Nicotinamide adenine dinucleotide (coenzyme I) is a coenzyme that transfers protons (more precisely, hydrogen ions). It appears in many metabolic reactions of cells. NADH or more accurately NADH + H+ is its reduced form, which carries up to two protons (written as NADH + H+) and has a standard electrode potential of -0.32V.
NAD+ is a coenzyme of dehydrogenases, such as alcohol dehydrogenase (ADH), which is used to oxidize ethanol. It plays an irreplaceable role in glycolysis, gluconeogenesis, tricarboxylic acid cycle and respiratory chain. The intermediate product will transfer the removed hydrogen to NAD, making it NAD + H+.
NAD+ H+ will serve as a carrier of hydrogen and synthesize ATP through chemical osmotic coupling in the electron transport chain.
In vivo, NAD can be synthesized from simple building blocks with the amino acids tryptophan or aspartate. Alternatively, a more complex combination of enzymes is taken from food, and this vitamin is called niacin. Similar compounds are released through reactions that break down the NAD structure. These prefabricated components then pass through a recycling tunnel that recycles them into active form. Some NAD is also converted into nicotinamide adenine dinucleotide phosphate (NADP); this related coenzyme is chemically similar to NAD but has a different role in metabolism. In metabolism, NAD+ participates in redox reactions, carrying electrons from one reaction to another. Therefore, coenzymes exist in two forms in cells: NAD+ is an oxidizing agent that accepts electrons from other molecules. This reaction forms NADH, which can then be used as a reducing agent to donate electrons. These electron transfer reactions are the primary function of NAD. However, it is also used in other cellular processes, most notably as a substrate for enzymes that add or remove chemical groups from proteins. Because of the importance of these functions, discovering enzymes that metabolize NAD are drug targets. Although NAD+ is written with a superscript plus sign because of the positive charge on a specific nitrogen atom, in most cases at physiological pH, it is actually a singly charged anion (negative charge is 1), while NADH is a doubly charged anion.
History
Coenzyme NAD+ was first discovered in 1906 by British biochemists Arthur Harden and William John Young. They noticed that the addition of boiled and filtered yeast extract greatly accelerated alcoholic fermentation in the uncooked yeast extract. They referred to the unknown factor that produces this effect as “coenzyme.” Through lengthy and difficult purification from yeast extract, this thermostable factor was identified by Olechelpi as a nucleotide sugar phosphate. In 1936, German scientist Otto Heinrich Warburg showed the function of nucleotide coenzymes in hydride transfer and identified the nicotinamide moiety as the site of redox reactions.
Indications
Basic and clinical research in recent years has confirmed that oxidative stress damage is one of the main pathogenesis mechanisms of diabetic nephropathy. Transgenic technology is used to overexpress antioxidant enzymes in the kidney, such as superoxide dismutase (SOD) or hydrogen peroxide. Enzyme (catalase) can significantly improve diabetic kidney damage. Based on the research foundation and status of existing technology, CN201610070262.4 provides new medicinal uses of the compound nicotinamide adenine dinucleotide phosphate (NADP), originally imported from Germany, specifically involving the compound nicotinamide adenine dinuclear Use of glycoside phosphate NADP in the preparation of drugs for preventing and treating diabetic nephropathy.
CN201610070262.4 has confirmed through in vitro cell experiments and in vivo animal experiments that the NADP can reduce the damage of high sugar to vascular endothelial cells, improve kidney damage in diabetic mice, and can further be used to prepare drugs for preventing and treating diabetic nephropathy. The medicine prepared according to the present invention can be used by intraperitoneal injection. The dose of NADP used is 5-20 mg.kg-1.d-1. The start time of use is preferably when diabetes is diagnosed, which can prevent diabetic nephropathy. and therapeutic effects. The present invention provides new targets and ideas for clinical prevention and treatment of diabetic nephropathy and improvement of renal lesions, and confirms the important role of improving kidney oxidative stress in the prevention and treatment of diabetic nephropathy.
Concentration and state in cells
In rat liver, the total amount of NAD+ and NADH is about 1 micromol per gram of wet weight, which is about 10 times the concentration of NADP+ and NADPH in the same cells. [2] The actual concentration of NAD+ in the cytosol is difficult to measure. Recent studies show that it is about 0.3mM in animal cells and about 1.0-2.0mM in yeast. [3] However, over 80% of NADH fluorescence in mitochondria is in the bound form, so the concentration in solution is much lower. Data in other studied cells are limited, although in mitochondria NAD+ concentrations are similar to those in the cytoplasm. [4] This NAD+ is carried into mitochondria by specific membrane transport proteins because the coenzyme cannot diffuse through the membrane.
