Nicotinamide phosphoribosyltransferase

Last updated

NAMPT
Protein PBEF1 PDB 2g95.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NAMPT , 1110035O14Rik, PBEF, PBEF1, VF, VISFATIN, nicotinamide phosphoribosyltransferase
External IDs OMIM: 608764; MGI: 1929865; HomoloGene: 4201; GeneCards: NAMPT; OMA:NAMPT - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10135

59027

Ensembl

ENSG00000105835

ENSMUSG00000020572

UniProt

P43490

Q99KQ4

RefSeq (mRNA)

NM_005746
NM_182790

NM_021524

RefSeq (protein)

NP_005737

NP_067499

Location (UCSC) Chr 7: 106.25 – 106.29 Mb Chr 12: 32.87 – 32.9 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
nicotinamide phosphoribosyltransferase
Identifiers
EC no. 2.4.2.12
CAS no. 9030-27-7
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
Search
PMC articles
PubMed articles
NCBI proteins

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

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

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

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

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

Extracellular NAMPT

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

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

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]

Related Research Articles

<span class="mw-page-title-main">Nicotinamide adenine dinucleotide</span> Chemical compound which is reduced and oxidized

Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other, nicotinamide. NAD exists in two forms: an oxidized and reduced form, abbreviated as NAD+ and NADH (H for hydrogen), respectively.

<span class="mw-page-title-main">Poly (ADP-ribose) polymerase</span> Family of proteins

Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death.

<span class="mw-page-title-main">CD38</span> Protein-coding gene in the species Homo sapiens

CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase is a glycoprotein found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes and natural killer cells. CD38 also functions in cell adhesion, signal transduction and calcium signaling.

<span class="mw-page-title-main">Sirtuin</span> Enzyme

Sirtuins are a family of signaling proteins involved in metabolic regulation. They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. Chemically, sirtuins are a class of proteins that possess either mono-ADP-ribosyltransferase or deacylase activity, including deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity. The name Sir2 comes from the yeast gene 'silent mating-type information regulation 2', the gene responsible for cellular regulation in yeast.

<span class="mw-page-title-main">CLOCK</span> Human protein and coding gene

CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.

<span class="mw-page-title-main">PARP1</span> Mammalian protein found in Homo sapiens

Poly [ADP-ribose] polymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly[ADP-ribose] synthase 1 is an enzyme that in humans is encoded by the PARP1 gene. It is the most abundant of the PARP family of enzymes, accounting for 90% of the NAD+ used by the family. PARP1 is mostly present in cell nucleus, but cytosolic fraction of this protein was also reported.

<span class="mw-page-title-main">Nicotinamide-nucleotide adenylyltransferase</span>

In enzymology, nicotinamide-nucleotide adenylyltransferase (NMNAT) (EC 2.7.7.1) are enzymes that catalyzes the chemical reaction

<span class="mw-page-title-main">Sirtuin 1</span> Protein

Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.

<span class="mw-page-title-main">NMNAT1</span> Protein-coding gene in the species Homo sapiens

Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) is an enzyme that in humans is encoded by the nmnat1 gene. It is a member of the nicotinamide-nucleotide adenylyltransferases (NMNATs) which catalyze nicotinamide adenine dinucleotide (NAD) synthesis.

<span class="mw-page-title-main">NNMT</span> Protein-coding gene in humans

Nicotinamide N-methyltransferase (NNMT) is an enzyme that in humans is encoded by the NNMT gene. NNMT catalyzes the methylation of nicotinamide and similar compounds using the methyl donor S-adenosyl methionine (SAM-e) to produce S-adenosyl-L-homocysteine (SAH) and 1-methylnicotinamide.

<span class="mw-page-title-main">NMNAT2</span> Protein-coding gene in the species Homo sapiens

Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is an enzyme that in humans is encoded by the NMNAT2 gene.

Sirtuin-activating compounds (STAC) are chemical compounds having an effect on sirtuins, a group of enzymes that use NAD+ to remove acetyl groups from proteins. They are caloric restriction mimetic compounds that may be helpful in treating various aging-related diseases.

<span class="mw-page-title-main">P7C3</span> Chemical compound

P7C3 (pool 7, compound 3) is a drug related to latrepirdine (dimebon) which has neuroprotective and proneurogenic effects and may be potentially useful for the treatment of Alzheimer's disease and similar neurodegenerative disorders. The pharmacological effects of P7C3 in vitro resemble those of endogenous proneurogenic peptides such as fibroblast growth factor 1 (FGF-1), and the proneurogenic activity of P7C3 was around thirty times that of latrepirdine when they were compared in mice. P7C3 was chosen for further animal studies on the basis of favorable pharmacokinetic factors, such as its high oral bioavailability and long duration of action, but several other related compounds showed similar activity such as the more potent fluorinated analogue P7C3A20 which is up to ten times stronger again, and the methoxy analogue P7C3-OMe, for which it was determined that the (R) enantiomer is the active form.

