Full text data of NAMPT
NAMPT
(PBEF, PBEF1)
[Confidence: low (only semi-automatic identification from reviews)]
Nicotinamide phosphoribosyltransferase; NAmPRTase; Nampt; 2.4.2.12 (Pre-B-cell colony-enhancing factor 1; Pre-B cell-enhancing factor; Visfatin)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Nicotinamide phosphoribosyltransferase; NAmPRTase; Nampt; 2.4.2.12 (Pre-B-cell colony-enhancing factor 1; Pre-B cell-enhancing factor; Visfatin)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P43490
ID NAMPT_HUMAN Reviewed; 491 AA.
AC P43490; A4D0Q9; A4D0R0; Q3KQV0; Q8WW95;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1995, sequence version 1.
DT 22-JAN-2014, entry version 129.
DE RecName: Full=Nicotinamide phosphoribosyltransferase;
DE Short=NAmPRTase;
DE Short=Nampt;
DE EC=2.4.2.12;
DE AltName: Full=Pre-B-cell colony-enhancing factor 1;
DE Short=Pre-B cell-enhancing factor;
DE AltName: Full=Visfatin;
GN Name=NAMPT; Synonyms=PBEF, PBEF1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Blood;
RX PubMed=8289818;
RA Samal B., Sun Y., Stearns G., Xie C., Suggs S., McNiece I.;
RT "Cloning and characterization of the cDNA encoding a novel human pre-
RT B-cell colony-enhancing factor.";
RL Mol. Cell. Biol. 14:1431-1437(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Trachea;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R.,
RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H.,
RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A.,
RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J.,
RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A.,
RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S.,
RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M.,
RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C.,
RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P.,
RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J.,
RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L.,
RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R.,
RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K.,
RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S.,
RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M.,
RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R.,
RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D.,
RA Waterston R.H., Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S.,
RA Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z.,
RA Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C.,
RA Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J.,
RA Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F.,
RA Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F.,
RA Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H.,
RA Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G.,
RA Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P.,
RA Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J.,
RA Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F.,
RA Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B.,
RA Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W.,
RA Mural R.J., Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [8]
RP REVIEW.
RX PubMed=22462624; DOI=10.1146/annurev-nutr-071811-150746;
RA Dahl T.B., Holm S., Aukrust P., Halvorsen B.;
RT "Visfatin/NAMPT: a multifaceted molecule with diverse roles in
RT physiology and pathophysiology.";
RL Annu. Rev. Nutr. 32:229-243(2012).
RN [9]
RP SUBCELLULAR LOCATION.
RX PubMed=21741723; DOI=10.1016/j.diabres.2011.06.009;
RA Bienertova-Vasku J., Bienert P., Zlamal F., Tomandl J., Tomandlova M.,
RA Dostalova Z., Vasku A.;
RT "Visfatin is secreted into the breast milk and is correlated with
RT weight changes of the infant after the birth.";
RL Diabetes Res. Clin. Pract. 96:355-361(2012).
RN [10]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=24130902; DOI=10.1371/journal.pone.0078283;
RA Romacho T., Villalobos L.A., Cercas E., Carraro R.,
RA Sanchez-Ferrer C.F., Peiro C.;
RT "Visfatin as a novel mediator released by inflamed human endothelial
RT cells.";
RL PLoS ONE 8:E78283-E78283(2013).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) IN COMPLEXES WITH SUBSTRATE;
RP PRODUCT AND INHIBITOR FK866, ENZYME REGULATION, MUTAGENESIS OF
RP ASP-219; HIS-247 AND ARG-311, AND SUBUNIT.
RX PubMed=16783377; DOI=10.1038/nsmb1105;
RA Khan J.A., Tao X., Tong L.;
RT "Molecular basis for the inhibition of human NMPRTase, a novel target
RT for anticancer agents.";
RL Nat. Struct. Mol. Biol. 13:582-588(2006).
RN [12]
RP VARIANT [LARGE SCALE ANALYSIS] SER-176.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Catalyzes the condensation of nicotinamide with 5-
CC phosphoribosyl-1-pyrophosphate to yield nicotinamide
CC mononucleotide, an intermediate in the biosynthesis of NAD. It is
CC the rate limiting component in the mammalian NAD biosynthesis
CC pathway. The secreted form behaves both as a cytokine with
CC immunomodulating properties and an adipokine with anti-diabetic
CC properties, it has no enzymatic activity, partly because of lack
CC of activation by ATP, which has a low level in extracellular space
CC and plasma.
CC -!- CATALYTIC ACTIVITY: Nicotinamide D-ribonucleotide + diphosphate =
CC nicotinamide + 5-phospho-alpha-D-ribose 1-diphosphate.
CC -!- ENZYME REGULATION: Inhibited by FK866. FK866 competes for the same
CC binding site as nicotinamide, but due to its very low dissociation
CC rate, it is essentially an irreversible inhibitor.
CC -!- PATHWAY: Cofactor biosynthesis; NAD(+) biosynthesis; nicotinamide
CC D-ribonucleotide from 5-phospho-alpha-D-ribose 1-diphosphate and
CC nicotinamide: step 1/1.
CC -!- SUBUNIT: Homodimer.
CC -!- INTERACTION:
CC P02792:FTL; NbExp=3; IntAct=EBI-2829310, EBI-713279;
CC Q01628:IFITM3; NbExp=3; IntAct=EBI-2829310, EBI-7932862;
CC P03886:MT-ND1; NbExp=3; IntAct=EBI-2829310, EBI-1246156;
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm (By similarity).
CC Secreted. Note=Under non-inflammatory conditions, visfatin
CC predominantly exhibits a granular pattern within the nucleus.
CC Secreted by endothelial cells upon IL-1beta stimulation.
CC Abundantly secreted in milk, reaching 100-fold higher
CC concentrations compared to maternal serum.
CC -!- TISSUE SPECIFICITY: Expressed in large amounts in bone marrow,
CC liver tissue, and muscle. Also present in heart, placenta, lung,
CC and kidney tissues.
CC -!- SIMILARITY: Belongs to the NAPRTase family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAQ96862.1; Type=Erroneous gene model prediction;
CC Sequence=EAL24400.1; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/NAMPTID43890ch7q22.html";
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DR EMBL; U02020; AAA17884.1; -; mRNA.
DR EMBL; AK292851; BAF85540.1; -; mRNA.
DR EMBL; AC007032; AAF19249.1; -; Genomic_DNA.
DR EMBL; AC007032; AAQ96862.1; ALT_SEQ; Genomic_DNA.
DR EMBL; CH236947; EAL24399.1; -; Genomic_DNA.
DR EMBL; CH236947; EAL24400.1; ALT_SEQ; Genomic_DNA.
DR EMBL; CH471070; EAW83382.1; -; Genomic_DNA.
DR EMBL; BC072439; AAH72439.1; -; mRNA.
DR EMBL; BC106046; AAI06047.1; -; mRNA.
DR PIR; A55927; A55927.
DR RefSeq; NP_005737.1; NM_005746.2.
DR RefSeq; XP_005250157.1; XM_005250100.1.
DR RefSeq; XP_005250158.1; XM_005250101.1.
DR UniGene; Hs.489615; -.
DR PDB; 2E5B; X-ray; 2.00 A; A/B=1-491.
DR PDB; 2E5C; X-ray; 2.20 A; A/B=1-491.
DR PDB; 2E5D; X-ray; 2.00 A; A/B=1-491.
DR PDB; 2GVG; X-ray; 2.20 A; A/B/C/D/E/F=1-491.
DR PDB; 2GVJ; X-ray; 2.10 A; A/B=1-491.
DR PDB; 3DGR; X-ray; 2.10 A; A/B=1-484.
DR PDB; 3DHD; X-ray; 2.00 A; A/B=1-484.
DR PDB; 3DHF; X-ray; 1.80 A; A/B=1-484.
DR PDB; 3DKJ; X-ray; 2.00 A; A/B=1-484.
DR PDB; 3DKL; X-ray; 1.89 A; A/B=1-484.
DR PDB; 4JNM; X-ray; 2.20 A; A/B=1-491.
DR PDB; 4JR5; X-ray; 1.91 A; A/B=1-491.
DR PDB; 4KFN; X-ray; 1.60 A; A/B=1-491.
DR PDB; 4KFO; X-ray; 1.60 A; A/B=1-491.
DR PDB; 4KFP; X-ray; 1.84 A; A/B=1-491.
DR PDB; 4LV9; X-ray; 1.81 A; A/B=1-491.
DR PDB; 4LVA; X-ray; 1.55 A; A/B=1-491.
DR PDB; 4LVB; X-ray; 1.84 A; A/B=1-491.
DR PDB; 4LVD; X-ray; 1.75 A; A/B=1-491.
