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3D model (JSmol) | |
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| ECHA InfoCard | 100.000.163 |
| MeSH | NADP |
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| Properties | |
| C21H28N7O17P3+ (oxidized) C21H29N7O17P3 (reduced) | |
| Molar mass | 744.4 g/mol (oxidized) 745.4 g/mol (reduced) |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Nicotinamide adenine dinucleotide phosphate, abbreviatedNADP[1][2] or, in older notation,TPN (triphosphopyridine nucleotide), is acofactor used inanabolic reactions, such as theCalvin cycle andlipid andnucleic acid syntheses, which requireNADPH as areducing agent ('hydrogen source'). NADPH is thereduced form, whereas NADP+ is theoxidized form. NADP+ is used by all forms of cellular life. NADP+ is essential for life because it is needed for cellular respiration.[3]
NADP+ differs fromNAD+ by the presence of an additionalphosphate group on the 2' position of theribose ring that carries theadeninemoiety. This extra phosphate is added byNAD+ kinase and removed by NADP+ phosphatase.[4]
In general, NADP+ is synthesized before NADPH is. Such a reaction usually starts withNAD+ from either the de-novo or the salvage pathway, withNAD+ kinase adding the extra phosphate group.ADP-ribosyl cyclase allows for synthesis fromnicotinamide in the salvage pathway, and NADP+ phosphatase can convert NADPH back to NADH to maintain a balance.[3] Some forms of the NAD+ kinase, notably the one in mitochondria, can also accept NADH to turn it directly into NADPH.[5][6] The prokaryotic pathway is less well understood, but with all the similar proteins the process should work in a similar way.[3]
NADPH is produced from NADP+. The major source of NADPH in animals and other non-photosynthetic organisms is thepentose phosphate pathway, byglucose-6-phosphate dehydrogenase (G6PDH) in the first step. The pentose phosphate pathway also produces pentose, another important part of NAD(P)H, from glucose. Some bacteria also use G6PDH for theEntner–Doudoroff pathway, but NADPH production remains the same.[3]
Ferredoxin–NADP+ reductase, present in all domains of life, is a major source of NADPH in photosynthetic organisms including plants and cyanobacteria. It appears in the last step of the electron chain of thelight reactions ofphotosynthesis. It is used as reducing power for the biosynthetic reactions in theCalvin cycle to assimilate carbon dioxide and help turn the carbon dioxide into glucose. It has functions in accepting electrons in other non-photosynthetic pathways as well: it is needed in the reduction of nitrate into ammonia for plant assimilation innitrogen cycle and in the production of oils.[3]
There are several other lesser-known mechanisms of generating NADPH, all of which depend on the presence ofmitochondria in eukaryotes. The key enzymes in these carbon-metabolism-related processes are NADP-linked isoforms ofmalic enzyme,isocitrate dehydrogenase (IDH), andglutamate dehydrogenase. In these reactions, NADP+ acts like NAD+ in other enzymes as an oxidizing agent.[7] The isocitrate dehydrogenase mechanism appears to be the major source of NADPH in fat and possibly also liver cells.[8] These processes are also found in bacteria. Bacteria can also use a NADP-dependentglyceraldehyde 3-phosphate dehydrogenase for the same purpose. Like the pentose phosphate pathway, these pathways are related to parts ofglycolysis.[3] Another carbon metabolism-related pathway involved in the generation of NADPH is the mitochondrial folate cycle, which uses principally serine as a source of one-carbon units to sustain nucleotide synthesis and redox homeostasis in mitochondria. Mitochondrial folate cycle has been recently suggested as the principal contributor to NADPH generation in mitochondria of cancer cells.[9]
NADPH can also be generated through pathways unrelated to carbon metabolism. The ferredoxin reductase is such an example.Nicotinamide nucleotide transhydrogenase transfers the hydrogen between NAD(P)H and NAD(P)+, and is found in eukaryotic mitochondria and many bacteria. There are versions that depend on aproton gradient to work and ones that do not. Some anaerobic organisms useNADP+-linked hydrogenase, ripping a hydride from hydrogen gas to produce a proton and NADPH.[3]
LikeNADH, NADPH isfluorescent. NADPH in aqueous solution excited at the nicotinamide absorbance of ~335 nm (near UV) has a fluorescence emission which peaks at 445-460 nm (violet to blue). NADP+ has no appreciable fluorescence.[10]
NADPH provides the reducing agents, usually hydrogen atoms, for biosynthetic reactions and theoxidation-reduction involved in protecting against the toxicity ofreactive oxygen species (ROS), allowing the regeneration ofglutathione (GSH).[11] NADPH is also used foranabolic pathways, such ascholesterol synthesis, steroid synthesis,[12] ascorbic acid synthesis,[12] xylitol synthesis,[12] cytosolic fatty acid synthesis[12] and microsomalfatty acid chain elongation.
The NADPH system is also responsible for generating free radicals in immune cells byNADPH oxidase. These radicals are used to destroy pathogens in a process termed therespiratory burst.[13]It is the source of reducing equivalents forcytochrome P450hydroxylation ofaromatic compounds,steroids,alcohols, anddrugs.
NADH and NADPH are very stable in basic solutions, but NAD+ and NADP+ are degraded in basic solutions into a fluorescent product that can be used conveniently for quantitation. Conversely, NADPH and NADH are degraded by acidic solutions while NAD+/NADP+ are fairly stable to acid.[14][15]
Many enzymes that bind NADP share a common super-secondary structure named the "Rossmann fold". The initial beta-alpha-beta (βαβ) fold is the most conserved segment of the Rossmann folds. This segment is in contact with the ADP portion of NADP. Therefore, it is also called an "ADP-binding βαβ fold".[16]
In 2018 and 2019, the first two reports of enzymes that catalyze the removal of the 2' phosphate of NADP(H) in eukaryotes emerged. First thecytoplasmic protein MESH1 (Q8N4P3),[19] then themitochondrial proteinnocturnin[20] were reported. Of note, the structures and NADPH binding of MESH1 (5VXA) and nocturnin (6NF0) are not related.
