Copper-Pteridine Chemistry. Structures, Properties, and Phenylalanine Hydroxylase Models

Abstract

Pterins are derivatives of 2-amino-4-hydroxypteridine and are widely distributed in nature.¹ They were originally isolated from the pigments of butterfly wings, ^1,2 and today a number of derivatives are known as cofactors for enzymes involved in the synthesis of neurotransmitters, amino acids, and nucleic bases (Figure 1). The tetrahydro form of folic acid, which is a pterin derivative having an aminobenzoylglutamate group attached to the pterin’s 6-methyl group (1), is involved in C₁ unit transfer in the biosynthesis and metabolism of nucleic bases and some amino acids.³ Biopterin (2) in its tetrahydro form is the cofactor for aromatic amino acid hydroxylases, phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase.⁴ Phenylalanine hydroxylase (PAH), which is the most studied of the three, converts phenylalanine to tyrosine by incorporating the oxygen atom from dioxygen into the benzene ring, which is the first step toward the synthesis of dopamine, epinephrine, etc. and the metabolism of phenylalanine. Deficiency of PAH and also of biopterin results in hyperphenyl-alaninemia and phenylketonurea,^4–6 because the oxidative degradation of phenylalanine by PAH through tyrosine is blocked. Oxomolybdenum enzymes such as xanthine oxidase require a cofactor called molybdopterin,⁷ whose structure has been concluded to be 3 having two vicinal thiol groups most probably as molybdenum binding sites.⁸ Direct molybdenum-pterin interactions have been shown for a Mo(VI)-xanthopterin complex by X-ray structural analysis.⁹