DR PDB; 4LVF; X-ray; 1.50 A; A/B=1-491.
DR PDB; 4LVG; X-ray; 1.70 A; A/B=1-491.
DR PDB; 4M6P; X-ray; 1.75 A; A/B=1-491.
DR PDB; 4M6Q; X-ray; 2.41 A; A/B=1-491.
DR PDBsum; 2E5B; -.
DR PDBsum; 2E5C; -.
DR PDBsum; 2E5D; -.
DR PDBsum; 2GVG; -.
DR PDBsum; 2GVJ; -.
DR PDBsum; 3DGR; -.
DR PDBsum; 3DHD; -.
DR PDBsum; 3DHF; -.
DR PDBsum; 3DKJ; -.
DR PDBsum; 3DKL; -.
DR PDBsum; 4JNM; -.
DR PDBsum; 4JR5; -.
DR PDBsum; 4KFN; -.
DR PDBsum; 4KFO; -.
DR PDBsum; 4KFP; -.
DR PDBsum; 4LV9; -.
DR PDBsum; 4LVA; -.
DR PDBsum; 4LVB; -.
DR PDBsum; 4LVD; -.
DR PDBsum; 4LVF; -.
DR PDBsum; 4LVG; -.
DR PDBsum; 4M6P; -.
DR PDBsum; 4M6Q; -.
DR ProteinModelPortal; P43490; -.
DR SMR; P43490; 8-489.
DR DIP; DIP-29218N; -.
DR IntAct; P43490; 10.
DR MINT; MINT-4530953; -.
DR STRING; 9606.ENSP00000222553; -.
DR BindingDB; P43490; -.
DR ChEMBL; CHEMBL1744525; -.
DR PhosphoSite; P43490; -.
DR DMDM; 1172027; -.
DR PaxDb; P43490; -.
DR PRIDE; P43490; -.
DR DNASU; 10135; -.
DR Ensembl; ENST00000222553; ENSP00000222553; ENSG00000105835.
DR Ensembl; ENST00000354289; ENSP00000346242; ENSG00000105835.
DR GeneID; 10135; -.
DR KEGG; hsa:10135; -.
DR UCSC; uc003vdq.3; human.
DR CTD; 10135; -.
DR GeneCards; GC07M105888; -.
DR HGNC; HGNC:30092; NAMPT.
DR HPA; CAB034349; -.
DR MIM; 608764; gene.
DR neXtProt; NX_P43490; -.
DR PharmGKB; PA162396933; -.
DR eggNOG; COG1488; -.
DR HOGENOM; HOG000216546; -.
DR HOVERGEN; HBG000336; -.
DR InParanoid; P43490; -.
DR KO; K03462; -.
DR OMA; SHYLQYP; -.
DR OrthoDB; EOG7PGDQH; -.
DR PhylomeDB; P43490; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_24941; Circadian Clock.
DR SABIO-RK; P43490; -.
DR UniPathway; UPA00253; UER00890.
DR ChiTaRS; NAMPT; human.
DR EvolutionaryTrace; P43490; -.
DR GeneWiki; Nicotinamide_phosphoribosyltransferase; -.
DR GenomeRNAi; 10135; -.
DR NextBio; 38341; -.
DR PRO; PR:P43490; -.
DR ArrayExpress; P43490; -.
DR Bgee; P43490; -.
DR CleanEx; HS_NAMPT; -.
DR Genevestigator; P43490; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005125; F:cytokine activity; TAS:ProtInc.
DR GO; GO:0047280; F:nicotinamide phosphoribosyltransferase activity; IEA:UniProtKB-EC.
DR GO; GO:0004514; F:nicotinate-nucleotide diphosphorylase (carboxylating) activity; IEA:InterPro.
DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR GO; GO:0009435; P:NAD biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0019674; P:NAD metabolic process; TAS:Reactome.
DR GO; GO:0006769; P:nicotinamide metabolic process; TAS:Reactome.
DR GO; GO:0008284; P:positive regulation of cell proliferation; TAS:ProtInc.
DR GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:BHF-UCL.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR InterPro; IPR007229; Nic_PRibTrfase-Fam.
DR InterPro; IPR016471; Nicotinamide_PRibTrfase.
DR InterPro; IPR002638; Quinolinate_PRibosylTrfase_C.
DR PANTHER; PTHR11098:SF2; PTHR11098:SF2; 1.
DR Pfam; PF04095; NAPRTase; 1.
DR PIRSF; PIRSF005943; NMPRT; 1.
DR SUPFAM; SSF51690; SSF51690; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Cytokine; Cytoplasm;
KW Glycosyltransferase; Nucleus; Polymorphism;
KW Pyridine nucleotide biosynthesis; Reference proteome; Secreted;
KW Transferase.
FT CHAIN 1 491 Nicotinamide phosphoribosyltransferase.
FT /FTId=PRO_0000205863.
FT REGION 311 313 Nicotinamide ribonucleotide binding.
FT REGION 353 354 Nicotinamide ribonucleotide binding.
FT BINDING 196 196 Diphosphate.
FT BINDING 219 219 Nicotinamide ribonucleotide.
FT BINDING 247 247 Diphosphate.
FT BINDING 311 311 Diphosphate.
FT BINDING 384 384 Nicotinamide ribonucleotide; via amide
FT nitrogen.
FT BINDING 392 392 Nicotinamide ribonucleotide.
FT VARIANT 176 176 L -> S (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036614.
FT MUTAGEN 219 219 D->N,S: No effect on activity towards
FT nicotinamide. Alters specificity, so that
FT the enzyme acquires activity towards
FT nicotinic acid.
FT MUTAGEN 247 247 H->A: Reduces activity towards
FT nicotinamide.
FT MUTAGEN 311 311 R->D: Reduces activity towards
FT nicotinamide.
FT HELIX 11 13
FT STRAND 14 16
FT HELIX 17 24
FT STRAND 30 39
FT STRAND 56 58
FT HELIX 62 69
FT HELIX 77 91
FT HELIX 98 108
FT STRAND 114 118
FT STRAND 124 126
FT STRAND 129 138
FT HELIX 139 141
FT HELIX 144 147
FT HELIX 149 153
FT HELIX 156 180
FT HELIX 186 188
FT STRAND 189 192
FT HELIX 195 197
FT HELIX 201 211
FT TURN 212 214
FT STRAND 216 220
FT HELIX 222 230
FT STRAND 234 236
FT HELIX 247 251
FT HELIX 255 257
FT HELIX 258 268
FT STRAND 270 272
FT STRAND 274 277
FT HELIX 283 288
FT HELIX 289 294
FT HELIX 296 299
FT STRAND 308 311
FT HELIX 317 331
FT STRAND 338 340
FT STRAND 348 352
FT HELIX 358 370
FT HELIX 375 377
FT STRAND 378 383
FT HELIX 384 387
FT TURN 392 396
FT STRAND 397 406
FT STRAND 409 412
FT HELIX 421 423
FT STRAND 431 434
FT STRAND 440 443
FT HELIX 447 450
FT STRAND 453 455
FT STRAND 459 463
FT HELIX 473 479
FT TURN 483 485
SQ SEQUENCE 491 AA; 55521 MW; 6BF07B631B589AC0 CRC64;
MNPAAEAEFN ILLATDSYKV THYKQYPPNT SKVYSYFECR EKKTENSKLR KVKYEETVFY
GLQYILNKYL KGKVVTKEKI QEAKDVYKEH FQDDVFNEKG WNYILEKYDG HLPIEIKAVP
EGFVIPRGNV LFTVENTDPE CYWLTNWIET ILVQSWYPIT VATNSREQKK ILAKYLLETS
GNLDGLEYKL HDFGYRGVSS QETAGIGASA HLVNFKGTDT VAGLALIKKY YGTKDPVPGY
SVPAAEHSTI TAWGKDHEKD AFEHIVTQFS SVPVSVVSDS YDIYNACEKI WGEDLRHLIV
SRSTQAPLII RPDSGNPLDT VLKVLEILGK KFPVTENSKG YKLLPPYLRV IQGDGVDINT
LQEIVEGMKQ KMWSIENIAF GSGGGLLQKL TRDLLNCSFK CSYVVTNGLG INVFKDPVAD
PNKRSKKGRL SLHRTPAGNF VTLEEGKGDL EEYGQDLLHT VFKNGKVTKS YSFDEIRKNA
QLNIELEAAH H
//
ID NAMPT_HUMAN Reviewed; 491 AA.
AC P43490; A4D0Q9; A4D0R0; Q3KQV0; Q8WW95;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1995, sequence version 1.
DT 22-JAN-2014, entry version 129.
