Nicotinamide phosphoribosyltransferase

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NAMPT
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNAMPT, 1110035O14Rik, PBEF, PBEF1, VF, VISFATIN, nicotinamide phosphoribosyltransferase
External IDsOMIM: 608764 MGI: 1929865 HomoloGene: 4201 GeneCards: NAMPT
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_005746
NM_182790

NM_021524

RefSeq (protein)

NP_005737

NP_067499

Location (UCSC)Chr 7: 106.25 – 106.29 MbChr 12: 32.87 – 32.9 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
nicotinamide phosphoribosyltransferase
Identifiers
EC no.2.4.2.12
CAS no.9030-27-7
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

Nicotinamide phosphoribosyltransferase (NAmPRTase or NAMPT), formerly known as pre-B-cell colony-enhancing factor 1 (PBEF1) or visfatin for its extracellular form (eNAMPT),[5] is an enzyme that in humans is encoded by the NAMPT gene.[6] The intracellular form of this protein (iNAMPT) is the rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD+) salvage pathway that converts nicotinamide to nicotinamide mononucleotide (NMN) which is responsible for most of the NAD+ formation in mammals.[7] iNAMPT can also catalyze the synthesis of NMN from phosphoribosyl pyrophosphate (PRPP) when ATP is present.[8] eNAMPT has been reported to be a cytokine (PBEF) that activates TLR4,[9] that promotes B cell maturation, and that inhibits neutrophil apoptosis.

Reaction[edit]

iNAMPT catalyzes the following chemical reaction:

nicotinamide + 5-phosphoribosyl-1-pyrophosphate (PRPP) nicotinamide mononucleotide (NMN) + pyrophosphate (PPi)

Thus, the two substrates of this enzyme are nicotinamide and 5-phosphoribosyl-1-pyrophosphate (PRRP), whereas its two products are nicotinamide mononucleotide and pyrophosphate.[7]

This enzyme belongs to the family of glycosyltransferases, to be specific, the pentosyltransferases. This enzyme participates in nicotinate and nicotinamide metabolism.

Expression and regulation[edit]

The liver has the highest iNAMPT activity of any organ, about 10-20 times greater activity than kidney, spleen, heart, muscle, brain or lung.[10] iNAMPT is downregulated by an increase of miR-34a in obesity via a 3'UTR functional binding site of iNAMPT mRNA resulting in a reduction of NAD(+) and decreased SIRT1 activity.[11]

Endurance-trained athletes have twice the expression of iNAMPT in skeletal muscle compared with sedentary type 2 diabetic persons.[12] In a six-week study comparing legs trained by endurance exercise with untrained legs, iNAMPT was increased in the endurance-trained legs.[12] A study of 21 young (under 36) and 22 old (over 54) adults subject to 12 weeks of aerobic and resistance exercise showed aerobic exercise to increase skeletal muscle iNAMPT 12% and 28% in young and old (respectively) and resistance exercise to increase skeletal muscle iNAMPT 25% and 30% in young and old (respectively).[13]

Aging, obesity, and chronic inflammation all reduce iNAMPT (and consequently NAD+) in multiple tissues,[14] and NAMPT activity was shown to promote a proinflammatory transcriptional reprogramming of immune cells (e.g. macrophages[15]) and brain-resident astrocytes.[16]

Function[edit]

iNAMPT catalyzes the condensation of nicotinamide (NAM) with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide (NMN), the first step in the biosynthesis of nicotinamide adenine dinucleotide (NAD+).[17] This salvage pathway, reusing NAM from enzymes using NAD+ (sirtuins, PARPs, CD38) and producing NAM as a waste product, is the major source of NAD+ production in the body.[17] De novo synthesis of NAD+ from tryptophan occurs only in the liver and kidney, overwhelmingly in the liver.[17]

Nomenclature[edit]

The systematic name of this enzyme class is nicotinamide-nucleotide:diphosphate phospho-alpha-D-ribosyltransferase. Other names in common use include:

  • NMN pyrophosphorylase,
  • nicotinamide mononucleotide pyrophosphorylase,
  • nicotinamide mononucleotide synthetase, and
  • NMN synthetase.

