HOW DOES NAD+ WORK?

 Key Pointers

  • NAD+ acts as coenzymes in the energy production of the cell.
  • NAD+ is used by the cell to work as a genomic modifier.
  • A key component in multiple DNA repair pathways.       

NAD+ is an essential coenzyme that takes part in various redox reactions. NAD present in mitochondria plays a key role in energy production for the cells by using energy production pathways, including fatty acid oxidation, oxidative phosphorylation, and tricarboxylic acid cycle. NAD+ along with its metabolites provides a regulator in different physiological processes. These effects of NAD+ are achieved by its capability of transferring an electron that takes part in the redox reaction.


Many enzymes use NAD+ as a substrate/coenzymes in multiple chemical reactions by post-translational modification of RNA, DNA, and proteins. NAD+ 

is cleaved by enzymes comprising of sirtuins, CD38, Poly ADP (Adenosine Diphosphate)-Ribose Polymerase (PARPs), and SARM1(sterile alpha and toll/interleukin receptor motif-containing protein 1) to generate NAM and ADP-ribose (ADPR).

 

Sirtuins act as a modulator of cell environments due to alteration of the energy status of the cell caused by different physiological stresses and pathological conditions by activation of oxidative metabolism. PARPs respond to the DNA damage caused by oxidative stress. CD38 uses NAD+ to synthesize second messengers that release calcium, such as ADPR. ADPR (ADP-ribose) takes part in age-related NAD+ decline.            


NAD+ has a significant role in redox homeostasis. Oxidants and antioxidants are produced in the cells, and an imbalance between them causes damage to lipids, protein, DNA, and RNA, causing inflammation and cell death.


NAD+ is a carrier of the electron in cellular respiration. When it transfers an electron, it is converted to NADH, a reduced form. NADH has a vital role in the generation of reactive oxygen species, acting as an electron donor. Most of the ROS species are produced in the mitochondria consuming NADH as the electron donor. Electrons are supplied to NADH dehydrogenase by mitochondrial NADH, and electrons from FADH2 are also utilized in the electron transport chain in the mitochondria to synthesize ATP.


When NAD+ is reduced and receives phosphate at position 2 of the adenosyl nucleotide through an ester bond, it is converted to NADPH. This form of NAD+ is used as an ultimate reducing power agent in the antioxidant defense system of the body. Glutathione reductases and thioredoxin reductases are enzymes that use NADPH as a source of electron donors for the reduction of disulfides to dithiol.

 

Through a complex mechanism and using multiple substrates and enzymes NADPH takes part in the detoxification of reactive oxygen species.


NAD+ also works as a cosubstrate in the multiple DNA repair pathways. DNA damage is a communal cellular phenomenon that occurs due to cellular stress from the radiation, chemicals, carcinogens, and reactive oxygen species of free radicals. NAD+ has been used as a cosubstrate in DNA repair pathways in which PARPs and sirtuins moderate post-translational modifications.


NAD metabolism is used to determine the role of infection in the body. Its levels regulate the reactive oxygen species, either acting as a defense against microorganisms or causing cell death in response to inflammation.


Conclusion


NAD+ is a vital component of the cell that has a role in redox reactions for the production of energy in the form of ATP. The metabolism (anabolism+ catabolism) in the cell also needs NAD+ as a coenzyme or cosubstrate. The NAD+ play an important role in DNA modification and repair. It also maintains homeostasis between free radical and antioxidant production.


References

  1. Jameson DM, Thomas V, Zhou DM (1989). "Time-resolved fluorescence studies on NADH bound to mitochondrial malate dehydrogenase". Biochim. Biophys. Acta. 994 (2): 187–90. doi:10.1016/0167-4838(89)90159-3. PMID 2910350.
  2. Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is a NAD-dependent histone deacetylase. Nature 403, 795–800 (2000).
  3.   Braidy, N. et al. Role of nicotinamide adenine dinucleotide and related precursors as therapeutic targets for age-related degenerative diseases: rationale, biochemistry, pharmacokinetics, and outcomes. Antioxid. Redox Signal. 30, 251–294 (2019).