Nicotinamide adenine dinucleotide or NAD+, a non-protein compound,  regulates enzymatic activity. This highly conserved compound , meaning that it is found in almost all organisms,  plays a role in many metabolic activities including cellular respiration.

Organisms can synthesize  NAD+  through a number of metabolic pathways. Simply put, it can either be assembled de novo from smaller molecular building blocks or through salvage pathways. Salvage pathways facilitate NAD+ synthesis by re-activating intermediates formed during NAD+ degradation. These intermediates include but are not limited to the following compounds: nicotinic acid (Na), nicotinamide (Nam) and nicotinamide riboside (NR).

A team of researchers led by Dr. Charles Brenner have recently discovered that the enzymes Isn 1 and Sdt1 are responsible for the regulation of key steps in NAD+ biosynthesis in yeast cells. Brenner served as a professor of genetics and biochemistry at Dartmouth Medical School from 2007 to 2009 and currently heads the Biochemistry department at University of Iowa Medical School.

Their findings, published in the October 2009 issue of The Journal of Biological Chemistry, shed light on the dynamics of NAD+ metabolism and have led to the proposition of a revised model of NAD+ metabolism in yeast.

Brenner and his team utilized knock-out mutants to study intracellular NAD+ synthesis.  Knock-out mutants are organisms in which specific genes have been intentionally deleted or inactivated. Thus, the phenotypic trait encoded by the gene is eliminated in the mutant, allowing scientists to infer the function of the removed gene.

Brenner used knocked-out yeast mutants to remove specific enzymes involved in various stages of the NAD+ salvage pathway. He then monitored the effects of these mutations on intracellular NAD+ levels. Researchers carried out these experiments on a number of growth media with varying concentrations of ions, sugars, and vitamins.

Through such experimentation, Brenner and his team observed the following: (1) The production of NR and NAR, two intracellular precursors to NAD+ in the salvage pathway, positively affect the production of NAD+. (2) Two enzymes, Isn 1 and Sdt 1, are responsible for the production of NR and NAR. (3) Expression of Isn 1 and Sdt 1is regulated by concentrations of glucose and certain vitamins in the growth media.

These findings suggest that in yeast, NAD+ metabolism via the savage pathway varies with environmental conditions.

Using their findings, Brenner and his team  proposed a revised model of NAD+ metabolism in yeast. This  model incorporates new steps to reflect the enzymatic activities of Isn 1 and Sdt 1. It also considers a novel mechanism by which calorie restrictions associated with extracellular glucose concentrations can regulate NAD+ synthesis.