Aldehyde Inhibitors of Aldehyde Dehydrogenases

Abstract

Aldehyde dehydrogenases catalyze aldehyde dehydrogenation as well as ester hydrolysis. Nitrate esters e.g. isosorbide nitrates and nitroglycerin inhibit the enzyme. Mechanism of inhibition which involves aldehyde dehydrogenase catalyzed formation of a reactive species (Mukerjee and Pietruszko, 1994), which inactivates the enzyme via covalent bond formation, was previously discussed (Pietruszko et al., 1995) in this series. In addition, aldehyde dehydrogenases share a common property of being inhibited by aldehyde inhibitors such as chloral, citral, methylglyoxal and 4-dia1ky1amino benzaldehyde, whose structure resembles that of aldehyde substrates (Figure I). It was interesting, therefore, to investigate how these compounds inhibit the enzyme. Methylglyoxal is a natural metabolite which is formed enzymatically and non-enzymatically from triose phosphates and from acetone by cytochrome P-450; it also arises from metabolism of threonine. Because of its chemical reactivity toward proteins and nucleic acids, methylglyoxal is considered to be a toxic compound (Kalapos, 1994; Chaplen et al., 1998); modification of proteins and nucleic acids by methylglyoxal has been postulated to be a possible cause of development of diabetic complications (Vander Jagt et al., 1992). Methylglyoxal is metabolized by glyoxalase which catalyzes the conversion of methyl glyoxal to D-Iactate in the presence of reduced glutathione. Aldose reductase and aldehyde reductase catalyze reduction of methylglyoxal to acetol and D-Iactaldehyde. Another metabolic route for methylglyoxal is its oxidation to pyruvate by α-ketoaldehyde dehydrogenase (Monder, 1967). The structure of methylglyoxal is shown in Figure 1.