NAD+, From Metabolism to Therapies

By | January 1, 2019

The role of NAD+ metabolism in health and diseases led to an interest in the emergence of the use of niacin as primary therapy for the treatment of hyperlipidemias. Niacin protects tissues and NAD+ metabolism in different stages of illnesses such as ischemia (stroke).

NAD+ Metabolism

The biosynthetic and recycling metabolism of vitamin B3 brings together all dinucleotides. Nicotinamide and niacin acid are synthesized within nucleotides or dinucleotides before being freed as species within cells. NAD+ synthesis is achieved through recycling pathways in most microbes found in human cells.

Recycling in Bacteria

Most organisms have recycling pathways that can synthesize NAD+ from vitamin B3 from the diet. Within the bacteria, decomposition of NAD+ takes place through the transfer of Adenosine Diphosphate Ribose (ADPR) from niacin. Bacteria will encode sirtuins, and the enzymes separate nicotinamide from NAD+. After that, the nicotinamide changes to niacin acid.

The second pathway of NAD+ decomposition involves the breaking down of phosphate anhydride bond to form Nicotinamide Mononucleotide (NMN) and Adenosine Monophosphate (AMP).

Both bacterial NAD+ and pyrophosphates catalyze the last reaction.

Recycling in Humans

In humans, the dominant pathway that decomposes NAD+ is catalyzed by ribosyltransferase. Studies indicate that NAD+ has a half-life of 10 hours in the liver. Nicotinamide formed from this process is never hydrolyzed.

The human genome encodes a Preiss-handler pathway that converts niacin to NAD+ through adenine dinucleotide. Humans use both the niacin and nicotinamide recycling to synthesize NAD buy use different pathways to be successful.

Clinical Manifestation of Niacin Deficiency

Despite the complex and diverse effects attributed to niacin in metabolism, there has been redundancy in NAD+ biosynthetic pathways in humans who make modern vitamin B3 deficiency rare. However, poor diets, alcoholism, AIDS, and other ailments can lead to niacin deficiency (pellagra). Symptoms associated with niacin deficiency include dementia and diarrhea. There is a noted increase in the risk of having cancer.

Ischemia and Stroke

NAD+ metabolism is at the center of damages associated with stroke. An injury from stroke is caused by a blockage of arterial blood flow to the brain, which leads to starvation of affected tissues for oxygen. The oxygenation of the tissues has a negative effect leading to the production of oxygen-reactive species such as peroxide, anion, and hydroxyl radicals. This burst in oxidative stress leads to serious tissue damage.

To resynthesize the NAD+ in large quantities puts a lot of strain on cells depleting them of energy. Nicotinamide effects may help in enhancing NAD+ synthesis, which happens to be more beneficial in ischemia models.

Nicotinamide and Fetal Alcohol Syndrome

The brain of a fetus is sensitive to alcohol and oxidative stress. The fetal brain must undergo pattern formation while connecting to other neurons to form correct synapses for better information processing. It is in these early stages that the brain becomes susceptible to immature cells.

Alcohol is a leading cause of mental degradation in fetal brains cells. As potential protection of these cells against oxidative stress such as lipid peroxidation, mothers’ needs to be, administered nicotinamide may have a chance of preventing early neural damage during the development stage.

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