O-, N- and S-Methyltransferases

  • C. R. Creveling
  • D. R. Thakker
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 112)


The existence of methylation as a metabolic conjugation reaction was first established over a century ago when N-methylpyridinium metabolite was detected by HIS (1887) in dog urine after administration of pyridine. Since then, methyl transfer has been shown as one of the most widely utilized conjugation reactions in nature. A wide variety of endogenous molecules as well as xenobiotics are metabolically transformed by methyl transfer reactions; these molecules include proteins, nucleic acids, phospholipids, catecholamines, steroids, alkyl- and arylamines, and thiols. The transfer of a methyl group to a variety of heteroatoms, such as oxygen, nitrogen, and sulfur, is catalyzed by many methyltransferase enzymes with varying degree of substrate selectivity. It is interesting to note that despite a diversity of enzymes catalyzing the methyl transfer reaction, a common methyl donor is shared by all these enzymes, i.e., S-adenosyl-L-methionine (AdoMet). The O-methylation (Thakker and Creveling 1990; Boudikova et al. 1990; Creveling 1993; Klein et al. 1992), N-methylation (Ansher and Jakoby 1990), and S-methylation (Stevens and Bakke 1990; Hoffman 1993) reactions have been discussed in recent comprehensive reviews.


COMT Inhibitor Methyl Transfer COMT Activity Metabolic Inactivation PNMT Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Acquas E, Carboni E, de Ree RHA, Da Prada M, Di Chiara G (1992) Extracellular concentrations of dopamine and metabolites in the rat caudate after oral admin istration of a novel catechol-O-methytransferase inhibitor Ro 40-7592. J Neurochem 59: 326–330PubMedGoogle Scholar
  2. Amin AM, Creveling CR, Lowe MC (1983) Immunocytochemical localization of catechol O-methyltransferase in normal and cancerous breast tissues of mouse and rat. JNCI 70: 337–342PubMedGoogle Scholar
  3. Ansher SS, Jakoby WB (1990) N-methylation. In: Mulder GJ (ed) Conjugation reactions in drug metabolism. Taylor and Francis, London, p 233Google Scholar
  4. Ansher SS, Cadet JL, Jakoby WB, Baker JK (1986) Role of TV-methyltransferases in the neurotoxicity associated with the metabolites of l-methyl-4-phenyl-l,2,3,4-tetrahydropyridine (MPTP) and other 4-substituted pyridines present in the environment. Biochm Pharmacol 35: 3359–3363Google Scholar
  5. Asano Y, Woodward WB, Houck DR, Floss HG (1984) Stereochemical course of the tranmethylation catalyzed by histamine Af-methyltransferase. Arch Biochem Biophys 231: 253–256PubMedGoogle Scholar
  6. Assicot M, Contesso G, Bohuon C (1977) Catechol-O-methyltransferase in human breast cancers. Eur J Cancer 13: 961–966PubMedGoogle Scholar
  7. Axelrod J, Tomchick R (1958) Enzymatic O-methylation of epinephrine and other catechols. J Biol Chem 233: 702–705PubMedGoogle Scholar
  8. Axelrod J, Weissbach H (1960) Enzymatic O-methylation of iV-acetylserotonin to melatonin. Science 131: 1312PubMedGoogle Scholar
  9. Axelrod J, Weissbach H (1961) Purification and properties of hydroxyindol 0-methyltransferase. J Biol Chem 236: 211–213PubMedGoogle Scholar
  10. Backstrom R, Honkanen E, Pippuri A, Kairisalo P, Pystynen J, Heinola K, Nissinen E, Linden I-B, Mannisto PT, Kaakkloa S, Pohto P (1989) Synthesis of some novel potent and selective catechol-O-methyltransferase inhibitors. J Med Chem 32: 841–846PubMedGoogle Scholar
  11. Baetge EE, Suh YH, Joh TH (1986) Complete nucleotide and deduced amino acid sequence of bovine phenylethanolamine iV-methyltransferase: partial amino acid homology with rat tyrosine hydroxylase. Proc Natl Acad Sci USA 83: 5454–5458PubMedGoogle Scholar
  12. Baetge EE, Behringer RR, Messing A, Brinster RL, Palmiter RD (1988) Transgenic mice express the human phenylethanolamine iV-methyltranferase gene in adrenal medulla and retina. Proc Natl Acad Sci USA 85: 3648–3652PubMedGoogle Scholar
  13. Batter DK, D’Mello SR, Turzai LM, Hughes HB III, Gioio AE, Kaplan BB (1988) The complete nucleotide sequence and structure of the gene encoding bovine phenylethanolamine iV-methyltransferase. J Neurosci Res 19: 367–376PubMedGoogle Scholar
  14. Bayliss DA, Wang Y-M, Zahnow CA, Joseph DR, Millhorn DE (1990) Localization of histidine decarboxylase mRNA in rat brain. Mol Cell Neurosci 1: 3–9PubMedGoogle Scholar
  15. Bertocci B, Garotta G, Zurcher G, Miggiano V, Da Prada M (1990) Monoclonal antibodies recognizing both soluble and membrane bound catechol-O-methyltransferase. J Neural Transm Suppl 32: 369–374PubMedGoogle Scholar
