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

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.