Extracellular NAMPT[edit]

Extracellular NAMPT (eNAMPT) is functionally different from intracellular NAMPT (iNAMPT), and less well understood (which is why the enzyme has been given so many names: NAMPT, PBEF and visfatin).[5] iNAMPT is secreted by many cell types (nobably adipocytes) to become eNAMPT. The sirtuin 1 (SIRT1) enzyme is required for eNAMPT secretion from adipose tissue.[18] eNAMPT may act more as a cytokine, although its receptor (possibly TLR4) has not been proven.[8] It has been demonstrated that eNAMPT could bind to and activate TLR4.[19]

eNAMPT can exist as a dimer or as a monomer, but is normally a circulating dimer.[18] As a monomer, eNAMPT has pro-inflammatory effects that are independent of NAD+, whereas the dimeric form of eNAMPT protects against these effects.[18]

eNAMPT/PBEF/visfatin was originally cloned as a putative cytokine shown to enhance the maturation of B cell precursors in the presence of Interleukin-7 (IL-7) and stem cell factor, it was therefore named "pre-B cell colony-enhancing factor" (PBEF).[6] When the gene encoding the bacterial nicotinamide phosphoribosyltransferase (nadV) was first isolated in Haemophilus ducreyi, it was found to exhibit significant homology to the mammalian PBEF gene.[20] Rongvaux et al.[21] demonstrated genetically that the mouse PBEF gene conferred Nampt enzymatic activity and NAD-independent growth to bacteria lacking nadV. Revollo et al.[22] determined biochemically that the mouse PBEF gene product encodes an eNAMPT enzyme, capable of modulating intracellular NAD levels. Others have since confirmed these findings.[23] More recently, several groups have reported the crystal structure of Nampt/PBEF/visfatin and they all show that this protein is a dimeric type II phosphoribosyltransferase enzyme involved in NAD biosynthesis.[24][25][26]

eNAMPT has been shown to be more enzymatically active than iNAMPT, supporting the proposal that eNAMPT from adipose tissue enhances NAD+ in tissues with low levels of iNAMPT, notably pancreatic beta cells and brain neurons.[27]

Hormone claim retracted[edit]

Although the original cytokine function of PBEF has not been confirmed to date, others have since reported or suggested a cytokine-like function for this protein.[28] In particular, Nampt/PBEF was recently re-identified as a "new visceral fat-derived hormone" named visfatin.[29] It is reported that visfatin is enriched in the visceral fat of both humans and mice and that its plasma levels increase during the development of obesity.[29] Noteworthy is that visfatin is reported to exert insulin-mimetic effects in cultured cells and to lower plasma glucose levels in mice by binding to and activating the insulin receptor.[29] However, the physiological relevance of visfatin is still in question because its plasma concentration is 40 to 100-fold lower than that of insulin despite having similar receptor-binding affinity.[29][30][31] In addition, the ability of visfatin to bind and activate the insulin-receptor has yet to be confirmed by other groups.

On 26 October 2007, A. Fukuhara (first author), I.Shimomura (senior author) and the other co-authors of the paper,[29] who first described Visfatin as a visceral-fat derived hormone that acts by binding and activating the insulin receptor, retracted the entire paper[29] at the suggestion of the editor of the journal 'Science' and recommendation of the Faculty Council of Osaka University Medical School after a report of the Committee for Research Integrity.[32]

As a drug target[edit]

Because cancer cells utilize increased glycolysis, and because NAD enhances glycolysis, iNAMPT is often amplified in cancer cells.[33][34] APO866 is an experimental drug that inhibits this enzyme.[35] It is being tested for treatment of advanced melanoma, cutaneous T-cell lymphoma (CTL), and refractory or relapsed B-chronic lymphocytic leukemia.

The NAMPT inhibitor FK866 has been shown to inhibit epithelial–mesenchymal transition (EMT), and may also inhibit tumor-associated angiogenesis.[9]

Anti-aging biomedical company Calico has licensed the experimental P7C3 analogs involved in enhancing iNAMPT activity.[36] P7C3 compounds have been shown in a number of publications to be beneficial in animal models for age-related neurodegeneration.[37][38]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000105835 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020572 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b Grolla AA, Travelli C, Genazzani AA, Sethi JK (July 2016). "Extracellular nicotinamide phosphoribosyltransferase, a new cancer metabokine". British Journal of Pharmacology. 173 (14): 2182–2194. doi:10.1111/bph.13505. PMC 4919578. PMID 27128025.
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  35. ^ APO866 Not Effective for Cutaneous T-Cell Lymphoma. March 2016
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Further reading[edit]

External links[edit]