  16. Bertocci B, Garotta G, Da Prada M, Lahm H-W, Zurcher G, Virgallita G, Miggiano V (1991a) Immunoaffinity purification and partial amino acid sequence analysis of catechol-O-methyltranferase from pig liver. Biochim Biophys Acta 1080: 103–109PubMedGoogle Scholar
  17. Bertocci B, Miggiano V, Da Prada M, Dembic Z, Lahm H-W, Malherbe P (1991b) Human catechol-O-methyltransferase: cloning and expression of the membraneassociated form. Proc Natl Acad Sci USA 88: 1416–1420PubMedGoogle Scholar
  18. Blaschko E, Hertting G (1971) Enzymatic methylation of L-ascorbic acid by catechol O-methyltransferase. Biochem Pharmacol 20: 1363–1370Google Scholar
  19. Borchardt RT, Cheng CF (1978) Purification and characterization of rat liver microsomal thiol methyltransferase. Biochim Biophys Acta 522: 340–353PubMedGoogle Scholar
  20. Borchardt RT, Thakker DR (1977) Evidence for sulfhydryl groups at the active site of catechol-O-methyltransferase. In: Usdin E, Weiner N, Youdim MBH (eds) Structure and function of monoamine enzymes. Dekker, New York, p 707Google Scholar
  21. Borchardt RT, Wu YS (1974) Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. I. Modification of the amino acid portion of S-adenosylhomocysteine. J Med Chem 17: 862–867Google Scholar
  22. Borehardt RT, Wu YS (1975) Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. III. Modifications of the sugar portion of S-adenosylhomocysteine. J Med Chem 18: 300–304Google Scholar
  23. Borehardt RT, Huber JA, Wu YS (1974) Potential inhibitors of S-adenosylmethionine-dependent methytransferases. II. Modification of the base portion of S-adenosylhomocysteine. J Med Chem 17: 868–873Google Scholar
  24. Borehardt RT, Huber JA, Wu YS (1976a) Potential inhibitors of S-adenosylmethionine dependent methyltransferases. IV. Futher modification of the amino acid and base portions of S-adenosylmethionine. J Med Chem 19: 1094–1099Google Scholar
  25. Borehardt RT, Wu YS, Huber JA, Wycpalek AF (1976b) Potential inhibitors of Sadenosylmethionine-dependent methyltransferases. V. The role of the asymmetric sulfonium pole in the enzymatic binding of S-adenosyl-L-methonine. J Med Chem 19: 1104–1110Google Scholar
  26. Borehardt RT, Wu YS, Wu BS (1978) Potential inhibitors of S-adenosylmethioninedependent methyltransferases. VII. Role of the ribosyl moiety in enzymatic binding of S-adenosyl-L-homocysteine and S-adenosyl-L-methionine. J Med Chem 21: 1307–1310Google Scholar
  27. Borehardt RT, Creveling CR, Ueland PM (eds) (1986) Biological methylation and drug design: experimental and clinical roles of S-adenosylmethionine. Humana, CliftonGoogle Scholar
  28. Borgulya J, Bruderer H, Bernauer K, Zurcher G, Da Prada M (1989) Catechol-0-methyltransferase-inhibiting pyrocatechol derivatives: synthesis and structureactivity studies. Helv Chim Acta 72: 952–968Google Scholar
  29. Boudikova B, Szumlanski C, Maidak B, Weinshilboum R (1990) Human liver catechol-0-methy transferase pharmacogenetics. Clin Pharmacol Ther 48: 381–389PubMedGoogle Scholar
  30. Brannan T, Martinez T, Yahr MD (1992) Catechol-0-methy transferase inhibition increases striatal L-dopa and dopamine: an in vivo study in rats. Neurology 42: 683–685PubMedGoogle Scholar
  31. Bremer J, Greenberg DM (1961a) Methyltransferring enzyme system of microsome in the biosynthesis of lecithin (phosphatidylcholine). Biochim Biophys Acta 46: 205–216Google Scholar
  32. Bremer J, Greenberg DM (1961b) Enzymic methylation of foreign compounds. Biochim Biophys Acta 46: 217–224Google Scholar
  33. Calne DB, Langstrom JE, Martin WRW, Stoessl AJ, Ruth TJ, Adam MJ, Pate BD, Schulzer M (1985) Positron emission tomography after MPTP, observations relating to the cause of Parkinson’s disease. Nature 317: 246–248PubMedGoogle Scholar
  34. Cantoni GL (1953) S-Adenosylmethionine; a new intermediate formed enzymatically from L-methionine and ATP. J Biol Chem 204: 403–416Google Scholar
  35. Cedarbaum J, Leger G, Reches A, Guttman M (1990) Effect of nitecapone (OR-462) on the pharmacokinetics of levodopa and 3-0-methyldopa formation in cynomolgus monkeys. Clin Neuropharmacol 13: 544–52PubMedGoogle Scholar
  36. Cedarbaum JM, Leger G, Guttman M (1991) Reduction of circulating 3-0-methyldopa by inhibition of catechol-0-methy transferase with OR-611 and OR-462 in Cynomolgus monkeys: implications for the treatment of Parkinson’s disease. Clin Neuropharmacol 14: 330–342PubMedGoogle Scholar
  37. Chakraborty C, Davis DL, Dey SK (1990) The O-methylation of catechol oestrogrens by pig conceptuses and endometrium during the peri-implantation period. J Endocrinol 127: 77–84PubMedGoogle Scholar
