Physiological Roles of Nicotinamide Nucleotide Transhydrogenases

As pointed out by Krebs and Veech 175), the relationship between the redox states of NAD and NADP in mammalian cells would be governed to a large extent by the substrate levels of NAD- and NADP-dependent dehydrogenases, interlinked by shared reactants. The coordination of these systems of interlinked dehydrogenases and, in particular, energy-linked transhydrogenase has been a matter of controversy. Funda- 

Krebs and R. L. Veech, in The Energy Level and Metabolic Control in Mitochondria (S. Papa et al., eds.), p. 329. Adriatica Editice, Bari, 1969. 

The majority of synthetic reactions in mammalian cells takes place in the cytosol. The intramitochondrial localization of transhydrogenase excludes a direct participation in these anabolic processes. Substrate shuttle mechanisms 176, 177) are required to allow for the interaction between intra- and extramitochondrial nicotinamide nucleotide-dependent reactions. In the first instance transhydrogenase can be regarded to be functionally related to intramitochondrial NADP-linked reactions. A number of studies on isolated mitochondria have elaborated these relationships in some detail, in particular with regard to mitochondrial monooxygenation reactions and to the metabolism of glutamate and isocitrate. 

Whereas these studies primarily emphasize the role of energy-linked transhydrogenase in the supply of reducing equivalents at the expense of energy, other authors 146, 155) regard the enzyme as a component of a fourth coupling site of the respiratory chain, which, when catalyzing the reduction of NAD+ by NADPH, may drive ion translocations 147, 157) and ATP synthesis 119), 

in Fimctionelle und morphologische Organization der Zelle, p. 137. Springer-Verlag, Berlin and New York, 1963. 

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