DE RecName: Full=Nicotinamide phosphoribosyltransferase;
DE Short=NAmPRTase;
DE Short=Nampt;
DE EC=2.4.2.12;
DE AltName: Full=Pre-B-cell colony-enhancing factor 1;
DE Short=Pre-B cell-enhancing factor;
DE AltName: Full=Visfatin;
GN Name=NAMPT; Synonyms=PBEF, PBEF1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Blood;
RX PubMed=8289818;
RA Samal B., Sun Y., Stearns G., Xie C., Suggs S., McNiece I.;
RT "Cloning and characterization of the cDNA encoding a novel human pre-
RT B-cell colony-enhancing factor.";
RL Mol. Cell. Biol. 14:1431-1437(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Trachea;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R.,
RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H.,
RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A.,
RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J.,
RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A.,
RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S.,
RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M.,
RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C.,
RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P.,
RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J.,
RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L.,
RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R.,
RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K.,
RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S.,
RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M.,
RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R.,
RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D.,
RA Waterston R.H., Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S.,
RA Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z.,
RA Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C.,
RA Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J.,
RA Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F.,
RA Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F.,
RA Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H.,
RA Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G.,
RA Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P.,
RA Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J.,
RA Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F.,
RA Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B.,
RA Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W.,
RA Mural R.J., Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [8]
RP REVIEW.
RX PubMed=22462624; DOI=10.1146/annurev-nutr-071811-150746;
RA Dahl T.B., Holm S., Aukrust P., Halvorsen B.;
RT "Visfatin/NAMPT: a multifaceted molecule with diverse roles in
RT physiology and pathophysiology.";
RL Annu. Rev. Nutr. 32:229-243(2012).
RN [9]
RP SUBCELLULAR LOCATION.
RX PubMed=21741723; DOI=10.1016/j.diabres.2011.06.009;
RA Bienertova-Vasku J., Bienert P., Zlamal F., Tomandl J., Tomandlova M.,
RA Dostalova Z., Vasku A.;
RT "Visfatin is secreted into the breast milk and is correlated with
RT weight changes of the infant after the birth.";
RL Diabetes Res. Clin. Pract. 96:355-361(2012).
RN [10]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=24130902; DOI=10.1371/journal.pone.0078283;
RA Romacho T., Villalobos L.A., Cercas E., Carraro R.,
RA Sanchez-Ferrer C.F., Peiro C.;
RT "Visfatin as a novel mediator released by inflamed human endothelial
RT cells.";
RL PLoS ONE 8:E78283-E78283(2013).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) IN COMPLEXES WITH SUBSTRATE;
RP PRODUCT AND INHIBITOR FK866, ENZYME REGULATION, MUTAGENESIS OF
RP ASP-219; HIS-247 AND ARG-311, AND SUBUNIT.
RX PubMed=16783377; DOI=10.1038/nsmb1105;
RA Khan J.A., Tao X., Tong L.;
RT "Molecular basis for the inhibition of human NMPRTase, a novel target
RT for anticancer agents.";
RL Nat. Struct. Mol. Biol. 13:582-588(2006).
RN [12]
RP VARIANT [LARGE SCALE ANALYSIS] SER-176.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Catalyzes the condensation of nicotinamide with 5-
CC phosphoribosyl-1-pyrophosphate to yield nicotinamide
CC mononucleotide, an intermediate in the biosynthesis of NAD. It is
CC the rate limiting component in the mammalian NAD biosynthesis
CC pathway. The secreted form behaves both as a cytokine with
CC immunomodulating properties and an adipokine with anti-diabetic
CC properties, it has no enzymatic activity, partly because of lack
CC of activation by ATP, which has a low level in extracellular space
CC and plasma.
CC -!- CATALYTIC ACTIVITY: Nicotinamide D-ribonucleotide + diphosphate =
CC nicotinamide + 5-phospho-alpha-D-ribose 1-diphosphate.
CC -!- ENZYME REGULATION: Inhibited by FK866. FK866 competes for the same
CC binding site as nicotinamide, but due to its very low dissociation
CC rate, it is essentially an irreversible inhibitor.
CC -!- PATHWAY: Cofactor biosynthesis; NAD(+) biosynthesis; nicotinamide
CC D-ribonucleotide from 5-phospho-alpha-D-ribose 1-diphosphate and
CC nicotinamide: step 1/1.
CC -!- SUBUNIT: Homodimer.
CC -!- INTERACTION:
CC P02792:FTL; NbExp=3; IntAct=EBI-2829310, EBI-713279;
CC Q01628:IFITM3; NbExp=3; IntAct=EBI-2829310, EBI-7932862;
CC P03886:MT-ND1; NbExp=3; IntAct=EBI-2829310, EBI-1246156;
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm (By similarity).
CC Secreted. Note=Under non-inflammatory conditions, visfatin
CC predominantly exhibits a granular pattern within the nucleus.
CC Secreted by endothelial cells upon IL-1beta stimulation.
CC Abundantly secreted in milk, reaching 100-fold higher
CC concentrations compared to maternal serum.
CC -!- TISSUE SPECIFICITY: Expressed in large amounts in bone marrow,
CC liver tissue, and muscle. Also present in heart, placenta, lung,
CC and kidney tissues.
CC -!- SIMILARITY: Belongs to the NAPRTase family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAQ96862.1; Type=Erroneous gene model prediction;
CC Sequence=EAL24400.1; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/NAMPTID43890ch7q22.html";
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DR EMBL; U02020; AAA17884.1; -; mRNA.
DR EMBL; AK292851; BAF85540.1; -; mRNA.
DR EMBL; AC007032; AAF19249.1; -; Genomic_DNA.
DR EMBL; AC007032; AAQ96862.1; ALT_SEQ; Genomic_DNA.
DR EMBL; CH236947; EAL24399.1; -; Genomic_DNA.
DR EMBL; CH236947; EAL24400.1; ALT_SEQ; Genomic_DNA.
DR EMBL; CH471070; EAW83382.1; -; Genomic_DNA.
DR EMBL; BC072439; AAH72439.1; -; mRNA.
DR EMBL; BC106046; AAI06047.1; -; mRNA.
DR PIR; A55927; A55927.
DR RefSeq; NP_005737.1; NM_005746.2.
DR RefSeq; XP_005250157.1; XM_005250100.1.
DR RefSeq; XP_005250158.1; XM_005250101.1.
DR UniGene; Hs.489615; -.
DR PDB; 2E5B; X-ray; 2.00 A; A/B=1-491.
DR PDB; 2E5C; X-ray; 2.20 A; A/B=1-491.
DR PDB; 2E5D; X-ray; 2.00 A; A/B=1-491.
DR PDB; 2GVG; X-ray; 2.20 A; A/B/C/D/E/F=1-491.
DR PDB; 2GVJ; X-ray; 2.10 A; A/B=1-491.
DR PDB; 3DGR; X-ray; 2.10 A; A/B=1-484.
DR PDB; 3DHD; X-ray; 2.00 A; A/B=1-484.
DR PDB; 3DHF; X-ray; 1.80 A; A/B=1-484.
DR PDB; 3DKJ; X-ray; 2.00 A; A/B=1-484.
DR PDB; 3DKL; X-ray; 1.89 A; A/B=1-484.
DR PDB; 4JNM; X-ray; 2.20 A; A/B=1-491.
DR PDB; 4JR5; X-ray; 1.91 A; A/B=1-491.
DR PDB; 4KFN; X-ray; 1.60 A; A/B=1-491.
DR PDB; 4KFO; X-ray; 1.60 A; A/B=1-491.
DR PDB; 4KFP; X-ray; 1.84 A; A/B=1-491.
DR PDB; 4LV9; X-ray; 1.81 A; A/B=1-491.
DR PDB; 4LVA; X-ray; 1.55 A; A/B=1-491.
DR PDB; 4LVB; X-ray; 1.84 A; A/B=1-491.
DR PDB; 4LVD; X-ray; 1.75 A; A/B=1-491.
DR PDB; 4LVF; X-ray; 1.50 A; A/B=1-491.
DR PDB; 4LVG; X-ray; 1.70 A; A/B=1-491.
DR PDB; 4M6P; X-ray; 1.75 A; A/B=1-491.
DR PDB; 4M6Q; X-ray; 2.41 A; A/B=1-491.
DR PDBsum; 2E5B; -.
DR PDBsum; 2E5C; -.
DR PDBsum; 2E5D; -.
DR PDBsum; 2GVG; -.
DR PDBsum; 2GVJ; -.
DR PDBsum; 3DGR; -.
DR PDBsum; 3DHD; -.
DR PDBsum; 3DHF; -.
DR PDBsum; 3DKJ; -.
DR PDBsum; 3DKL; -.