  38. Cornforth JW, Reichard SA, Talalay P, Correll HL, Glusker JP (1977) Determination of the absolute configuration at the sulfonium center of S-adenosylmethionine. Correlation with the absolute configuration of the diastereomeric Scarboxymethyl-(S)-methionine salts. J Am Chem Soc 99: 7292–7300PubMedGoogle Scholar
  39. Coward JK, Slisz EP (1973) Analogs of S-adenosylhomocysteine as potential inhibitors of biological transmethylation. Specificity of the S-adenosylhomocysteine binding site. J Med Chem 16: 460–463Google Scholar
  40. Coward JK, Sweet WD (1972) Analogs of S-adenosylhomocysteine as potential inhibitors of biological transmethylation. Synthesis and biological activity of homocysteine derivatives bridged to adenine. J Med Chem 15: 381–384Google Scholar
  41. Coward JK, D’Urso-Scott M, Sweet WD (1972) Inhibition of catechol-O-methyltransferase by S-adenosylhomocysteine and by S-adenosylhomocysteine sulfoxide, a potential transition-state analog. Biochem Pharmacol 21: 1200–1203PubMedGoogle Scholar
  42. Coward JK, Bussolloti DL, Cheng CD (1974) Analogs of S-adenosylhomocysteine as potential inhibitors of biological transmethylation: inhibition of several methylases by S-Tubercidinylhomocysteine. J Med Chem 17: 1286–1289PubMedGoogle Scholar
  43. Creveling CR (1993) Catechol-O-methyltransferase. In: Nagatsu T, Parvez SN, Parvez S (eds) Methods in neurotransmitter research. Elsevier, Amsterdam, pp 375–406Google Scholar
  44. Creveling CR, Hartman BK (1982) Relationships between the cellular localization and the physiological function of catechol-O-methyl transferase. In: Usdin E, Borchardt RT, Creveling CR (eds) Biochemistry of S-adenosylmethionine and related compounds. Macmillan, London, p 479Google Scholar
  45. Da Prada M (1990) Catechol-O-methyltransferase inhibitors: their role in the therapy of Parkinson’s disease. Eur J Pharmacol 183: 4–5Google Scholar
  46. Da Prada M (1991) New approaches to the treatment of age-related brain disorders. Can J Neurol Sei 18: 384–386Google Scholar
  47. De La Haba G, Jamieson GA, Mudd SH, Richards HH (1959) S-adenosylmethionine: the relation of configuration at the sulfonium center to enzymatic activity. J Am Chem Soc 81: 3975–3980Google Scholar
  48. Donohue SJ, Roseboom PH, Klein DC (1992) Bovine hydroxyindole O-methyltransferase: significant sequence revision. J Biol Chem 267: 5184–5185PubMedGoogle Scholar
  49. Drummer OH, Miach P, Jarrott B (1983) S-methylation of Captopril: demonstration of Captopril thiol methyltransferase activity in human eruthrocytes and enzyme distribution in rat tissues. Biochem Pharmacol 32: 1557–1562PubMedGoogle Scholar
  50. Eloranta TO (1977) Tissue distribution of S-adenosylmethionine and S-adenosylhomocysteine in the rat. Biochem J 166: 521–529PubMedGoogle Scholar
  51. Evered D, Clark C (eds) (1985) Photoperiodism, melatonin and the pineal. Ciba Found Symp 117Google Scholar
  52. Evinger MJ, Joh TH (1989) Strain-specific differences in transcription of the gene for the epinephrine-synthesizing enzyme phenylethanolamine N-methyl transferase. Mol Brain Res 5: 141–147PubMedGoogle Scholar
  53. Falany CN, Vazquez ME, Heroux JA, Roth JA (1990) Purification and characterization of human liver phenol-sulfating phenolsulfotransferase. Arch Biochem Biophys 278: 312–318PubMedGoogle Scholar
  54. Feldman JM, Reintgen DS, Seigier HF (1979) Monoamine oxidase and catechol O–methyltransferase activity in hamster and rat insulinomas. Diabetologia 17: 249–256PubMedGoogle Scholar
  55. Floss G, Woodward R (1982) Further stereochemical studies on methyl transfer reactions. In: Usdin E, Borchardt RT, Creveling CR (eds) Biochemistry of Sadenosylmethionine and related compounds. Macmillan, London, p 539Google Scholar
  56. Francis DM, Thomson MF, Greaves MW (1980) The kinetic properties and reaction mechanism of histamine methyltransferase from human skin. Biochem J 187: 819–828PubMedGoogle Scholar
  57. Friedgen B, Halbrugge T, Graefe K-H (1993) The part played by catechol-Omethyltransferase in the plasma kinetics of 3,4-dihydroxyphenylglycol and 3,4-dihydroxyphenylalanine in the anesthetized rabbit. Naunyn Schmiedebergs Arch Pharmacol 347: 155–161PubMedGoogle Scholar
  58. Fuller RW (1987) Norepinephrine N-me thy transferase from rabbit adrenal glands. Methods Enzymol 142: 655–660PubMedGoogle Scholar
  59. Fuller RW, Perry KW, Hemrick-Luecke SK (1983) Tropolone antagonism of the Ldopa-induced elevation of S-adenosylhomocysteine: S-adenosylmethionine ratio but not depletion of adrenaline in rat hypothalamus. J Pharm Pharmacol 36: 419–429Google Scholar
