Interaction of organophosphorus analogues of amino acids with P450

Abstract

1. This study deals with the oxidation of organophosphorus amino acid analogues by phenobarbital-induced rabbit liver microsomes. It has been shown that 1-aminoalkylphosphonous and 1-aminoalkylthiophosphonic acids are converted by P450 to 1-aminoalkylphosphonous acids.

2. Phosphonous analogues of amino acids cause type I spectral changes, and thiophosphonic analogues produce reverse type I changes in difference spectra.

3. In the presence of NADPH, the 1-aminoalkylphosphonous acids from the corresponding 1-aminoalkylphosphonic acids by the reaction P-H←P-OH, as monitored using ¹H nmr spectroscopy.

4. Aminoalkylthiophosphonic acids have also proven to be the substrates for the NADPH-dependent monoxygenase system. During the course of oxidative desulphuration 1-aminoalkylphosphonic acids were formed by the reaction P=S←P=O, as monitored by ³¹P-nmr spectroscopy.

5. Using resonance Raman (RR) spectroscopy, the interaction of 1-aminoisobutyl-phosphonous acid with P450 was investigated, and characteristic changes in spectral frequencies in the region between 1370 and 1700cm⁻¹ were demonstrated. These latter changes indicate that substrate binding of organophosphorus compounds leads to alterations in haem conformation and to redistribution of the electron density.