DR PDBsum; 4JNM; -.
DR PDBsum; 4JR5; -.
DR PDBsum; 4KFN; -.
DR PDBsum; 4KFO; -.
DR PDBsum; 4KFP; -.
DR PDBsum; 4LV9; -.
DR PDBsum; 4LVA; -.
DR PDBsum; 4LVB; -.
DR PDBsum; 4LVD; -.
DR PDBsum; 4LVF; -.
DR PDBsum; 4LVG; -.
DR PDBsum; 4M6P; -.
DR PDBsum; 4M6Q; -.
DR ProteinModelPortal; P43490; -.
DR SMR; P43490; 8-489.
DR DIP; DIP-29218N; -.
DR IntAct; P43490; 10.
DR MINT; MINT-4530953; -.
DR STRING; 9606.ENSP00000222553; -.
DR BindingDB; P43490; -.
DR ChEMBL; CHEMBL1744525; -.
DR PhosphoSite; P43490; -.
DR DMDM; 1172027; -.
DR PaxDb; P43490; -.
DR PRIDE; P43490; -.
DR DNASU; 10135; -.
DR Ensembl; ENST00000222553; ENSP00000222553; ENSG00000105835.
DR Ensembl; ENST00000354289; ENSP00000346242; ENSG00000105835.
DR GeneID; 10135; -.
DR KEGG; hsa:10135; -.
DR UCSC; uc003vdq.3; human.
DR CTD; 10135; -.
DR GeneCards; GC07M105888; -.
DR HGNC; HGNC:30092; NAMPT.
DR HPA; CAB034349; -.
DR MIM; 608764; gene.
DR neXtProt; NX_P43490; -.
DR PharmGKB; PA162396933; -.
DR eggNOG; COG1488; -.
DR HOGENOM; HOG000216546; -.
DR HOVERGEN; HBG000336; -.
DR InParanoid; P43490; -.
DR KO; K03462; -.
DR OMA; SHYLQYP; -.
DR OrthoDB; EOG7PGDQH; -.
DR PhylomeDB; P43490; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_24941; Circadian Clock.
DR SABIO-RK; P43490; -.
DR UniPathway; UPA00253; UER00890.
DR ChiTaRS; NAMPT; human.
DR EvolutionaryTrace; P43490; -.
DR GeneWiki; Nicotinamide_phosphoribosyltransferase; -.
DR GenomeRNAi; 10135; -.
DR NextBio; 38341; -.
DR PRO; PR:P43490; -.
DR ArrayExpress; P43490; -.
DR Bgee; P43490; -.
DR CleanEx; HS_NAMPT; -.
DR Genevestigator; P43490; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005125; F:cytokine activity; TAS:ProtInc.
DR GO; GO:0047280; F:nicotinamide phosphoribosyltransferase activity; IEA:UniProtKB-EC.
DR GO; GO:0004514; F:nicotinate-nucleotide diphosphorylase (carboxylating) activity; IEA:InterPro.
DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR GO; GO:0009435; P:NAD biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0019674; P:NAD metabolic process; TAS:Reactome.
DR GO; GO:0006769; P:nicotinamide metabolic process; TAS:Reactome.
DR GO; GO:0008284; P:positive regulation of cell proliferation; TAS:ProtInc.
DR GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:BHF-UCL.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR InterPro; IPR007229; Nic_PRibTrfase-Fam.
DR InterPro; IPR016471; Nicotinamide_PRibTrfase.
DR InterPro; IPR002638; Quinolinate_PRibosylTrfase_C.
DR PANTHER; PTHR11098:SF2; PTHR11098:SF2; 1.
DR Pfam; PF04095; NAPRTase; 1.
DR PIRSF; PIRSF005943; NMPRT; 1.
DR SUPFAM; SSF51690; SSF51690; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Cytokine; Cytoplasm;
KW Glycosyltransferase; Nucleus; Polymorphism;
KW Pyridine nucleotide biosynthesis; Reference proteome; Secreted;
KW Transferase.
FT CHAIN 1 491 Nicotinamide phosphoribosyltransferase.
FT /FTId=PRO_0000205863.
FT REGION 311 313 Nicotinamide ribonucleotide binding.
FT REGION 353 354 Nicotinamide ribonucleotide binding.
FT BINDING 196 196 Diphosphate.
FT BINDING 219 219 Nicotinamide ribonucleotide.
FT BINDING 247 247 Diphosphate.
FT BINDING 311 311 Diphosphate.
FT BINDING 384 384 Nicotinamide ribonucleotide; via amide
FT nitrogen.
FT BINDING 392 392 Nicotinamide ribonucleotide.
FT VARIANT 176 176 L -> S (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036614.
FT MUTAGEN 219 219 D->N,S: No effect on activity towards
FT nicotinamide. Alters specificity, so that
FT the enzyme acquires activity towards
FT nicotinic acid.
FT MUTAGEN 247 247 H->A: Reduces activity towards
FT nicotinamide.
FT MUTAGEN 311 311 R->D: Reduces activity towards
FT nicotinamide.
FT HELIX 11 13
FT STRAND 14 16
FT HELIX 17 24
FT STRAND 30 39
FT STRAND 56 58
FT HELIX 62 69
FT HELIX 77 91
FT HELIX 98 108
FT STRAND 114 118
FT STRAND 124 126
FT STRAND 129 138
FT HELIX 139 141
FT HELIX 144 147
FT HELIX 149 153
FT HELIX 156 180
FT HELIX 186 188
FT STRAND 189 192
FT HELIX 195 197
FT HELIX 201 211
FT TURN 212 214
FT STRAND 216 220
FT HELIX 222 230
FT STRAND 234 236
FT HELIX 247 251
FT HELIX 255 257
FT HELIX 258 268
FT STRAND 270 272
FT STRAND 274 277
FT HELIX 283 288
FT HELIX 289 294
FT HELIX 296 299
FT STRAND 308 311
FT HELIX 317 331
FT STRAND 338 340
FT STRAND 348 352
FT HELIX 358 370
FT HELIX 375 377
FT STRAND 378 383
FT HELIX 384 387
FT TURN 392 396
FT STRAND 397 406
FT STRAND 409 412
FT HELIX 421 423
FT STRAND 431 434
FT STRAND 440 443
FT HELIX 447 450
FT STRAND 453 455
FT STRAND 459 463
FT HELIX 473 479
FT TURN 483 485
SQ SEQUENCE 491 AA; 55521 MW; 6BF07B631B589AC0 CRC64;
MNPAAEAEFN ILLATDSYKV THYKQYPPNT SKVYSYFECR EKKTENSKLR KVKYEETVFY
GLQYILNKYL KGKVVTKEKI QEAKDVYKEH FQDDVFNEKG WNYILEKYDG HLPIEIKAVP
EGFVIPRGNV LFTVENTDPE CYWLTNWIET ILVQSWYPIT VATNSREQKK ILAKYLLETS
GNLDGLEYKL HDFGYRGVSS QETAGIGASA HLVNFKGTDT VAGLALIKKY YGTKDPVPGY
SVPAAEHSTI TAWGKDHEKD AFEHIVTQFS SVPVSVVSDS YDIYNACEKI WGEDLRHLIV
SRSTQAPLII RPDSGNPLDT VLKVLEILGK KFPVTENSKG YKLLPPYLRV IQGDGVDINT
LQEIVEGMKQ KMWSIENIAF GSGGGLLQKL TRDLLNCSFK CSYVVTNGLG INVFKDPVAD
PNKRSKKGRL SLHRTPAGNF VTLEEGKGDL EEYGQDLLHT VFKNGKVTKS YSFDEIRKNA
QLNIELEAAH H
//
MIM
608764
*RECORD*
*FIELD* NO
608764
*FIELD* TI
*608764 NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE; NAMPT
;;PRE-B-CELL COLONY-ENHANCING FACTOR 1; PBEF1;;
read morePBEF;;
VISFATIN; VF
*FIELD* TX
DESCRIPTION
The enzyme NAMPT (EC 2.4.2.12) converts nicotinamide (vitamin B3) to
nicotinamide mononucleotide. NAMPT is the rate-limiting component of the
nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway (summary
by Revollo et al., 2004).
CLONING
Using a degenerate probe to screen an activated lymphocyte cDNA library,
Samal et al. (1994) cloned PBEF. The 3-prime UTR of PBEF contains
several TATT motifs, destabilizing sequences characteristic of cytokine
messages. The deduced 473-amino acid protein has a calculated molecular
mass of 52 kD. PBEF has a hydrophobic N terminus, 2 N-glycosylation
sites, several putative phosphorylation sites, and 6 cysteines. Northern
blot analysis detected transcripts of about 2.0, 2.4, and 4.0 kb in all
tissues examined, with highest expression in liver, followed by muscle.