  60. Gitomer WL, Tipton KF (1986) Purification and kinetic properties of ox brain histamine iV-methy transferase. Biochem J 233: 669–676PubMedGoogle Scholar
  61. Goldstein DS, Grossman E, Tamrat M, Chang PC, Eisenhofer G, Bacher J, Kirk KL, Bacharach S, Kopin IJ (1991) Positron emission imaging of cardiac sympathetic innervation and function using 18F-6-fluorodopamine: effects of chemical sympathectomy by 6-hydroxydopamine. J Hypertens 9: 417–423PubMedGoogle Scholar
  62. Griffith OW, Anderson ME, Meister A (1979) Inhibition of glutathione biosynthesis by protamine sulfoxime ( S-n-propylhomocysteine sulfoxime), a selective inhibitor of y-glutamyleysteine synthetase. J Biol Chem 254: 1205–1210Google Scholar
  63. Grossman MH, Creveling CR, Rybcznski R, Braverman M, Isersky C, Breakfield XO (1985) Soluble and particulate forms of rat cetechol-O-methy transferase distinguished by gel electrophoresis and immune fixation. J Neurochem 44: 421–432PubMedGoogle Scholar
  64. Grossman MH, Creveling CR, Breakfield XO (1989) Isolation of the mRNA encoding rat liver catechol-O-methytransferase. Biochem Biophys Res Commun 158: 776–782PubMedGoogle Scholar
  65. Grossman MH, Emanuel BS, Budarf ML (1992a) Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.21 to q11.2. Genomics 12: 822–825Google Scholar
  66. Grossman MH, Szumlanski C, Littreil JB, Weinstein R, Weinshiboum RM (1992b) Electrophoretic analysis of low and high activity forms of catechol-O-methyltransferase in human erythrocytes. Life Sei 50: 473–480Google Scholar
  67. Grunewald GL, Grindel JM, Vincek WC, Borchardt RT (1975) Importance of aromatic ring in adrenergic amines. Nonaromatic analogues of phenethanolamine as substrates for phenethanolamine N-methytransferase. Mol Pharmacol 11: 694–699Google Scholar
  68. Guldberg HC, Marsden CA (1975) Catechol-O-methyltransferase: pharmacological aspects and physiological role. Pharmacol Rev 27: 135–206PubMedGoogle Scholar
  69. Halbrugge T, Friedgen B, Ludwig J, Graefe K-H (1993) Effects of catechol-Omethyltransferase inhibition on the plasma clearance of noradrenaline and the formation of 3,4-dihydroxyphenylglycol in the rabbit. Naunyn Schmiedebergs Arch Pharmacol (in press)Google Scholar
  70. Higazi MF, Borchardt RT, Schowen RL (1976) SN2-like transition state for methyltransfer catelyzed by catechol-O-methyltransferase. J Am Chem Soc 98: 3048 - 3049Google Scholar
  71. His W (1887) Über das Stoffwechselproduct des Pyridine. Arch Exp Pathol Pharmakol 22: 253–260Google Scholar
  72. Hoffman AR, Paul SM, Axelrod J (1979) Catecholestrogens: synthesis and metabolism by human breast tumors in vitro. Cancer Res 39: 4584–4587PubMedGoogle Scholar
  73. Hoffman JL (1979) Inhibition of S-adenosyl sulfur amino acid metabolism: periodateoxidized nucleosides as potent inhibitors of S-adenosylhomocysteine hydrolase. In: Usdin E, Borchardt RT, Creveling CR (eds) Transmethylation. Elsevier North Holland, New York, p 181Google Scholar
  74. Hoffman JL (1993) Xenobiotic activation by S-adenosylation and N- and S-methylation. In: Anders MV (ed) Conjugation-dependent bioactivation. University of Rochester Press, RochesterGoogle Scholar
  75. Horn AS, Dijkstra D, Mulder TBA, Rollema H, Westerink BHC (1981) Eur J Med Chem 16: 469–472Google Scholar
  76. Hough LB, Khandelwal JK, Mittag TW (1981) Alpha-methylhistamine methylation by histamine methytransferase. Agents Action 11: 425–428Google Scholar
  77. Inoue K, Creveling CR (1991) Induction of catechol-O-methyltransferase in the luminal epithelium of rat uterus by progesterone. J Histochem Cytochem 39: 823–828PubMedGoogle Scholar
  78. Ishida I, Obinata M, Deguchi T (1987) Molecular cloning and nucleotide sequence of cDNA encoding hydroxyindole O-methytransferase of bovine pineal glands. J Biol Chem 262: 2895–2899PubMedGoogle Scholar
  79. Jackson RL, Lovenberg W (1971) Isolation and characterization of multiple forms of hydroxyindole-O-methyltransferase. J Biol Chem 246: 4280–4285PubMedGoogle Scholar
  80. Jakoby WB, Stevens J, Duffel MW, Weisiger RA (1984) The terminal enzymes of mercapturate formation and the thiomethyl shunt. Rev Biochem Toxicol 6: 158–169Google Scholar
  81. Joh TH, Baetge EE, Ross ME, Feis DJ (1983) Evidence for the exsistence of homologous gene coding regions for the catecholamine biosynthetic enzymes. Cold Spring Harbor Symp Quant Biol 48: 327–335PubMedGoogle Scholar
  82. Joh TH, Baetge EE, Ross ME, Lai C-Y, Docherty M, Bradford H, Reis DJ (1985) Genes for neurotransmitter synthesis, storage and uptake. Fed Proc 44: 2723–2779Google Scholar
