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Nicotinamide

• Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells. The compound is a dinucleotide, because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide. Nicotinamide adenine dinucleotide exists in two forms, an oxidized and reduced form abbreviated as NAD+ and NADH respectively.

Introduction

Fig: Nicotinamide adenine dinucleotide

• NADH, short for nicotinamide adenine dinucleotide, is an important pyridine nucleotide that functions as an oxidative cofactor in eukaryotic cells.

• NADH plays a key role in the production of energy through redox reactions.

• NAD serves as a cofactor for dehydrogenases, reductases and hydroxylases, making it a major carrier of H+ and e- in major metabolic pathways such as glycolic acid, fatty acid synthesis, steroid synthesis.

Involved in redox reactions Takes part in cellular processes, DNA repair, signal transduction,

etc. Also involved in de novo biosynthesis, slavage pathway Used for discovery & development of novel treatments of

medical conditions like cancer, aging

Concept

NAD is oxidized form and become reduced this forms NADH which can be used as reducing agent to donate electrons.

At physiological PH NAD is singly charged anion while NADH is doubly charged anion

In organisms, NAD is synthesized by de-novo pathway from amino acids tryptophan or aspartic acid.

Alternately it can also be taken from food as vitamin known as niacin

History

In early 19th century over consumption of corn or corn meal caused a disease “Pellagra” in Europe, U.S, Italy.

Dr. Joseph Goldberger of U.S Public Health Services demonstrated that Pellagra was a dietary disease. In the late 1930s, studies by Dr. Tom Spies and Clark Cooper established that niacin cured pellagra in humans.

Pellagra is a vitamin deficiency disease most frequently caused by a chronic lack of niacin in the diet. Pellagra developed classically as a result of niacin (vitamin B3) deficiency, tryptophan deficiency which resulted in decreased NAD (nicotinamide adenine dinucleotide) production leading to most of the pathology since NAD and its phosphorylated NADP form are cofactors required in many body processes.

The human body converts tryptophan to nicotinic acid. It was proven correct with the isolation of nicotinic acid which cured

pellagra.

Niacin is involved metabolic reactions of FA, amino acids & carbohydrates.

Niacin serves as a component of cosubtsrates NAD & NADP which are key components of redox reactions & participate in many cellular processes.

The body readily converts nicotinic acid to nicotinamide but a little of it is stored as NAD n NADP in body.

Thus, niacin deficiency was produced in humans fed with corn meal which consisted of low niacin & tryptophan levels.

Nicotinic acid & nicotinamide are major forms of niacin & exert their physiological functions as precursors of nicotinamide adenine dinucleotide (NAD).

ReactionsNAD + and NADP + play an essential role in many biochemical reactions, especially redox reactions in which oxidoreductase enzymes transfer hydrogenNAD + and NADP + act as electron acceptors in oxidoreductase catalyzed reactions; NADH and NADPH act as electron donors.

Reactions catalyzed by Nucleotide containing enzymes:1) The redox reaction shown in Figure below is catalyzed by the oxidoreductase enzyme alcohol dehydrogenase.

Fig:Reduction of NAD to NADH

Mechanism: Hydride mechanism

2)Conversion of Imine of alpha-ketoglutrate to a-ketoglutrate.The reaction is catalyzed by glutamate dehydrogenase.

3)Conversion of Glyceraldehyde-3-Phosphate to 1,3-Biphosphoglycerate catalyzed by enzyme Glyceraldehyde-3-phosphate dehydrogenase.One of the most important step in Glycolysis pathway.

4)Glucose-6-phosphate catalyzes oxidation of aldehyde(hemiacetal),atC1of glucose-6-phophate,to a carboxylic acid in ester linkage(lactone).NADP servers as electron acceptor.This is a step involved in pentose phosphate pathway.

One electron mechanism

ADVANTAGESEffectively treat acne by its anti inflammatory action and

reducing sebum.Improve skin barrier function through decreasing water loss

through the epidermis,thus increasing skin hydration.Reduce actinic keratoses and possibly reduce the risk of skin

cancer.Extends replicative lifespan of human cells.

DISADVANTAGESAvoided in patients with active peptic ulcer disease.At high doses causes nausea, diarrhoa,bleeding, updet stomach.Loss of appetiteAvoided in patients with severe hypotension.

APPLICATION

NAD+ is direct target of the drug isoniazid, which is used in the treatment of tuberculosis, an infection caused by mycobacerium tuberculosis.Isoniazid is a prodrug and once it has entered the bacteria, it is activated by a peroxidase enzyme, which oxidizes the compound into a free radical form, this radical then reacts with NADH, to produce adducts that are very potent inhibitors of the enzymes enoyl-acyl carrier protein reductase and dihydrofolate reductase.

Nicotinamide, also known as niacinamide or nicotinic acid amide active form of vitamin B3. It is essential for good health; deficiency leads to a serious illness, pellagra. Oral nicotinamide can be used effectively to treat pellagra.

NADH stands for "nicotinamide adenine dinucleotide (NAD) + hydrogen (H)." This chemical occurs naturally in the body and plays a role in the chemical process that generates energy. People use NADH supplements as medicine.

NADH is used for improving mental clarity, alertness, concentration, and memory; as well as for treating Alzheimer’s disease. Because of its role in energy production, NADH is also used for improving athletic endurance and treating chronic fatigue syndrome (CFS).