Although PBEF lacks a typical signal sequence for secretion, transfected
COS-7 and mouse embryonic fibroblasts secreted PBEF into the culture
medium. Western blot analysis detected PBEF at an apparent molecular
mass of 52 kD.
GENE FUNCTION
Samal et al. (1994) found that recombinant PBEF secreted from
transfected COS-7 and mouse embryonic fibroblasts was not itself active
in a pre-B-cell colony formation assay, but it synergized the pre-B-cell
colony formation activity of stem cell factor (184745) and interleukin-7
(146660). Increased activity was PBEF dose dependent. PBEF showed no
effect with cells of myeloid or erythroid lineages. Expression of PBEF
was induced in human peripheral blood lymphocytes by pokeweed mitogen
and was superinduced by cycloheximide. It was also induced by phorbol
ester treatment in a T-lymphoblastoid cell line.
In neutrophils from healthy donors, Jia et al. (2004) found that PBEF1
was upregulated by IL1-beta (147720) and by lipopolysaccharide.
Prevention of PBEF1 translation with an antisense oligonucleotide
completely abrogated the inhibitory effects of lipopolysaccharide,
IL1-beta, GMCSF (CSF2; 138960), IL8 (146930), and TNF-alpha (191160) on
neutrophil apoptosis. Immunoreactive PBEF1 was detectable in culture
supernatants from lipopolysaccharide-stimulated neutrophils, and a
recombinant PBEF1 fusion protein inhibited neutrophil apoptosis. PBEF1
was also expressed in neutrophils from critically ill patients with
sepsis and delayed apoptosis; the expression occurred at higher levels
than seen in experimental inflammation, and a PBEF1 antisense
oligonucleotide significantly restored the normal kinetics of apoptosis
in septic polymorphonuclear neutrophils. Inhibition of apoptosis by
PBEF1 was associated with reduced activity of caspase-8 (601763) and
caspase-3 (600636), but not caspase-9 (602234). Jia et al. (2004)
concluded that PBEF1 is an inflammatory cytokine that plays a requisite
role in the delayed neutrophil apoptosis of sepsis.
Revollo et al. (2004) identified NAMPT as the rate-limiting component in
the mammalian NAD biosynthesis pathway. Increased doses of Nampt, but
not Nmnat1 (608700), increased total cellular NAD and enhanced the
transcriptional regulatory activity of the catalytic domain of Sirt1
(604479) in mouse fibroblasts. Revollo et al. (2004) concluded that NAD
biosynthesis mediated by NAMPT regulates the function of SIRT1.
Fukuhara et al. (2005) isolated visfatin, an adipocytokine highly
enriched in the visceral fat of both humans and mice and whose
expression level in plasma increased during development of obesity.
Visfatin corresponds to PBEF, a 52-kD cytokine expressed in lymphocytes.
Visfatin exerted insulin-mimetic effects in cultured cells and lowered
plasma glucose levels in mice. Mice heterozygous for a targeted mutation
in the visfatin gene had modestly higher levels of plasma glucose
relative to wildtype littermates. Surprisingly, Fukuhara et al. (2005)
found that visfatin bound and activated the insulin receptor (147670).
In 2007, concerns about their biochemical analysis indicating an
interaction between visfatin and the insulin receptor led Fukuhara et
al. (2005) to retract their paper. They noted, however, that they still
considered most of their data to be correct and reproducible.
Using ELISA, RT-PCR, and FACS analyses, Moschen et al. (2007) showed
that visfatin activated human leukocytes and induced production of IL1B,
TNF, and especially IL6 (147620). It also increased surface expression
of CD54 (ICAM1; 147840), CD40 (109535), and CD80 (112203). Visfatin
stimulation enhanced phagocytic activity and signal transduction through
p38 (MAPK14; 600289) and MEK1 (MAP2K1; 176872) pathways. Administration
of visfatin induced circulating Il6 in mice. Patients with inflammatory
bowel disease (see 266600) had increased plasma levels of visfatin and
increased visfatin mRNA expression in colonic tissue. Moschen et al.
(2007) concluded that visfatin is a proinflammatory adipocytokine.
Varma et al. (2007) examined association of VF with insulin sensitivity,
intramyocellular lipids, and inflammation in humans. They found that VF
mRNA expression in subcutaneous adipose tissue was high in lean, more
insulin-sensitive subjects, whereas VF mRNA expression in subcutaneous
adipose tissue was attenuated in subjects with high intramyocellular
lipids, low insulin sensitivity, and high levels of inflammatory
markers. VF mRNA in visceral adipose tissue was positively associated
with body mass index (BMI), whereas VF mRNA in subcutaneous adipose
tissue decreased with BMI.
Using chick and mouse models and human cells, Kim et al. (2007) showed
that visfatin promoted angiogenesis by activating MAP kinase ERK1
(MAPK3; 601795) and ERK2 (MAPK1; 176948) pathways.
Van der Veer et al. (2007) found that NAMPT expression and activity
declined significantly as human vascular smooth muscle cells (SMCs)
approached senescence, indicating that regeneration of NAD+ from
nicotinamide became exhausted as SMCs approached senescence.
Introduction of NAMPT cDNA enhanced the life span of SMCs and human
fibroblasts derived from a patient with progeria (176670). The NAMPT
antagonist FK866 shortened senescence-free survival of SMCs.
Overexpression of NAMPT increased SIRT1 activity and protein expression,
as well as p53 (TP53; 191170) degradation. NAMPT-mediated extension of
SMC life span was abrogated in SMCs expressing a dominant-negative SIRT1
mutant or in which p53 was reintroduced. Time-lapse microscopy
demonstrated that NAMPT overexpression enhanced not only life span and
population doubling of SMCs, but also protected against oxidative cell
damage. Van der Veer et al. (2007) concluded that NAMPT is a longevity
protein that adds stress-resistant life to SMCs by optimizing
SIRT-mediated p53 degradation.
Using ELISA, Filippatos et al. (2007) showed that visfatin plasma levels
were increased in overweight and obese subjects with metabolic syndrome
(see 605552) compared with similar individuals without metabolic
syndrome.
Revollo et al. (2007) found that extracellular Nampt did not exert
insulin-mimetic effects in vitro or in vivo, but that it exhibited
robust NAD biosynthetic activity. Nampt +/- female mice had moderately
impaired glucose tolerance and reduced glucose-stimulated insulin
secretion, and wildtype mice treated with an Nampt antagonist showed a
similar phenotype. Defects in NAD biosynthesis could be corrected by the
Nampt reaction product, NMN, in vitro and in vivo. NMN was present in
high concentration in wildtype mouse plasma and at reduced levels in
Nampt +/- females. Revollo et al. (2007) concluded that NAMPT-mediated
systemic biosynthesis plays a critical role in beta-cell function.
Ramsey et al. (2009) reported that both NAMPT, the rate-limiting enzyme
in mammalian NAD biosynthesis, and levels of NAD+ display circadian
oscillations that are regulated by the core clock machinery in mice.
Inhibition of NAMPT promotes oscillation of the clock gene Per2 (603426)
by releasing CLOCK:BMAL1 (601851; 602550) from suppression by SIRT1
(604479). In turn, the circadian transcription factor CLOCK binds to and
upregulates Nampt, thus completing a feedback loop involving NAMPT/NAD+
and SIRT1/CLOCK:BMAL1.
Nakahata et al. (2009) showed that intracellular NAD+ levels cycle with
a 24-hour rhythm, an oscillation driven by the circadian clock.
CLOCK:BMAL1 regulates the circadian expression of NAMPT, an enzyme that
provides a rate-limiting step in the NAD+ salvage pathway. SIRT1 is
recruited to the Nampt promoter and contributes to the circadian
synthesis of its own coenzyme. Using the specific inhibitor FK866,
Nakahata et al. (2009) demonstrated that NAMPT is required to modulate
circadian gene expression. Nakahata et al. (2009) concluded that their
findings in mouse embryo fibroblasts revealed an interlocked
transcriptional-enzymatic feedback loop that governs the molecular
interplay between cellular metabolism and circadian rhythms.
Skokowa et al. (2009) found that treatment with GCSF increased NAMPT
expression and intracellular NAD+ content in myeloid cells of normal
individuals and those with congenital neutropenia. Extracellular or
intracellular administration of NAMPT induced granulocytic
differentiation of CD34 (142230)-positive hematopoietic progenitor cells
and HL-60 promyelocytic leukemia cells. Plasma and myeloid cells from
subjects with congenital neutropenia had elevated amounts of NAMPT and
NAD+ compared with normal controls, suggesting a compensatory mechanism.