  83. Kaakkola S, Gordin A, Jarvinen M, Wikberg T, Schultz E, Nissinen E, Pentikainen PJ, Rita H (1990) Effect of a novel catechol-O-methyltransferase inhibitor, nitecapone, on the metabolism of L-DOPA in healthy volunteers. Clin Neuropharmacol 13: 436–447PubMedGoogle Scholar
  84. Kaneda N, Ichinose H, Kobayashi K, Oka K, Kishi F, Nakazawa Y, Fujita K, Nagatsu T (1988) Molecular cloning of cDNA and chromosomal assignment of the gene for human phenylethanolamine N-methytransferase, the enzyme for epinephrine biosynthesis. J Biol Chem 263: 7672–7677PubMedGoogle Scholar
  85. Karsch FJ, Woodfill CJI, Malpaus B, Robinson JE, Wayne NL (1991) Melatonin and mammalian photoperiodism; synchronization and annual reproductive cycles. In: Klein DC, Moore RY, Repert S (eds) Suprachiasmatic nucleus. The mind’s clock. Oxford University Press, New York, p 217Google Scholar
  86. Keith RA, Otterness DM, Kerremans AL, Weinshilboum RM (1985) S-methylation of D- and L-penicillamine by human erythrocyte membrane thiol methyltransferase. Drug Metab Dispos 13: 669–676PubMedGoogle Scholar
  87. Keller BT, Borchardt RT (1986) Metabolism and mechanism of action of nepanocin A - a potent inhibitor of S-adenosylhomocysteine hydrolase. In: Borchardt RT, Creveling CR, Ueland PM (eds) Biological methylation and drug design. Experimental and clinical roles of S-adenosylmethionine. Humana, New York, p 385Google Scholar
  88. Kerremans AL, Lipsky JJ, van Loon J, Gallego MO, Weishilboum RM (1985) Cephalosporin–induced hypothrombinemia: possible role for thiol methylation of l-methyltetrazole-5-thiol and 2-methyl-l,2,3-thiadiazole-5-thiol. J Pharmacol Exp Ther 235: 382–388PubMedGoogle Scholar
  89. Klein DC, Roseboom PH, Donohue SJ, Marrs BL (1992) Evolution of melatonin as a night signal: contribution from a primitive photosynthetic organism. Mol Cell Neurosci 3: 181–183PubMedGoogle Scholar
  90. Korkolainen T, Nissinen E (1989) Purification of rat liver soluble catechol-O-methyltransferase by high performance liquid chromatography. Biomed Chromatogr 3: 127–130PubMedGoogle Scholar
  91. Kredich NM, Hershfield MS (1980) Perturbations in S-adenosylhomocysteine and Sadenosylmethionine metabolism. Adv Enzyme Regul 18: 181–191PubMedGoogle Scholar
  92. Kuwano R, Takahashi Y (1980) S-adenosylhomocysteine is bound to pineal hydroxyindole O-methytransferase. Life Sci 27: 1321–1326PubMedGoogle Scholar
  93. Kuwano R, Takahashi Y (1984) Binding of S-adenosylhomocysteine to hydroxyindole 0-methyltransferase. Biochim Biophys Acta 787: 1–7PubMedGoogle Scholar
  94. Kuwano R, Yoshida Y, Takahashi Y (1978) Purification of bovine pineal hydroxylindole-O-methytransferase by immunoadsorption chromatography. J Neurochem 31: 815–824PubMedGoogle Scholar
  95. Lennard L, van Loon JA, Lilleyman JS, Weinshilboum RM (1987) Thiopurine pharmacogenetics in leukemia: correlation of erythocyte thiopurine methytransferase activity and 6-thioguanine nucleotide concentrations. Clin Pharmacol 41: 18–25Google Scholar
  96. Li SA, Purdy RH, Li J J (1989) Variation in catechol O-methy transferase activity in rodent tissues: possible role in estrogen carcinogenicity. Carcinogenesis 10: 63–67PubMedGoogle Scholar
  97. Linden I-B, Nissinen E, Etemadzadeh E, Kaakola S, Mannisto R, Pohto P (1988) Favorable effects of catechol-O-methyltransferase inhibition by OR-462 in experimental models of Parkinson’s disease. J Pharmacol Exp Ther 247: 289–293PubMedGoogle Scholar
  98. Longcope C (1983) Assay and metabolism of catechol estrogens. In: Merriam GR, Lipsett MB (eds) Catechol estrogens. Raven, New York, p 144Google Scholar
  99. Lotta T, Takinen J, Backstrom R, Nissinen E (1992) PLS modelling of structureactivity relationships of catechol-O-methyltranferase inhibitors. J Comput Aided Mol Des 6: 253–257PubMedGoogle Scholar
  100. Lundstrom K, Salminen M, Jalanko A, Savolainen R, Ulmanen I (1991) Cloning and characterization of hyman placental catechol-O-methyltransferase cDNA. DNA Cell Biol 10: 181–189PubMedGoogle Scholar
  101. Lundstrom K, Tilgmann C, Peranen J, Kalkkinen N, Ulmanen I (1992) Expression of enzymatically active rat liver and human placental catechol-O-methyltransferase in Escherichia coli; purification and partial characterization of the enzyme. Biochim Biophys Acta 1129: 149–154PubMedGoogle Scholar
  102. Luwano R, Takahashi Y (1984) Binding of S-adenosylhomocysteine to hydroxyindole O-methytransferase. Biochim Biophys Acta 787: 1–7Google Scholar
  103. Maj J, Rogoz Z, Sowinska H, Superata J (1992) Behavioural and neurochemical effects of R0 40-7592, a new COMT inhibitor with a potential therapeutic activity in Parkinson’s disease, J Neural Transm Park Dis Dement Sect 2: 101–112Google Scholar
