Inhibition of Glutamic Dehydrogenase by N1-Alkylnicotinamide Chlorides

Abstract

Abstract Eleven N1-alkylnicotinamide chlorides, varying in the size of the alkyl substituent from the N1-methyl to the N1-dodecyl derivative, were studied as possible inhibitors of catalytic activities associated with crystalline bovine liver glutamic dehydrogenase. The longer chain derivatives (C8 to C12, inclusive) inhibited glutamic dehydrogenase activity with a concomitant stimulation of alanine dehydrogenase activity. This inhibition was demonstrated to be noncompetitive with respect to nicotinamide adenine dinucleotide when studied in a low NAD+ concentration range and was greatly facilitated by the presence of NADH. These longer chain derivatives were also shown to reverse the adenosine diphosphate activation of glutamic dehydrogenase activity. A chain length effect was observed in the inhibition of glutamic dehydrogenase by these compounds, indicating the importance of hydrophobic interactions in their functioning, which was suggested to occur through the stabilization of the monomeric form of the enzyme having alanine dehydrogenase activity. Shorter chain N1-alkylnicotinamide chlorides (N1-hexyl or smaller) were shown to stimulate glutamic dehydrogenase activity with a concomitant inhibition of alanine dehydrogenase activity. No chain length effect was observed in the functioning of these shorter chain derivatives.