Treatment of healthy individuals with high doses of vitamin B3 also
induced neutrophilic granulocyte differentiation. NAMPT triggered
NAD(+)-dependent Sirt1 activation, followed by induction of the
transcription factors CEBP-alpha (CEBPA; 116897) and CEBP-beta (CEBPB;
189965) and upregulated expression of GCSF and GCSF receptor (CSF3R;
138971). GCSF, in turn, further increased NAMPT levels in a positive
feedback loop. Skokowa et al. (2009) concluded that NAD+ has a decisive
role in GCSF-triggered myelopoiesis.
By immunohistochemical examination of term and preterm placenta,
Ognjanovic et al. (2001) observed that PBEF was expressed in the
cytoplasm of normal fetal membranes, and that expression in fetal cells
and invading maternal neutrophils increased with chorioamnionitis. PBEF
transcripts of 2.0, 2.4, and 4.0 kb were detected, and highest
expression was associated with severe infection. In cultured WISH
amniotic epithelial cells, lipopolysaccharide, IL1B, TNF-alpha, and IL6,
but not IL8, induced PBEF mRNA. Dexamethasone reduced PBEF expression in
response to IL1B and TNF-alpha.
GENE STRUCTURE
Ognjanovic et al. (2001) determined that the NAMPT gene contains 11
coding exons and spans 34.7 kb. It has a 1 major and several minor
transcription initiation sites, as well as proximal and distal promoter
regions. The proximal promoter lacks TATA or CAAT boxes, but it has a
high GC content and several possible SP1 (189906)-binding GC boxes. The
distal promoter contains several TATA and CAAT boxes. Both promoters
have numerous regulatory elements, including putative binding sites for
AP2 (TFAP2A; 107580), NF1 (162200), CREB (CREB1; 123810), IL6, and
glucocorticoid receptor (GCCR; 138040). Intron 3 has an NF-kappa-B (see
164011)-binding site, whereas introns 5, 8, 9, and 10 have
NF-kappa-B-like elements.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the NAMPT
gene to chromosome 7 (TMAP SHGC-33252).
*FIELD* RF
1. Filippatos, T. D.; Derdemezis, C. S.; Kiortsis, D. N.; Tselepis,
A. D.; Elisaf, M. S.: Increased plasma levels of visfatin/pre-B cell
colony-enhancing factor in obese and overweight patients with metabolic
syndrome. J. Endocr. Invest. 30: 323-326, 2007.
2. Fukuhara, A.; Matsuda, M.; Nishizawa, M.; Segawa, K.; Tanaka, M.;
Kishimoto, K.; Matsuki, Y. Murakami, M.; Ichisaka, T.; Murakami, H.;
Watanabe, E.; Takagi, T.; and 10 others: Visfatin: a protein secreted
by visceral fat that mimics the effects of insulin. Science 307:
426-430, 2005. Note: Retraction: Science 318: 565 only, 2007.
3. Jia, S. H.; Li, Y.; Parodo, J.; Kapus, A.; Fan, L.; Rotstein, O.
D.; Marshall, J. C.: Pre-B cell colony-enhancing factor inhibits
neutrophil apoptosis in experimental inflammation and clinical sepsis. J.
Clin. Invest. 113: 1318-1327, 2004.
4. Kim, S.-R.; Bae, S.-K.; Choi, K.-S.; Park, S.-Y.; Jun, H. O.; Lee,
J.-Y.; Jang, H.-O.; Yun, I.; Yoon, K.-H.; Kim, Y.-J.; Yoo, M.-A.;
Kim, K.-W.; Bae, M.-K.: Visfatin promotes angiogenesis by activation
of extracellular signal-regulated kinase 1/2. Biochem. Biophys. Res.
Commun. 357: 150-156, 2007.
5. Moschen, A. R.; Kaser, A.; Enrich, B.; Mosheimer, B.; Theurl, M.;
Niederegger, H.; Tilg, H.: Visfatin, an adipocytokine with proinflammatory
and immunomodulating properties. J. Immun. 178: 1748-1758, 2007.
6. Nakahata, Y.; Sahar, S.; Astarita, G.; Kaluzova, M.; Sassone-Corsi,
P.: Circadian control of the NAD+ salvage pathway by CLOCK:SIRT1. Science 324:
654-657, 2009.
7. Ognjanovic, S.; Bao, S.; Yamamoto, S. Y.; Garibay-Tupas, J.; Samal,
B.; Bryant-Greenwood, G. D.: Genomic organization of the gene coding
for human pre-B-cell colony enhancing factor and expression in human
fetal membranes. J. Molec. Endocr. 26: 107-117, 2001.
8. Ramsey, K. M.; Yoshino, J.; Brace, C. S.; Abrassart, D.; Kobayashi,
Y.; Marcheva, B.; Hong, H.-K.; Chong, J. L.; Buhr, E. D.; Lee, C.;
Takahashi, J. S.; Imai, S.; Bass, J.: Circadian clock feedback cycle
through NAMPT-mediated NAD+ biosynthesis. Science 324: 651-655,
2009.
9. Revollo, J. R.; Grimm, A. A.; Imai, S.: The NAD biosynthesis pathway
mediated by nicotinamide phosphoribosyltransferase regulates Sir2
activity in mammalian cells. J. Biol. Chem. 279: 50754-50763, 2004.
10. Revollo, J. R.; Korner, A.; Mills, K. F.; Satoh, A.; Wang, T.;
Garten, A.; Dasgupta, B.; Sasaki, Y.; Wolberger, C.; Townsend, R.
R.; Milbrandt, J.; Kiess, W.; Imai, S.-I.: Nampt/PBEF/visfatin regulates
insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell
Metab. 6: 363-375, 2007.
11. Samal, B.; Sun, Y.; Stearns, G.; Xie, C.; Suggs, S.; McNiece,
I.: Cloning and characterization of the cDNA encoding a novel human
pre-B-cell colony-enhancing factor. Molec. Cell. Biol. 14: 1431-1437,
1994.
12. Skokowa, J.; Lan, D.; Thakur, B. K.; Wang, F.; Gupta, K.; Cario,
G.; Brechlin, A. M.; Schambach, A.; Hinrichsen, L.; Meyer, G.; Gaestel,
M.; Stanulla, M.; Tong, Q.; Welte, K.: NAMPT is essential for the
G-CSF-induced myeloid differentiation via a NAD+-sirtuin-1-dependent
pathway. Nature Med. 15: 151-158, 2009.
13. van der Veer, E.; Ho, C.; O'Neil, C.; Barbosa, N.; Scott, R.;
Cregan, S. P.; Pickering, J. G.: Extension of human cell lifespan
by nicotinamide phosphoribosyltransferase. J. Biol. Chem. 282: 10841-10845,
2007.
14. Varma, V.; Yao-Borengasser, A.; Rasouli, N.; Bodles, A. M.; Phanavanh,
B.; Lee, M.-J.; Starks, T.; Kern, L. M.; Spencer, H. J., III; McGehee,
R. E., Jr.; Fried, S. K.; Kern, P. A.: Human visfatin expression:
relationship to insulin sensitivity, intramyocellular lipids, and
inflammation. J. Clin. Endocr. Metab. 92: 666-672, 2007.
*FIELD* CN
Patricia A. Hartz - updated: 7/5/2011
Ada Hamosh - updated: 7/28/2009
Paul J. Converse - updated: 6/3/2008
Paul J. Converse - updated: 11/15/2007
Paul J. Converse - updated: 10/31/2007
Ada Hamosh - updated: 2/2/2005
Marla J. F. O'Neill - updated: 7/1/2004
*FIELD* CD
Patricia A. Hartz: 6/29/2004
*FIELD* ED
mgross: 09/06/2011
mgross: 9/6/2011
terry: 7/5/2011
carol: 6/20/2011
alopez: 8/4/2009
terry: 7/28/2009
mgross: 7/9/2008
terry: 6/3/2008
carol: 4/8/2008
wwang: 2/27/2008
mgross: 2/22/2008
terry: 11/15/2007
mgross: 10/31/2007
alopez: 2/22/2005
terry: 2/2/2005
carol: 7/2/2004
terry: 7/1/2004
mgross: 6/29/2004
*RECORD*
*FIELD* NO
608764
*FIELD* TI
*608764 NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE; NAMPT
;;PRE-B-CELL COLONY-ENHANCING FACTOR 1; PBEF1;;
read morePBEF;;
VISFATIN; VF
*FIELD* TX
DESCRIPTION
The enzyme NAMPT (EC 2.4.2.12) converts nicotinamide (vitamin B3) to
nicotinamide mononucleotide. NAMPT is the rate-limiting component of the
nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway (summary
by Revollo et al., 2004).
