Oxidoreductases constitute a very large class of enzymes. They are dehydrogenases and reductases that catalyze the removal or addition of the elements of molecular hydrogen to or from substrates. Enzymatic dehydrogenation is sometimes linked to auxiliary functions such as decarboxylation, deamination, or dehydration of the substrate, as in the actions of isocitrate dehydrogenase (decarboxylation), glutamate dehydrogenase (deamination), and ribonucleotide reductase (deoxygenation). The best known oxidoreductases are the NAD-dependent dehydrogenases, and a thorough discussion of the actions of these enzymes could easily fill a volume the size of this book. For this reason, this discussion must focus on the salient aspects of reaction mechanisms that represent the major classes of oxidoreductases. Authoritative reviews on the kinetics and structures of the main dehydrogenases are available (Banaszak et al., 1975; Branden et al., 1975; Dalziel, 1975; Harris and Waters, 1976; Holbrook et al., 1975; Rossman et al., 1975; Smith et al., 1975; Williams, 1976). In this chapter, we emphasize the diverse oxidoreduction mechanisms and place less emphasis on auxiliary functions such as decarboxylation, the mechanisms of which are similar to the actions of enzymes discussed in earlier chapters of this book.
Discussions of several dehydrogenases not included in this chapter can be found in other chapters. These include methanol, glucose, and methylamine dehydrogenases in chapter 3, dimethylsulfoxide reductase in chapter 4, and dihydrofolate reductase and P-hydroxymethylglutaryl CoA reductase in chapter 5. Pyruvate and a-ketoglutarate dehydrogenases are discussed in chapter 18.
Enzymatic addition or removal of the elements of hydrogen to or from an organic molecule generally requires the action of a coenzyme. In principle, the process may proceed by any of several mechanisms, including the formal transfer of a hydride and a proton; or the transfer of two electrons and two protons; or the transfer of a hydrogen atom, an electron, and a proton; or any of several other sequences. Proteins alone do not efficiently catalyze these processes; coenzymes and cofactors generally provide the essential chemistry for catalysis by oxidoreductases.
Many enzymes catalyze the dehydrogenation of an alcoholic group to a ketone or aldehyde coupled with the reduction of NAD+ to NADH. Enzymes of this type in glycolysis and the tricarboxylic acid cycle include alcohol dehydrogenase, lactate dehydrogenase, malate dehy-drogenase, glyceraldehydes-3-P dehydrogenase, isocitrate dehydrogenase, and pyruvate and a-ketoglutarate dehydrogenases. In this section, we emphasize one example of each class or type of NAD+-dependent dehydrogenase.
A striking feature of nicotinamide nucleotide-dependent dehydrogenases is the similarity of the binding sites for NAD+/NADP+. Most members of this family incorporate the same folding motif for binding the nicotinamide nucleotide, the dinucleotide fold, often referred to as the Rossman fold (Rossman et al., 1975). An exception is isocitrate dehydrogenase, which has a completely different structure.
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