Nicotinamide adenine dinucleotide phosphate

Nicotinamide adenine dinucleotide phosphate, abbreviated NADP<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite book</ref> or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NADPH as a reducing agent ('hydrogen source'). NADPH is the reduced form, whereas NADPTemplate:+ is the oxidized form. NADPTemplate:+ is used by all forms of cellular life. NADPTemplate:+ is essential for life because it is needed for cellular respiration.<ref name="pmid26284036">Template:Cite journal</ref>

NADPTemplate:+ differs from [[NAD+|NADTemplate:+]] by the presence of an additional phosphate group on the 2' position of the ribose ring that carries the adenine moiety. This extra phosphate is added by NAD⁺ kinase and removed by NADP⁺ phosphatase.<ref>Template:Cite journal</ref>

Biosynthesis

NADPTemplate:+

In general, NADP⁺ is synthesized before NADPH is. Such a reaction usually starts with NAD⁺ from either the de-novo or the salvage pathway, with NAD⁺ kinase adding the extra phosphate group. ADP-ribosyl cyclase allows for synthesis from nicotinamide in the salvage pathway, and NADP⁺ phosphatase can convert NADPH back to NADH to maintain a balance.<ref name="pmid26284036"/> Some forms of the NAD⁺ kinase, notably the one in mitochondria, can also accept NADH to turn it directly into NADPH.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> The prokaryotic pathway is less well understood, but with all the similar proteins the process should work in a similar way.<ref name="pmid26284036"/>

NADPH

NADPH is produced from NADP⁺. The major source of NADPH in animals and other non-photosynthetic organisms is the pentose phosphate pathway, by glucose-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 the Entner–Doudoroff pathway, but NADPH production remains the same.<ref name="pmid26284036"/>

[[Ferredoxin—NADP(+) reductase|Ferredoxin–NADPTemplate:+ 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 the light reactions of photosynthesis. It is used as reducing power for the biosynthetic reactions in the Calvin 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 in nitrogen cycle and in the production of oils.<ref name="pmid26284036"/>

There are several other lesser-known mechanisms of generating NADPH, all of which depend on the presence of mitochondria in eukaryotes. The key enzymes in these carbon-metabolism-related processes are NADP-linked isoforms of malic enzyme, isocitrate dehydrogenase (IDH), and glutamate dehydrogenase. In these reactions, NADP⁺ acts like NAD⁺ in other enzymes as an oxidizing agent.<ref>Template:Cite journal</ref> The isocitrate dehydrogenase mechanism appears to be the major source of NADPH in fat and possibly also liver cells.<ref name=Palmer>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> These processes are also found in bacteria. Bacteria can also use a NADP-dependent glyceraldehyde 3-phosphate dehydrogenase for the same purpose. Like the pentose phosphate pathway, these pathways are related to parts of glycolysis.<ref name="pmid26284036"/> 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.<ref>Template:Cite journal</ref>

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 a proton gradient to work and ones that do not. Some anaerobic organisms use NADP⁺-linked hydrogenase, ripping a hydride from hydrogen gas to produce a proton and NADPH.<ref name="pmid26284036"/>

Like NADH, NADPH is fluorescent. 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). NADPTemplate:+ has no appreciable fluorescence.<ref name="Blacker Mann Gale Ziegler p. ">Template:Cite journal</ref>

Function

NADPH provides the reducing agents, usually hydrogen atoms, for biosynthetic reactions and the oxidation-reduction involved in protecting against the toxicity of reactive oxygen species (ROS), allowing the regeneration of glutathione (GSH).<ref>Template:Cite journal</ref> NADPH is also used for anabolic pathways, such as cholesterol synthesis, steroid synthesis,<ref name=":0">Template:Cite book</ref> ascorbic acid synthesis,<ref name=":0" /> xylitol synthesis,<ref name=":0" /> cytosolic fatty acid synthesis<ref name=":0" /> and microsomal fatty acid chain elongation.

The NADPH system is also responsible for generating free radicals in immune cells by NADPH oxidase. These radicals are used to destroy pathogens in a process termed the respiratory burst.<ref>Template:Cite journal</ref> It is the source of reducing equivalents for cytochrome P450 hydroxylation of aromatic compounds, steroids, alcohols, and drugs.

Stability

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.<ref name="Passonneau1993">Template:Cite book</ref><ref>Template:Cite journal</ref>

Enzymes that use NADP(H) as a coenzyme

Many enzymes that bind NADP share a common super-secondary structure named 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".<ref name="2015-Hanukoglu">Template:Cite journal</ref>

• Adrenodoxin reductase: This enzyme is present ubiquitously in most organisms.<ref name="2017-Hanukoglu-JME">Template:Cite journal</ref> It transfers two electrons from NADPH to FAD. In vertebrates, it serves as the first enzyme in the chain of mitochondrial P450 systems that synthesize steroid hormones.<ref name="1992-Hanukoglu">Template:Cite journal</ref>

Enzymes that use NADP(H) as a substrate

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 the cytoplasmic protein MESH1 (Template:Uniprot),<ref name="Ding 2018">Template:Cite journal</ref> then the mitochondrial protein nocturnin<ref name="Estrella 2019">Template:Cite journal</ref> were reported. Of note, the structures and NADPH binding of MESH1 (5VXA) and nocturnin (6NF0) are not related.

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