<span class="mw-page-title-main">Nicotinamide riboside</span> Chemical compound

Nicotinamide riboside (NR, SR647) is a pyridine-nucleoside and a form of vitamin B3. It functions as a precursor to nicotinamide adenine dinucleotide, or NAD+, through a two-step and a three-step pathway.

<span class="mw-page-title-main">MIR34A</span> Non-coding RNA in the species Homo sapiens

MicroRNA 34a (miR-34a) is a MicroRNA that in humans is encoded by the MIR34A gene.

The Nicotinamide Ribonucleoside (NR) Uptake Permease (PnuC) Family is a family of transmembrane transporters that is part of the TOG superfamily. Close PnuC homologues are found in a wide range of Gram-negative and Gram-positive bacteria, archaea and eukaryotes.

<span class="mw-page-title-main">Nicotinamide mononucleotide</span> Chemical compound

Nicotinamide mononucleotide is a nucleotide derived from ribose, nicotinamide, nicotinamide riboside and niacin. In humans, several enzymes use NMN to generate nicotinamide adenine dinucleotide (NADH). In mice, it has been proposed that NMN is absorbed via the small intestine within 10 minutes of oral uptake and converted to nicotinamide adenine dinucleotide (NAD+) through the Slc12a8 transporter. However, this observation has been challenged, and the matter remains unsettled.

Nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3) is an enzyme that in humans is encoded by the NMNAT3 gene.

<span class="mw-page-title-main">SARM1</span> Protein-coding gene in the species Homo sapiens

Sterile alpha and TIR motif containing 1 Is an enzyme that in humans is encoded by the SARM1 gene. It is the most evolutionarily conserved member of the Toll/Interleukin receptor-1 (TIR) family. SARM1's TIR domain has intrinsic NADase enzymatic activity that is highly conserved from archaea, plants, nematode worms, fruit flies, and humans. In mammals, SARM1 is highly expressed in neurons, where it resides in both cell bodies and axons, and can be associated with mitochondria.

