Reduced nicotinamide-adenine dinucleotide as a rate-limiting factor in gluconeogenesis

Abstract

The reason why oxaloacetate or pyruvate when added as substrates to liver and kidney preparations are less effective as gluconeogenic precursors than malate or lactate (although they are intermediates in the glucose formation from the latter two substances respectively) was investigated. Determinations of the concentrations of nicotinamide adenine dinucleotide, reduced nicotinamide adenine dinucleotide (NADH2), nicotinamide adenine dinucleotide phosphate, and reduced nicotinamide adenine dinucleotide phosphate in liver and kidney preparations show that oxaloacetate or pyruvate can cause a major fall in the concentration of NADH2 and that this fall is accompanied by af ormation of malate and lactate respectively. As NADH2 is required in gluconeogenesis to reduce diphosphoglycerate to glyceraldehyde phosphate, the inhibition of gluconeogenesis by the [alpha]-oxo acids can be explained by their competition for NADH2. Though NADH2 can limit the rate of gluconeogenesis under well-defined experimental conditions, there is no evidence that it can do so in vivo. The inhibition of gluconeogenesis by other [alpha]-oxo acids (e.g. [gamma]-methylthio-[alpha]-oxobutyrate) is not accompanied by changes in the concentration of NADH2.