  104. Mannisto PT, Kaakkola S (1990) Rationale for selective COMT inhibitors as adjuncts in the drug treatment of Parkinson’s disease. Pharmacol Toxicol 66: 317–323PubMedGoogle Scholar
  105. Mannisto PT, Kaakkola S, Nissinen E, Linden I-B, Pohto P (1988) Properties of novel effective and highly selective inhibitors of catechol-O-methyltransferase. Life Sci 43: 1465–1471PubMedGoogle Scholar
  106. Mannisto PT, Tuomainen P, Tuomainen RK (1992) Different in vivo properties of three new inhibitors of catechol-O-methyltransferase in the rat. Br J Pharmacol 105: 569–574PubMedGoogle Scholar
  107. Mezey E (1989) Cloning of the rat medullary phenylethanolamine iV-methytransferase. Nucleic Acids Res 17: 2125PubMedGoogle Scholar
  108. Morris ND, McNeal ET, Creveling CR (1973) On the role of sulfhydryl groups in the active site of catechol-O-methyltransferase (Abst F19). ACS Middle Atlantic Regional Meeting, Jan 14-17, WashingtonGoogle Scholar
  109. Mozier NM, McConnell KP, Hoffman JL (1988) S-adenosyl-L-methionine:thioether S-methytransferase, a new enzyme in sulfur and selenium metabolism. J Biol Chem 263: 4527–4531PubMedGoogle Scholar
  110. Mulder GJ, Krijgsheld KR (1984) In: Roe DA, Campbell TC (eds) Drugs and nutrients. Dekker, New York, p 119Google Scholar
  111. Nic a’Bhaird N, Goldberg R, Tipton KF (1990) Catechol-O-methyltransferase and its role in catecholamine metabolism. Adv Neurol 53: 489Google Scholar
  112. Nikodejevic B, Senoh S, Daly JW, Creveling CR (1970) Cateehol-O-methyltransferase II: a new class of inhibitors of catechol-O-methyltransferase; 3,5-dihydroxy-4-methylbenzoic acid and related compounds. J Pharmacol Exp Ther 174: 83–93PubMedGoogle Scholar
  113. Nissinen E (1984) The site of O-methylation by membrane-bound catechol-Omethyltransferase. Biochem Pharmacol 33: 3105–3108PubMedGoogle Scholar
  114. Nissinen E, Linden I-B, Schultz E, Kaakkola S (1988a) Catechol-O-methyltransferase activity in human and rat small intestine. Life Sci 42: 2609–2614PubMedGoogle Scholar
  115. Nissinen E, Linden I-B, Schultz E, Kaakkola S, Mannisto PT, Pohto P (1988b) Inhibition of catechol-O-methyltransferase by two novel disubstituted catechols in the rat. Eur J Pharmacol 153: 263–269PubMedGoogle Scholar
  116. Norin NAB, Tipton KF (1991) Catechol-O-methyltransferase from human placenta: purification and some properties. Biochem Soc Trans 19: 20SGoogle Scholar
  117. Nosenko ND (1990) Neuroendocrine effects of neonatal action of catechol-Omethyltransferase and sex steroids inhibitor. Neurosci Behav Physiol 20: 462–465PubMedGoogle Scholar
  118. Ozawa S, Nagata K, Gong D, Yamazoe Y, Kato R (1990) Nucleotide sequence of a full-length cDNA (PST-1) for aryl sulfotransferase from rat liver. Nucleic Acids Res 18: 4001PubMedGoogle Scholar
  119. Piedrafita FJ, Elorriaga C, Fernadez-Alvarez E, Nieto O (1990) Inhibition of catechol-O-methyltransferase by iV-(3,4-dihyroxyphenyl)maleimide. J Enzym Inhib 4: 43–50PubMedGoogle Scholar
  120. Rafferty MF, Grunewald GL (1982) The remarkable substrate activity for phenethanolamine iV-methyltransferase of some configurationally defined phenethylamines lacking a side chain hydroxy 1 group: conformationally defined adrenergic agents 6. Mol Pharmacol 22: 127–132PubMedGoogle Scholar
  121. Remy CN (1963) Metabolism of thiopyrimidines and thiopurines. J Biol Chem 238: 1078–1084PubMedGoogle Scholar
  122. Roth J A (1992) Membrane-bound catechol-O-methyltransferase: a reevaluation of its role in the O-methylation of the catecholamine neurotransmitters. Rev Physiol Biochem Pharmacol 120: 2–29Google Scholar
  123. Roth JA, Grossman MH, Adolf M (1990) Variation in hepatic membrane-bound catechol-O-methyltransferase activity in Fischer and Wistar-Furth strain of rat. Biochem Pharmacol 40: 1151–1153PubMedGoogle Scholar
  124. Roy D, Weisz J, Liehr JG (1990) The O-methylation of 4-hydroxyestradiol is inhibited by 2-hydroxyestradiol: implications for estrogen-induced carcinogenesis. Carcinogenesis 11: 459–462PubMedGoogle Scholar
  125. Salminen M, Lundstrom K, Tilgmann C, Savolainen R, Kalkkinen N, Ulmanen I (1990) Molecular cloning and characterization of rat liver catechol-O-methyltransferase. Gene 93: 241–247PubMedGoogle Scholar
  126. Sasaoka T, Kanada N, Kurosawa Y, Fujita K, Nagatsu T (1989) Structure of human phenylethanolamine N-methyltransferase gene: existence of two types of mRNA with different transcription initiation site. Neurochem Int 15: 555–565PubMedGoogle Scholar
