Origin and Role in Enzymes
Nicotinamide coenzymes are synthesized in the body from specific precursor molecules. The main building block for their formation is vitamin $PP$ (also known as niacin or vitamin $B_3$). Chemically, the precursors are nicotinic acid and nicotinamide.
In biochemical reactions, NAD+ and NADP+ do not work on their own. They are coenzymes—non-protein parts of complex enzymes belonging to the class of oxidoreductases. To be more precise, they are part of the dehydrogenase subclass—enzymes that catalyze the removal of hydrogen atoms from a substrate.
Mechanism of Action: Electron and Proton Transfer
The main task of nicotinamide coenzymes is to participate in substrate oxidation. In this case, the substrate acts as a proton donor (often designated by the letter $D$ in diagrams). The process proceeds via a strictly defined mechanism:
- A total of 2 protons ($2H^+$) and 2 electrons ($2e^-$) are cleaved from the molecule of the oxidized substrate.
- The coenzyme (NAD+ or NADP+) does not take all of these particles. Only 1 proton ($H^+$) and 2 electrons ($2e^-$) attach to it. This combination (one proton plus two electrons) is called a hydride ion.
- The remaining, second proton ($H^+$), does not bind to the coenzyme molecule but is released into the surrounding environment (solution).
This is why the reduced form of the coenzyme is always written with the addition of a free proton: $NADH + H^+$ (or $NADPH + H^+$).
Chemical Reaction and Structural Changes
The addition of a hydride ion leads to significant changes in the structure of the active part of the coenzyme—the nicotinamide pyridine ring.
- Oxidized form ($NAD^+$ / $NADP^+$): the pyridine ring is aromatic. A positive charge is present on the nitrogen atom in this ring.
- Reduced form ($NADH$ / $NADPH$): reduction of the pyridine ring occurs. The aromaticity of the molecule is disrupted, and hydrogen attaches to the carbon in the para-position relative to the nitrogen atom.
This transition between the oxidized (aromatic, charged) and reduced (non-aromatic, uncharged) states provides the ability of coenzymes to transfer reducing equivalents within the cell.
Briefly: answers to topical questions
What is the biochemical difference between the functions of NAD+ and NADP+ in cellular metabolism?
The functions of these coenzymes differ due to the participation of their oxidized and reduced forms in metabolic reactions.
| Coenzyme | Function |
|---|---|
| $NAD^+$ / $NADH$ | $NAD^+$ participates in the oxidation of substrates and is reduced to $NADH+H^+$. In glycolysis, during the oxidation of glyceraldehyde-3-phosphate, $NADH+H^+$ is formed; under anaerobic conditions, $NADH$ is used to reduce pyruvate to lactate with the regeneration of $NAD^+$. Ethanol catabolism requires $NAD^+$, and the amount of $NADH$ increases. |
| $NADP^+$ / $NADPH$ | $NADP^+$ is reduced to $NADPH+H^+$ in the oxidative phase of the pentose phosphate pathway. $NADPH$ is used as a hydrogen donor in reduction reactions, including the synthesis of fatty acids and cholesterol, participates in hydroxylation reactions during the detoxification of xenobiotics, glutathione reduction, and the formation of reactive oxygen species during the respiratory burst. |
What are some examples of NAD-dependent dehydrogenases?
Examples of NAD-dependent dehydrogenases from sources:
- 3-Phosphoglycerate dehydrogenase — catalyzes the conversion of 3-phosphoglycerate to 3-phosphohydroxypyruvate; concomitantly, $NAD^+$ is reduced to $NADH+H^+$.
- Glyceraldehyde-3-phosphate dehydrogenase — oxidizes glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate; the reaction product is $NADH+H^+$.
- Lactate dehydrogenase — catalyzes the reaction: pyruvate + $NADH+H^+$ ⇄ lactate + $NAD^+$.
- Alcohol dehydrogenase — an enzyme of ethanol metabolism; $NAD^+$ is required for the oxidation of ethanol.
In which specific metabolic pathways does NADPH formation occur?
NADPH formation occurs during several specific metabolic pathways and reactions.
- Pentose phosphate pathway — oxidative phase (reactions catalyzed by glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase).
- Conversion of malate to pyruvate — decarboxylation of malate mediated by the malic enzyme.
- Isocitrate oxidation — the reaction is catalyzed by cytosolic isocitrate dehydrogenase.
It is easy to remember the distribution of hydrogen: the substrate gives away the "full kit" (2 protons and 2 electrons), but the coenzyme takes only the hydride ion (1 proton + 2 electrons) for itself, and simply "throws" the remaining 1 proton into the medium. Hence the notation: NADH + H+.
Class and exam questions
Which vitamin is the precursor for NAD+ and NADP+?
Their precursor is vitamin PP (niacin, vitamin B3), in the form of nicotinic acid or nicotinamide.
Which enzymes contain nicotinamide coenzymes?
They function as part of oxidoreductase class enzymes, specifically the dehydrogenase subclass.
How does the structure of NAD+ change upon reduction?
The pyridine ring of nicotinamide undergoes reduction: aromaticity is disrupted, and hydrogen is added at the para-position to the nitrogen atom.
How many protons and electrons does the coenzyme accept from the substrate?
The coenzyme molecule itself accepts 1 proton and 2 electrons (a hydride ion). The second proton cleaved from the substrate goes into the surrounding environment.
What else to study on this topic
- Structure and Functions of Flavin Adenine Dinucleotide (FAD)
- Flavin Mononucleotide (FMN): Differences and Similarities
- Classification of Oxidoreductases
- Chemical Structure of the Pyridine Ring
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