<span class="mw-page-title-main">CD38-IN-78c</span> Chemical compound

CD38-IN-78c is a drug which acts as a potent and selective inhibitor of the glycoprotein enzyme CD38. In animal studies it boosts levels of nicotinamide adenine dinucleotide (NAD+) in tissues via inhibition of CD38 mediated breakdown of nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), and has been shown to ameliorate metabolic dysfunction associated with the aging process. It also has potential therapeutic application in the treatment of asthma.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000105835 – Ensembl, May 2017
  2. 1 2 3 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. 1 2 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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  11. ↑ Choi SE, Fu T, Seok S, Kim DH, Yu E, Lee KW, et al. (December 2013). "Elevated microRNA-34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT". Aging Cell. 12 (6): 1062–1072. doi:10.1111/acel.12135. PMC   3838500 . PMID   23834033.
  12. 1 2 Jadeja RN, Thounaojam MC, Bartoli M, Martin PM (2020). "Implications of NAD+ Metabolism in the Aging Retina and Retinal Degeneration". Oxidative Medicine and Cellular Longevity. 2020: 2692794. doi: 10.1155/2020/2692794 . PMC   7238357 . PMID   32454935.
  13. ↑ de Guia RM, Agerholm M, Nielsen TS, Consitt LA, Søgaard D, Helge JW, et al. (July 2019). "Aerobic and resistance exercise training reverses age-dependent decline in NAD+ salvage capacity in human skeletal muscle". Physiological Reports. 7 (12): e14139. doi:10.14814/phy2.14139. PMC   6577427 . PMID   31207144.
  14. ↑ Poljsak B (June 2018). "NAMPT-Mediated NAD Biosynthesis as the Internal Timing Mechanism: In NAD+ World, Time Is Running in Its Own Way". Rejuvenation Research. 21 (3): 210–224. doi:10.1089/rej.2017.1975. PMID   28756747. S2CID   196644501.
  15. ↑ Cameron AM, Castoldi A, Sanin DE, Flachsmann LJ, Field CS, Puleston DJ, et al. (April 2019). "Inflammatory macrophage dependence on NAD+ salvage is a consequence of reactive oxygen species-mediated DNA damage". Nature Immunology. 20 (4): 420–432. doi:10.1038/s41590-019-0336-y. PMID   30858618. S2CID   73728924.
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  19. ↑ Camp SM, Ceco E, Evenoski CL, Danilov SM, Zhou T, Chiang ET, et al. (August 2015). "Unique Toll-Like Receptor 4 Activation by NAMPT/PBEF Induces NFκB Signaling and Inflammatory Lung Injury". Scientific Reports. 5: 13135. Bibcode:2015NatSR...513135C. doi:10.1038/srep13135. PMC   4536637 . PMID   26272519.
  20. ↑ Martin PR, Shea RJ, Mulks MH (February 2001). "Identification of a plasmid-encoded gene from Haemophilus ducreyi which confers NAD independence". Journal of Bacteriology. 183 (4): 1168–1174. doi:10.1128/JB.183.4.1168-1174.2001. PMC   94989 . PMID   11157928.
  21. ↑ Rongvaux A, Shea RJ, Mulks MH, Gigot D, Urbain J, Leo O, et al. (November 2002). "Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis". European Journal of Immunology. 32 (11): 3225–3234. doi: 10.1002/1521-4141(200211)32:11<3225::AID-IMMU3225>3.0.CO;2-L . PMID   12555668. S2CID   11043568.
  22. ↑ Revollo JR, Grimm AA, Imai S (December 2004). "The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells". The Journal of Biological Chemistry. 279 (49): 50754–50763. doi: 10.1074/jbc.M408388200 . PMID   15381699.
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  24. ↑ Wang T, Zhang X, Bheda P, Revollo JR, Imai S, Wolberger C (July 2006). "Structure of Nampt/PBEF/visfatin, a mammalian NAD+ biosynthetic enzyme". Nature Structural & Molecular Biology. 13 (7): 661–662. doi:10.1038/nsmb1114. PMID   16783373. S2CID   28674013.
  25. ↑ Kim MK, Lee JH, Kim H, Park SJ, Kim SH, Kang GB, et al. (September 2006). "Crystal structure of visfatin/pre-B cell colony-enhancing factor 1/nicotinamide phosphoribosyltransferase, free and in complex with the anti-cancer agent FK-866". Journal of Molecular Biology. 362 (1): 66–77. doi:10.1016/j.jmb.2006.06.082. PMID   16901503.
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  27. ↑ Imai SI (2016). "The NAD World 2.0: the importance of the inter-tissue communication mediated by NAMPT/NAD+/SIRT1 in mammalian aging and longevity control". npj Systems Biology and Applications. 2: 16018. doi:10.1038/npjsba.2016.18. PMC   5516857 . PMID   28725474.
  28. ↑ Jia SH, Li Y, Parodo J, Kapus A, Fan L, Rotstein OD, et al. (May 2004). "Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis". The Journal of Clinical Investigation. 113 (9): 1318–1327. doi:10.1172/JCI19930. PMC   398427 . PMID   15124023.
  29. 1 2 3 4 5 6 Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, et al. (January 2005). "Visfatin: a protein secreted by visceral fat that mimics the effects of insulin". Science. 307 (5708): 426–430. Bibcode:2005Sci...307..426F. doi: 10.1126/science.1097243 . PMID   15604363. S2CID   86231101. (Retracted, see doi:10.1126/science.318.5850.565b, PMID   17962537,  Retraction Watch)
  30. ↑ Stephens JM, Vidal-Puig AJ (April 2006). "An update on visfatin/pre-B cell colony-enhancing factor, an ubiquitously expressed, illusive cytokine that is regulated in obesity". Current Opinion in Lipidology. 17 (2): 128–131. doi:10.1097/01.mol.0000217893.77746.4b. PMID   16531748. S2CID   46178743.
  31. ↑ Arner P (January 2006). "Visfatin--a true or false trail to type 2 diabetes mellitus". The Journal of Clinical Endocrinology and Metabolism. 91 (1): 28–30. doi: 10.1210/jc.2005-2391 . PMID   16401830.
  32. ↑ Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, et al. (October 2007). "Retraction". Science. 318 (5850): 565. doi:10.1126/science.318.5850.565b. PMID   17962537. S2CID   220091956.
  33. ↑ Yaku K, Okabe K, Hikosaka K, Nakagawa T (2018). "NAD Metabolism in Cancer Therapeutics". Frontiers in Oncology. 8: 622. doi: 10.3389/fonc.2018.00622 . PMC   6315198 . PMID   30631755.
  34. ↑ Pramono AA, Rather GM, Herman H, Lestari K, Bertino JR (February 2020). "NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview". Biomolecules. 10 (3): 358. doi: 10.3390/biom10030358 . PMC   7175141 . PMID   32111066.
  35. ↑ APO866 Not Effective for Cutaneous T-Cell Lymphoma. March 2016
  36. ↑ "UT Southwestern researchers discover novel class of NAMPT activators for neurodegenerative disease; Calico enters into exclusive collaboration with 2M to develop UTSW technology" (Press release).
  37. ↑ Cain C (2014). "NAMPT neuroprotection". Science-Business EXchange. 7 (38): 1112. doi:10.1038/scibx.2014.1112.
  38. ↑ Wang G, Han T, Nijhawan D, Theodoropoulos P, Naidoo J, Yadavalli S, et al. (September 2014). "P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage". Cell. 158 (6): 1324–1334. doi:10.1016/j.cell.2014.07.040. PMC   4163014 . PMID   25215490.

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