Elsevier

Biochemical Pharmacology

Volume 31, Issue 3, 1 February 1982, Pages 433-437
Biochemical Pharmacology

Substrate stereospecificity and selectivity of catechol-O-methyltransferase for DOPA, DOPA derivatives and α-substituted catecholamines

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Abstract

The substrate specificity of highly purified pig liver catechol-O-methyltransferase has been investigated kinetically. This enzyme shows stereospecificity towards the naturally occurring l-isomer of 3,4-dihydroxyphenylalanine (DOPA) which has a higher affinity and maximal velocity as a substrate than the d-form. We have confirmed the implication of the in vivo study of Ito et al. [1], that methylation of 5-S-l-cysteinyl-l-DOPA is catalysed extremely slowly by catechol-O-methyltransferase, despite the comparatively high affinity of the enzyme for the substrate. Salbutamol is not a substrate for the enzyme and dl-threo-3,4-dihydroxyphenylserine (DOPS) is such a poor substrate that accurate kinetic analysis proved impossible. Alpha-substitution of DOPA, noradrenaline and isoprenaline causes a decrease in the affinity of catechol-O-methyltransferase for these compounds. However, the ‘suicide’ inhibitors of aromatic-l-amino acid decarboxylase (DOPA decarboxylase), fluoro- and difluoro-α-methyl DOPA are more superior catechol-O-methyltransferase substrates than α-methyl DOPA, presumably because the electron-withdrawing effect of the presence of fluorine in their structure overcomes the steric influence of the α-methyl group. A DOPA decarboxylase inhibitor in clinical use, benserazide, is, however, a much superior catechol-O-methyltransferase substrate and may have the therapeutic advantage of decreasing methylation of l-DOPA [2]. α-Methyl dopamine has a lower Km and higher Vmax than the parent compound.

References (32)

  • R.M. Hagan et al.

    Biochem. Pharmac.

    (1980)
  • G.M. McKenzie et al.

    Biochem. Pharmac.

    (1973)
  • W.F. Herblin

    Analyt. Biochem.

    (1973)
  • M. Alberici et al.

    Life Sci.

    (1965)
  • J. Axelrod et al.

    J. biol. Chem.

    (1958)
  • C.-M. Lo et al.

    Neuropharmacology

    (1976)
  • P.A. Gulliver et al.

    Biochem. Pharmac.

    (1978)
  • T.K. Sharpless et al.
  • J.K. Coward et al.

    Analyt. Biochem.

    (1973)
  • A.G. Gornall et al.

    J. biol. Chem.

    (1949)
  • W. Mejbaum-Katzenellenbogen et al.

    Clin. Chem. Acta

    (1959)
  • S. Ito et al.

    Biochem. Pharmac.

    (1980)
  • J. Pellerin et al.

    Can. J. Biochem. Physiol.

    (1958)
  • C.R. Creveling et al.

    Molec. Pharmac.

    (1970)
  • P. Bade et al.

    Naunyn-Schmiedeberg's Arch. Pharmac.

    (1974)
  • D.F. Sharman

    Br. Med. Bull.

    (1973)
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    Present address: Toxicology Unit, School of Pharmacy, University of London, 29/39 Brunswick Square, London, U.K.

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