  127. Satake N, Morton B (1979) Pineal hydroxyindol O-methyltransferase: mechanism, and inhibition by scotophobin A. Pharmacol Biochem Behav 10: 457–462PubMedGoogle Scholar
  128. Schultz E (1991) Catechol-O-methyltransferase and aromatic L-amino acid decarboxylase activies in human gastrointesinal tissues. Life Sci 49: 721–725PubMedGoogle Scholar
  129. Schultz E, Tapila S, Bachstrom A-C, Gordin A, Nissinen E, Pohto P (1991) Inhibition of human erythrocyte and gastroduodenal catechol-O-methyltransferase activity by niteeapone. Eur J Clin Pharmacol 40: 577–580PubMedGoogle Scholar
  130. Shinagawa Y (1992) Molecular orbital studies on the structure-activity relationships of catechol O-methyltransferase inhibitors. Jpn J Pharmacol 58: 95–106PubMedGoogle Scholar
  131. Shull KH, McConomy J, Vogt M, Castillo A, Farber E (1966) On the mechanism of induction of hepatic adenosine triphosphate deficiency by ethionine. J Biol Chem 241: 5060 - 5070PubMedGoogle Scholar
  132. Steel RD, Benevenga NJ (1979) The metabolism of 3-methylthiopropionate in rat liver homogenates. J Biol Chem 254: 8885–8890Google Scholar
  133. Stevens JL, Bakke JE (1990) S-methylation. In: Mulder GJ (ed) Conjugation reactions in drug metabolism. Taylor and Francis, London, p 251Google Scholar
  134. Sugden D, Cena V, Klein DC (1987) Hydroxyindole O-methyltransferase. Methods Enzymol 142: 590–596PubMedGoogle Scholar
  135. Takemura M, Tanaka T, Taguchi Y, Imamura I, Mizuguchi H, Kuroda M, Fukui H, Yamatodani A, Wada H (1992) Histamine N-methyltransferase from rat kidney: cloning, nucleotide sequence, and expression in E. coli cells. J Biol Chem 267: 15687–15691Google Scholar
  136. Taskinen J, Vidgren J, Ovaska M, Backstrom R, Pippuri A, Nissinen E (1989) QSAR and binding model for inhibition of rat liver catechol-O-methyltransferase by l,5-substituted-3,4-dihydroxybenzenes. Quant Struct Act Relat 8: 210–213Google Scholar
  137. Taskinen J, Wikberg T, Ottoila P, Kanner L, Lotta T, Pippuri A, Backstrom R (1991) Identification of major metabolites of the catechol-O-methyltransferaseinhibitor niteeapone in human urine. Drug Metab Dispos 19: 178–183PubMedGoogle Scholar
  138. Thakker DR, Creveling CR (1990) O-Methylation. In: Mulder GJ (ed) Conjugation reactions in drug metabolism. Taylor and Francis, London, p 193Google Scholar
  139. Thakker DR, Boehlert C, Kirk KL, Antkowiak R, Creveling CR (1986) Regioselectivity of catechol-0-methytransferase. J Biol Chem 261: 178–184PubMedGoogle Scholar
  140. Thithapandha A, Cohn VH (1978) Brain histimine N-methytransferase purification, mechanism of action, and inhibition by drugs. Biochem Pharmacol 27: 263–271PubMedGoogle Scholar
  141. Tilgmann C, Kalkkinen N (1991) Purification and partial sequence analysis of the soluble catechol-0-methy transferase from human placenta: comparison to the rat liver enzyme. Biochem Biophys Res Commun 174: 995–1002PubMedGoogle Scholar
  142. Tilgmann C, Melen K, Lundstrom K, Jalanko A, Julkunen I, Kalkkinen N, Ulmanen I (1992) Expression of recombinant soluble and membrane-bound catechol Omethyltranferase in eukaryotic cells and identification of the respective enzymes in rat brain. Eur J Biochem 207: 813–821PubMedGoogle Scholar
  143. Timm U, Erdin R (1992) Determination of the catechol-0-methy transferase inhibitor Ro 40-7592 in human plasma by high performance liquid chromatography with eoulometric detection. J Chromatogr 593: 63–68PubMedGoogle Scholar
  144. Tisdale MJ (1980) The effect of the methionine antagonist L-2-amino-4-methoxytrans-3-butenoic acid on the growth and metabolism of Walker carcinoma in vitro. Biochem Pharmacol 29: 501–508PubMedGoogle Scholar
  145. Tornwall M, Mannisto PT (1991) Acute toxicity of three new selective COMT inhibitors in mice with special emphasis on interactions with drugs increasing catecholaminergic neurotransmission. Pharmacol Toxicol 69: 64–70PubMedGoogle Scholar
  146. Tsukuda K, Yamano S, Abe T, Okada G (1980) Ethionine–induced changes in the activities of S-adenosylmethionine synthetase isozymes form rat liver. Biochem Biophys Res Commun 95: 1160–1167Google Scholar
  147. Ulmanen I, Lundstrom K (1991) Cell-free synthesis of rat and human catechol 0-methytransferase; insertion of the membrane-bound from into microsomal membranes in vitro. Eur J Biochem 202: 1013–1020PubMedGoogle Scholar
  148. Usdin E, Borchardt RT, Creveling CR (eds) (1982) Biochemistry of S-adenosylmethionine and related compounds. Macmillan, LondonGoogle Scholar
  149. Veser J, May W (1986) A rapid purification procedure for S-adenosyl-L-methionine: catechol-0-methytransferase by high-performance ion exchange chromatography and subsequent affinity chromatography. Chromatographia 22: 7–12Google Scholar
