting that the enzyme has the capacity to hydroxylate in the para position if the meta position is not substituted (39, Jfl). The highly purified adrenal enzyme is said to hydroxylate phenylalanine as rapidly as it does tyrosine if tetrahydrobiopterin, rather than DMPH4, is used as cofactor (19). The ability of tyrosine hydroxylase to accept phenylalanine as a substrate is one of the many significant interactions between the principal hydroxylating enzymes which may have some im­ portance in vivo.
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