The balance between the redox forms of nicotinamide adenine dinucleotide is called the NAD+/NADH ratio. This ratio is an important component of the so-called redox state of the cell, which reflects the metabolic activity and health of the cell. The effects of the NAD+/NADH ratio are complex, controlling the activity of several key enzymes. In healthy mammalian tissues, the ratio between free NAD+ and NADH in the cytoplasm is usually about 700; this ratio therefore favors oxidative reactions. The total NAD+/NADH ratio is much lower, with estimates in mammals ranging from 3-10. In comparison, the NADP+/NADPH ratio is typically around 0.005, so NADPH is the main form of this coenzyme. These different ratios are key to the different metabolic effects of NADH and NADPH.
Biosynthesis
Synthesis
NAD+ is synthesized through two metabolic pathways: by combining existing components such as nicotinamide and recycling them back into NAD+, or by de novo synthesis from amino acids. Most organisms synthesize NAD+ from simple components. The specific set of reactions will vary between organisms, but a common feature is the amino acid tryptophan in animals and some bacteria or aspartame in some bacteria and plants. Quinolinic acid (QA) is produced between amino acids. [8] Convert quinolinic acid into nicotinic acid mononucleotide (NaMN) by transferring the phosphodisaccharide moiety. The adenylate moiety is then transferred to form nicotinic adenine dinucleotide (NAD). Finally, the niacin moiety in NAD is amidated into the nicotinamide (Nam) moiety, forming NAD+. Further, some NAD+ will be converted into NADP+, phosphorylated NAD+, by NAD+ kinase. In most organisms, this enzyme uses ATP as a pathway to make phosphate groups. Although several bacteria such as Mycobacterium tuberculosis and hyperthermophilic archaea use inorganic polyphosphates as alternative phosphate donors.
Repair Pathways
In addition to assembling NAD+ from simple amino acid precursors, cells also recycle compounds containing pyridine bases. Three vitamin precursors used in these repair metabolisms are niacin, niacinamide, and niacin. These compounds can be obtained from the diet and are called vitamin B3 or niacin. However, these compounds are also produced within cells and through the digestion of NAD+. Some of the enzymes involved in these salvage pathways appear to be concentrated in the nucleus, which may compensate for the depletion of NAD+ levels in this organelle. The rescue response is essential in humans; a lack of niacin in the diet causes vitamin-deficient skin diseases. Since NAD+ cycles between oxidized and reduced forms in redox reactions without changing the overall level of the coenzyme, the high demand for NAD+ is due to the constant consumption of the coenzyme in the reaction.
Microorganisms use different remediation pathways than mammals. Some pathogens, such as the yeast Candida and Haemophilus influenzae bacteria, are NAD+ auxotrophs, thus rendering them unable to synthesize NAD+. However, they also have salvage uses and therefore rely on foreign NAD+ or other precursors. Even more surprising is the intracellular pathogen Chlamydia trachomatis, which lacks identifiable candidates for NAD+ and NADP+ biosynthesis or any genes and must obtain these coenzymes from its host.
Function
NAD+ has several important roles in metabolism. It serves as a coenzyme in redox reactions as a precursor to the ADP-ribose moiety in the ADP-ribosylation reaction, as a precursor to the second messenger molecule cyclic ADP-ribose, and as a substrate for bacterial DNA ligases and moieties Known as silent enzymes, they use NAD+ to remove acetyl groups from proteins. In addition to its metabolic functions, NAD+ occurs as an adenine nucleotide, which can be released spontaneously from cells through regulatory mechanisms and therefore can have important extracellular effects.
NAD+ is an energy-providing molecule found in every cell of the body and is used for metabolism, building new cells, fighting free radicals and DNA damage, and sending signals within cells. It enables mitochondria to convert the food we eat into our The body requires energy to maintain all its functions. There is also a need to “turn off” genes that speed up the aging process. NAD+ is essential for life. Healthy mitochondrial function is an important component of human aging. Our bodies have the ability to make NAD+ from components in the foods we eat. Studies in experimental animals and humans show that NAD+ levels decline significantly with age. This decline puts us at greater risk for nerve and muscle degeneration, cardiometabolic health, and repair and resiliency. Scientists at renowned research institutions have been investigating NAD+-boosting strategies as treatments for degenerative conditions associated with aging. Research shows that NAD+ plays a unique role in muscle and tissue protection while also improving lifespan.
Business applications
NAD+ is also called oxidized coenzyme I in mainland China, and NADH is called reduced coenzyme I. In Hong Kong’s health care product market, “Noga Factor” is used as the Chinese name of NAD+.
