Coenzyme--substrate adducts as inhibitors of mouse liver 3,4-dihydroxyphenylalanine decarboxylase

J Med Chem. 1979 Mar;22(3):233-7. doi: 10.1021/jm00189a003.

Abstract

N-(5'-Phosphopyridoxyl) derivatives of several aromatic amino acids have been prepared by conventional methods and tested as inhibitors of mouse liver L-3,4-dihydroxyphenylalanine (Dopa) decarboxylase (EC 4.1.1.26; L-aromatic-amino-acid decarboxylase). The L-tyrosine, L-phenylalanine, and DL-2-hydroxyphenylalanine derivatives were effective inhibitors at concentrations of 10(-5) M. Because of the spontaneous formation of a tetrahydroisoquinoline cyclic condensation product with pyridoxal phosphate (Pictet--Spengler reaction), the Dopa derivative could not be prepared by the usual procedures. The synthesis of the desired N-(5'-phosphopyridoxyl)-Dopa was accomplished using selective blocking--deblocking methods; its properties are described. This proved to be the most effective inhibitor of those tested. Neither the tetrahydroisoquinoline of L-Dopa and pyridoxal phosphate nor the N-(5'-deoxypyridoxyl)-Dopa was an effective inhibitor of Dopa decarboxylase. These coenzyme amino acid adducts are suggested to act as stage inhibitors of the enzyme.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acids / pharmacology
  • Animals
  • Aromatic Amino Acid Decarboxylase Inhibitors*
  • Dihydroxyphenylalanine / analogs & derivatives*
  • Dihydroxyphenylalanine / chemical synthesis
  • Dihydroxyphenylalanine / pharmacology
  • In Vitro Techniques
  • Kinetics
  • Liver / enzymology*
  • Mice

Substances

  • Amino Acids
  • Aromatic Amino Acid Decarboxylase Inhibitors
  • Dihydroxyphenylalanine