CLONING
Using a degenerate probe to screen an activated lymphocyte cDNA library,
Samal et al. (1994) cloned PBEF. The 3-prime UTR of PBEF contains
several TATT motifs, destabilizing sequences characteristic of cytokine
messages. The deduced 473-amino acid protein has a calculated molecular
mass of 52 kD. PBEF has a hydrophobic N terminus, 2 N-glycosylation
sites, several putative phosphorylation sites, and 6 cysteines. Northern
blot analysis detected transcripts of about 2.0, 2.4, and 4.0 kb in all
tissues examined, with highest expression in liver, followed by muscle.
Although PBEF lacks a typical signal sequence for secretion, transfected
COS-7 and mouse embryonic fibroblasts secreted PBEF into the culture
medium. Western blot analysis detected PBEF at an apparent molecular
mass of 52 kD.
GENE FUNCTION
Samal et al. (1994) found that recombinant PBEF secreted from
transfected COS-7 and mouse embryonic fibroblasts was not itself active
in a pre-B-cell colony formation assay, but it synergized the pre-B-cell
colony formation activity of stem cell factor (184745) and interleukin-7
(146660). Increased activity was PBEF dose dependent. PBEF showed no
effect with cells of myeloid or erythroid lineages. Expression of PBEF
was induced in human peripheral blood lymphocytes by pokeweed mitogen
and was superinduced by cycloheximide. It was also induced by phorbol
ester treatment in a T-lymphoblastoid cell line.
In neutrophils from healthy donors, Jia et al. (2004) found that PBEF1
was upregulated by IL1-beta (147720) and by lipopolysaccharide.
Prevention of PBEF1 translation with an antisense oligonucleotide
completely abrogated the inhibitory effects of lipopolysaccharide,
IL1-beta, GMCSF (CSF2; 138960), IL8 (146930), and TNF-alpha (191160) on
neutrophil apoptosis. Immunoreactive PBEF1 was detectable in culture
supernatants from lipopolysaccharide-stimulated neutrophils, and a
recombinant PBEF1 fusion protein inhibited neutrophil apoptosis. PBEF1
was also expressed in neutrophils from critically ill patients with
sepsis and delayed apoptosis; the expression occurred at higher levels
than seen in experimental inflammation, and a PBEF1 antisense
oligonucleotide significantly restored the normal kinetics of apoptosis
in septic polymorphonuclear neutrophils. Inhibition of apoptosis by
PBEF1 was associated with reduced activity of caspase-8 (601763) and
caspase-3 (600636), but not caspase-9 (602234). Jia et al. (2004)
concluded that PBEF1 is an inflammatory cytokine that plays a requisite
role in the delayed neutrophil apoptosis of sepsis.
Revollo et al. (2004) identified NAMPT as the rate-limiting component in
the mammalian NAD biosynthesis pathway. Increased doses of Nampt, but
not Nmnat1 (608700), increased total cellular NAD and enhanced the
transcriptional regulatory activity of the catalytic domain of Sirt1
(604479) in mouse fibroblasts. Revollo et al. (2004) concluded that NAD
biosynthesis mediated by NAMPT regulates the function of SIRT1.
Fukuhara et al. (2005) isolated visfatin, an adipocytokine highly
enriched in the visceral fat of both humans and mice and whose
expression level in plasma increased during development of obesity.
Visfatin corresponds to PBEF, a 52-kD cytokine expressed in lymphocytes.
Visfatin exerted insulin-mimetic effects in cultured cells and lowered
plasma glucose levels in mice. Mice heterozygous for a targeted mutation
in the visfatin gene had modestly higher levels of plasma glucose
relative to wildtype littermates. Surprisingly, Fukuhara et al. (2005)
found that visfatin bound and activated the insulin receptor (147670).
In 2007, concerns about their biochemical analysis indicating an
interaction between visfatin and the insulin receptor led Fukuhara et
al. (2005) to retract their paper. They noted, however, that they still
considered most of their data to be correct and reproducible.
Using ELISA, RT-PCR, and FACS analyses, Moschen et al. (2007) showed
that visfatin activated human leukocytes and induced production of IL1B,
TNF, and especially IL6 (147620). It also increased surface expression
of CD54 (ICAM1; 147840), CD40 (109535), and CD80 (112203). Visfatin
stimulation enhanced phagocytic activity and signal transduction through
p38 (MAPK14; 600289) and MEK1 (MAP2K1; 176872) pathways. Administration
of visfatin induced circulating Il6 in mice. Patients with inflammatory
bowel disease (see 266600) had increased plasma levels of visfatin and
increased visfatin mRNA expression in colonic tissue. Moschen et al.
(2007) concluded that visfatin is a proinflammatory adipocytokine.
Varma et al. (2007) examined association of VF with insulin sensitivity,
intramyocellular lipids, and inflammation in humans. They found that VF
mRNA expression in subcutaneous adipose tissue was high in lean, more
insulin-sensitive subjects, whereas VF mRNA expression in subcutaneous
adipose tissue was attenuated in subjects with high intramyocellular
lipids, low insulin sensitivity, and high levels of inflammatory
markers. VF mRNA in visceral adipose tissue was positively associated
with body mass index (BMI), whereas VF mRNA in subcutaneous adipose
tissue decreased with BMI.
Using chick and mouse models and human cells, Kim et al. (2007) showed
that visfatin promoted angiogenesis by activating MAP kinase ERK1
(MAPK3; 601795) and ERK2 (MAPK1; 176948) pathways.
Van der Veer et al. (2007) found that NAMPT expression and activity
declined significantly as human vascular smooth muscle cells (SMCs)
approached senescence, indicating that regeneration of NAD+ from
nicotinamide became exhausted as SMCs approached senescence.
Introduction of NAMPT cDNA enhanced the life span of SMCs and human
fibroblasts derived from a patient with progeria (176670). The NAMPT
antagonist FK866 shortened senescence-free survival of SMCs.
Overexpression of NAMPT increased SIRT1 activity and protein expression,
as well as p53 (TP53; 191170) degradation. NAMPT-mediated extension of
SMC life span was abrogated in SMCs expressing a dominant-negative SIRT1
mutant or in which p53 was reintroduced. Time-lapse microscopy
demonstrated that NAMPT overexpression enhanced not only life span and
population doubling of SMCs, but also protected against oxidative cell
damage. Van der Veer et al. (2007) concluded that NAMPT is a longevity
protein that adds stress-resistant life to SMCs by optimizing
SIRT-mediated p53 degradation.
Using ELISA, Filippatos et al. (2007) showed that visfatin plasma levels
were increased in overweight and obese subjects with metabolic syndrome
(see 605552) compared with similar individuals without metabolic
syndrome.
Revollo et al. (2007) found that extracellular Nampt did not exert
insulin-mimetic effects in vitro or in vivo, but that it exhibited
robust NAD biosynthetic activity. Nampt +/- female mice had moderately
impaired glucose tolerance and reduced glucose-stimulated insulin
secretion, and wildtype mice treated with an Nampt antagonist showed a
similar phenotype. Defects in NAD biosynthesis could be corrected by the
Nampt reaction product, NMN, in vitro and in vivo. NMN was present in
high concentration in wildtype mouse plasma and at reduced levels in
Nampt +/- females. Revollo et al. (2007) concluded that NAMPT-mediated
systemic biosynthesis plays a critical role in beta-cell function.
Ramsey et al. (2009) reported that both NAMPT, the rate-limiting enzyme
in mammalian NAD biosynthesis, and levels of NAD+ display circadian
oscillations that are regulated by the core clock machinery in mice.
Inhibition of NAMPT promotes oscillation of the clock gene Per2 (603426)
by releasing CLOCK:BMAL1 (601851; 602550) from suppression by SIRT1
(604479). In turn, the circadian transcription factor CLOCK binds to and
upregulates Nampt, thus completing a feedback loop involving NAMPT/NAD+
and SIRT1/CLOCK:BMAL1.
Nakahata et al. (2009) showed that intracellular NAD+ levels cycle with
a 24-hour rhythm, an oscillation driven by the circadian clock.
CLOCK:BMAL1 regulates the circadian expression of NAMPT, an enzyme that
provides a rate-limiting step in the NAD+ salvage pathway. SIRT1 is
recruited to the Nampt promoter and contributes to the circadian
synthesis of its own coenzyme. Using the specific inhibitor FK866,
Nakahata et al. (2009) demonstrated that NAMPT is required to modulate
circadian gene expression. Nakahata et al. (2009) concluded that their
findings in mouse embryo fibroblasts revealed an interlocked
transcriptional-enzymatic feedback loop that governs the molecular
interplay between cellular metabolism and circadian rhythms.