  150. Vidgren J, Tilgmann C, Lunstrom K, Lijas A (1991) Crystallization and preliminary X-ray investigation of a recombinant form of rat catechol 0-methy transferase. Proteins Struct Funct Genet 11: 233–236PubMedGoogle Scholar
  151. Villa-Trevino S, Shull KH, Farber E (1966) The inhibition of liver ribonucleic acid synthesis by ethionine. J Biol Chem 241: 4670–4676PubMedGoogle Scholar
  152. Voisin P, Guerlotte J, Bernard M, Collin JP, Cogne M (1992) Molecular cloning and nucleotide sequence of a cDNA encoding hyroxyindole-0-methy transferase from chicken pineal gland. Biochem J 282: 571–576PubMedGoogle Scholar
  153. Wada H, Watanabe T, Yamatodani A, Maeyama K, Itoi N, Cacabelos R, Seo M, Kiyono S, Nagai K, Nagagawa H (1985) Physiological function of histamine in the brain. Adv Biosci 51: 225Google Scholar
  154. Wade L, Katzman R (1975) 3-0-Methyldopa inhibition of L-dopa at the blood-brain barrier. Life Sci 17:131–136Google Scholar
  155. Waldmeier PC, Baumann PA, Feldtrauer J-J, Hauser K, Bittiger H, Bischoff S, von Sprecher G (1990) CGP 28014, a new inhibitor of catechol-0-methylation with a non-catechol structure. Naunyn Schmiedebergs Arch Pharmacol 342: 305–311PubMedGoogle Scholar
  156. Warner DR (1992) Cloning and active site labelling of thioether me thy transferase. PhD dissertation, University of LouisvilleGoogle Scholar
  157. Watanabe R, Taguche Y, Shiosaka S, Tanaka J, Kubota H, Terano Y, Tohyama M, Wada H (1984) Distribution of the histaminergic neuron system in the central nervous system of rats: a fluorescent immunohistochemical analysis with histidine decarboxylase as a marker. Brain Res 295: 13–25PubMedGoogle Scholar
  158. Weinshilboum R (1986) Sulfate conjugation of neurotransmitters and drugs. Fed Proc 45: 2220–2222PubMedGoogle Scholar
  159. Weinshilboum R (1988a) Phenol sulfotransferase inheritance. Cell Mol Neurobiol 8: 27–34PubMedGoogle Scholar
  160. Weinshilboum R (1988b) Pharmacogenetics of methylation: relationship to drug metabolism. Clin Biochem 21: 201–210PubMedGoogle Scholar
  161. Weinshilboum R (1989) Methyltransferase pharmacogenetics. Pharmacol Ther 43: 77–90PubMedGoogle Scholar
  162. Weinshilboum R (1991) In: Damani LA (ed) Sulfur drugs and related organic chemicals: chemistry, biochemistry, and toxicology. Horwood, ChichesterGoogle Scholar
  163. Weisiger RA, Jakoby WB (1979) Thiol S-methyltransferase from rat liver. Arch Biochem Biophys 196: 631–637PubMedGoogle Scholar
  164. Weisiger RA, Jakoby WB (1980) S-Methylation: thiol S-methy transferases. In: Jakoby WB (ed) Enzymatic basis of detoxification, vol 2. Academic, New York, p 131Google Scholar
  165. Windquist R, Lundstrom K, Salminen M, Laatikainen M, Ulmanen I (1992) The human catechol-0-methyltransferase (COMT) gene maps to band qll.2 of chromosome 22 and shows a frequest RFLP with Bg/I. Cytogenet Cell Genet 59: 253–257Google Scholar
  166. Woodward RW, Tsai MD, Floss HG, Gooks PA, Coward JK (1980) Stereochemical course of the transmethylation catalyzed by catechol-0-methyltransferase. J Biol Chem 255: 9124–9127Google Scholar
  167. Youde IR, Raxworthy MJ, Gulliver PA, Dijkstra D, Horn AS (1984) The metabolism of dopamine, 7V,iV-dialkylated dopamines and derivatives of dopamine agonist 2-amino-dihydroxy-l,2,3,4-tetrahydronaphthaliene (ADTN) by catechol 0-methy transferase. J Pharm Pharmacol 36: 309–313PubMedGoogle Scholar
  168. Zapia V, Zydeck-Cwich CR, Schlenk F (1969) The specificiy of S-adenosylmethionine derivatives in methyltransfer reactions. J Biol Chem 214: 4499–1509Google Scholar
  169. Ziegler DM (1985) Molecular basis for N-oxygenation of sec- and tert-amines. In: Gorrod J, Damani LA (eds) Biological oxidation of nitrogen in organic molecules. Horwood, Chichester, p 43Google Scholar
  170. Ziegler DM, Ansher SS, Nagata T, Kadluber FF, Jakoby WB (1988) TV-Methylation: potential mechanism for metabolic activation of carcinogenic primary arylamines. Proc Natl Acad Sci USA 85: 2514–2517PubMedGoogle Scholar
  171. Zimmerman TP, Wolberg G, Duncan GS, Elion GB (1980) Adenosine analogues as substrates and inhibitors of S-adenosylhomocysteine hydrolase in intact lymphocytes. Biochemistry 19: 2252–2259PubMedGoogle Scholar
  172. Zurcher G, Colzi A, Da Prada M (1990) Ro 40-7592: inhibition of COMT in rat brain and extracerebral tissues. J Neural Transm Suppl 32: 375–380PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1994

Authors and Affiliations

  • C. R. Creveling
  • D. R. Thakker

There are no affiliations available

Personalised recommendations