Diaphorase

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Diaphorase or dihydrolipoyl dehydrogenase (EC 1.8.1.4) is a flavoprotein enzyme capable of oxidizing the reduced form of NAD (NADH). This lipoamide dehydrogenase is a component of the glycine cleavage system, as well as of the alpha-ketoacid dehydrogenase complexes. Diaphorase is a type of dehydrogenase that catalyzes reactions involving nicotinamide adenine dinucleotide cofactors. Two specific members of this class of enzymes, called NADH diaphorase and NADPH diaphorase, are responsible for the dehydrogenation of reduced forms of NAD and NADP, respectively. These enzymes are naturally present in all animal tissues and were first extracted in pure form by Straub in 1939.

Mechanism of action

In the family of nicotinamide adenine dinucleotide compounds, two members (NAD and NADP) act as hydride acceptors, while their respective reduced forms (NADH and NADPH) act as hydride donors. The role of diaphorase is to transfer hydrogen ions between donor and acceptor molecules. For example, the dehydrogenation of reduced form of NADPH requires the target molecule itself, H+ and acceptor molecules. Therefore, the result of this reaction is a NADP molecule and a reduced receptor.

Role in living tissue

Through the mechanism of transferring electrons between the reduced and oxidized forms of NAD, diaphorase supports many key processes in living tissues. One of such processes is the continuous conversion of methemoglobin to normal hemoglobin. In this process, NADH diaphorase and cytochrome b5 reductase act synergistically to oxidize NADH and reduce methemoglobin, thereby producing hemoglobin. Therefore, the deficiency of NADH diaphorase and cytochrome b5 reductase in leukocytes and platelet cells is related to hereditary methemoglobinemia. NADPH diaphorase is also known to act in certain types of neurons. Non-pyramidal neurons with high concentrations of NADPH diaphorase synthesize nitric oxide, which is an essential compound in all aspects of the brain and nervous system. Specifically, it is known that nitric oxide can cause the release of certain neurotransmitters and neuroactive amino acids. It has also been shown that NO supports the expression of proteins related to neuroplasticity.

Current research field

Because they are closely related to the cofactor NAD, diaphorase has played an important role in recent research on the role of this compound in the aging process. Recent studies have shown that the level of NAD decreases with age, which leads to decreased sirtuin protein expression and mitochondrial function, as well as other downstream effects. In several studies related to the role of NAD in mitochondrial aging, diaphorase has been used as a component of the cyclic analysis mixture.

Other research involves the role of NADPH dehydrogenase quinone 1 (also known as DT-diaphorase or DTD) in certain types of cancer. Among several tumor cells, the level of DTD in non-tumor tissues exceeds normal levels. As a result, DTD has been studied as a potential target for new chemotherapeutic agents. Although it may be effective, research on DTD as a chemotherapy target requires the development of drugs other than the widely used mitomycin C, which requires specific pH conditions to be metabolized.

Reference

1. Frederick, David W., et al. Increasing NAD synthesis in muscle via nicotinamide phosphoribosyltransferase is not sufficient to promote oxidative metabolism. Journal of Biological Chemistry. 2015, 290: 1546-1558.