Nicotinamide Adenine Dinucleotide - History

History

The coenzyme NAD+ was first discovered by the British biochemists Arthur Harden and William Youndin in 1906. They noticed that adding boiled and filtered yeast extract greatly accelerated alcoholic fermentation in unboiled yeast extracts. They called the unidentified factor responsible for this effect a coferment. Through a long and difficult purification from yeast extracts, this heat-stable factor was identified as a nucleotide sugar phosphate by Hans von Euler-Chelpin. In 1936, the German scientist Otto Heinrich Warburg showed the function of the nucleotide coenzyme in hydride transfer and identified the nicotinamide portion as the site of redox reactions.

A source of nicotinamide was identified in 1938, when Conrad Elvehjem purified niacin from liver and showed this vitamin contained nicotinic acid and nicotinamide. Then, in 1939, he provided the first strong evidence that niacin was used to synthesize NAD+. In the early 1940s, Arthur Kornberg made another important contribution towards understanding NAD+ metabolism, by being the first to detect an enzyme in the biosynthetic pathway. Subsequently, in 1949, the American biochemists Morris Friedkin and Albert L. Lehninger proved that NADH linked metabolic pathways such as the citric acid cycle with the synthesis of ATP in oxidative phosphorylation. Finally, in 1959, Jack Preiss and Philip Handler discovered the intermediates and enzymes involved in the biosynthesis of NAD+; consequently, de novo synthesis is often called the Preiss-Handler pathway in their honor.

The non-redox roles of NAD(P) are a recent discovery. The first of these functions to be identified was the use of NAD+ as the ADP-ribose donor in ADP-ribosylation reactions, observed in the early 1960s. Later studies in the 1980s and 1990s revealed the activities of NAD+ and NADP+ metabolites in cell signaling – such as the action of cyclic ADP-ribose, which was discovered in 1987. The metabolism of NAD+ has remained an area of intense research into the 21st century, with interest being heightened after the discovery of the NAD+-dependent protein deacetylases called sirtuins in 2000, by Shinichiro Imai and coworkers at the Massachusetts Institute of Technology.