Skokowa et al. (2009) found that treatment with GCSF increased NAMPT
expression and intracellular NAD+ content in myeloid cells of normal
individuals and those with congenital neutropenia. Extracellular or
intracellular administration of NAMPT induced granulocytic
differentiation of CD34 (142230)-positive hematopoietic progenitor cells
and HL-60 promyelocytic leukemia cells. Plasma and myeloid cells from
subjects with congenital neutropenia had elevated amounts of NAMPT and
NAD+ compared with normal controls, suggesting a compensatory mechanism.
Treatment of healthy individuals with high doses of vitamin B3 also
induced neutrophilic granulocyte differentiation. NAMPT triggered
NAD(+)-dependent Sirt1 activation, followed by induction of the
transcription factors CEBP-alpha (CEBPA; 116897) and CEBP-beta (CEBPB;
189965) and upregulated expression of GCSF and GCSF receptor (CSF3R;
138971). GCSF, in turn, further increased NAMPT levels in a positive
feedback loop. Skokowa et al. (2009) concluded that NAD+ has a decisive
role in GCSF-triggered myelopoiesis.
By immunohistochemical examination of term and preterm placenta,
Ognjanovic et al. (2001) observed that PBEF was expressed in the
cytoplasm of normal fetal membranes, and that expression in fetal cells
and invading maternal neutrophils increased with chorioamnionitis. PBEF
transcripts of 2.0, 2.4, and 4.0 kb were detected, and highest
expression was associated with severe infection. In cultured WISH
amniotic epithelial cells, lipopolysaccharide, IL1B, TNF-alpha, and IL6,
but not IL8, induced PBEF mRNA. Dexamethasone reduced PBEF expression in
response to IL1B and TNF-alpha.
GENE STRUCTURE
Ognjanovic et al. (2001) determined that the NAMPT gene contains 11
coding exons and spans 34.7 kb. It has a 1 major and several minor
transcription initiation sites, as well as proximal and distal promoter
regions. The proximal promoter lacks TATA or CAAT boxes, but it has a
high GC content and several possible SP1 (189906)-binding GC boxes. The
distal promoter contains several TATA and CAAT boxes. Both promoters
have numerous regulatory elements, including putative binding sites for
AP2 (TFAP2A; 107580), NF1 (162200), CREB (CREB1; 123810), IL6, and
glucocorticoid receptor (GCCR; 138040). Intron 3 has an NF-kappa-B (see
164011)-binding site, whereas introns 5, 8, 9, and 10 have
NF-kappa-B-like elements.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the NAMPT
gene to chromosome 7 (TMAP SHGC-33252).
*FIELD* RF
1. Filippatos, T. D.; Derdemezis, C. S.; Kiortsis, D. N.; Tselepis,
A. D.; Elisaf, M. S.: Increased plasma levels of visfatin/pre-B cell
colony-enhancing factor in obese and overweight patients with metabolic
syndrome. J. Endocr. Invest. 30: 323-326, 2007.
2. Fukuhara, A.; Matsuda, M.; Nishizawa, M.; Segawa, K.; Tanaka, M.;
Kishimoto, K.; Matsuki, Y. Murakami, M.; Ichisaka, T.; Murakami, H.;
Watanabe, E.; Takagi, T.; and 10 others: Visfatin: a protein secreted
by visceral fat that mimics the effects of insulin. Science 307:
426-430, 2005. Note: Retraction: Science 318: 565 only, 2007.
3. Jia, S. H.; Li, Y.; Parodo, J.; Kapus, A.; Fan, L.; Rotstein, O.
D.; Marshall, J. C.: Pre-B cell colony-enhancing factor inhibits
neutrophil apoptosis in experimental inflammation and clinical sepsis. J.
Clin. Invest. 113: 1318-1327, 2004.
4. Kim, S.-R.; Bae, S.-K.; Choi, K.-S.; Park, S.-Y.; Jun, H. O.; Lee,
J.-Y.; Jang, H.-O.; Yun, I.; Yoon, K.-H.; Kim, Y.-J.; Yoo, M.-A.;
Kim, K.-W.; Bae, M.-K.: Visfatin promotes angiogenesis by activation
of extracellular signal-regulated kinase 1/2. Biochem. Biophys. Res.
Commun. 357: 150-156, 2007.
5. Moschen, A. R.; Kaser, A.; Enrich, B.; Mosheimer, B.; Theurl, M.;
Niederegger, H.; Tilg, H.: Visfatin, an adipocytokine with proinflammatory
and immunomodulating properties. J. Immun. 178: 1748-1758, 2007.
6. Nakahata, Y.; Sahar, S.; Astarita, G.; Kaluzova, M.; Sassone-Corsi,
P.: Circadian control of the NAD+ salvage pathway by CLOCK:SIRT1. Science 324:
654-657, 2009.
7. Ognjanovic, S.; Bao, S.; Yamamoto, S. Y.; Garibay-Tupas, J.; Samal,
B.; Bryant-Greenwood, G. D.: Genomic organization of the gene coding
for human pre-B-cell colony enhancing factor and expression in human
fetal membranes. J. Molec. Endocr. 26: 107-117, 2001.
8. Ramsey, K. M.; Yoshino, J.; Brace, C. S.; Abrassart, D.; Kobayashi,
Y.; Marcheva, B.; Hong, H.-K.; Chong, J. L.; Buhr, E. D.; Lee, C.;
Takahashi, J. S.; Imai, S.; Bass, J.: Circadian clock feedback cycle
through NAMPT-mediated NAD+ biosynthesis. Science 324: 651-655,
2009.
9. Revollo, J. R.; Grimm, A. A.; Imai, S.: The NAD biosynthesis pathway
mediated by nicotinamide phosphoribosyltransferase regulates Sir2
activity in mammalian cells. J. Biol. Chem. 279: 50754-50763, 2004.
10. Revollo, J. R.; Korner, A.; Mills, K. F.; Satoh, A.; Wang, T.;
Garten, A.; Dasgupta, B.; Sasaki, Y.; Wolberger, C.; Townsend, R.
R.; Milbrandt, J.; Kiess, W.; Imai, S.-I.: Nampt/PBEF/visfatin regulates
insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell
Metab. 6: 363-375, 2007.
11. Samal, B.; Sun, Y.; Stearns, G.; Xie, C.; Suggs, S.; McNiece,
I.: Cloning and characterization of the cDNA encoding a novel human
pre-B-cell colony-enhancing factor. Molec. Cell. Biol. 14: 1431-1437,
1994.
12. Skokowa, J.; Lan, D.; Thakur, B. K.; Wang, F.; Gupta, K.; Cario,
G.; Brechlin, A. M.; Schambach, A.; Hinrichsen, L.; Meyer, G.; Gaestel,
M.; Stanulla, M.; Tong, Q.; Welte, K.: NAMPT is essential for the
G-CSF-induced myeloid differentiation via a NAD+-sirtuin-1-dependent
pathway. Nature Med. 15: 151-158, 2009.
13. van der Veer, E.; Ho, C.; O'Neil, C.; Barbosa, N.; Scott, R.;
Cregan, S. P.; Pickering, J. G.: Extension of human cell lifespan
by nicotinamide phosphoribosyltransferase. J. Biol. Chem. 282: 10841-10845,
2007.
14. Varma, V.; Yao-Borengasser, A.; Rasouli, N.; Bodles, A. M.; Phanavanh,
B.; Lee, M.-J.; Starks, T.; Kern, L. M.; Spencer, H. J., III; McGehee,
R. E., Jr.; Fried, S. K.; Kern, P. A.: Human visfatin expression:
relationship to insulin sensitivity, intramyocellular lipids, and
inflammation. J. Clin. Endocr. Metab. 92: 666-672, 2007.
*FIELD* CN
Patricia A. Hartz - updated: 7/5/2011
Ada Hamosh - updated: 7/28/2009
Paul J. Converse - updated: 6/3/2008
Paul J. Converse - updated: 11/15/2007
Paul J. Converse - updated: 10/31/2007
Ada Hamosh - updated: 2/2/2005
Marla J. F. O'Neill - updated: 7/1/2004
*FIELD* CD
Patricia A. Hartz: 6/29/2004
*FIELD* ED
mgross: 09/06/2011
mgross: 9/6/2011
terry: 7/5/2011
carol: 6/20/2011
alopez: 8/4/2009
terry: 7/28/2009
mgross: 7/9/2008
terry: 6/3/2008
carol: 4/8/2008
wwang: 2/27/2008
mgross: 2/22/2008
terry: 11/15/2007
mgross: 10/31/2007
alopez: 2/22/2005
terry: 2/2/2005
carol: 7/2/2004
terry: 7/1/2004
mgross: 6/29/2004