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Showing Protein NAD(+) hydrolase SARM1 (HMDBP12375)

IdentificationBiological propertiesGene propertiesProtein propertiesExternal linksReferencesXMLShow 1 metabolite
Identification
HMDB Protein ID HMDBP12375
Secondary Accession Numbers None
Name NAD(+) hydrolase SARM1
Synonyms
  1. NADase SARM1
  2. hSARM1
  3. NADP(+) hydrolase SARM1
  4. Sterile alpha and Armadillo repeat protein
  5. Sterile alpha and TIR motif-containing protein 1
  6. Sterile alpha motif domain-containing protein 2
  7. Tir-1 homolog
  8. MyD88-5
  9. SAM domain-containing protein 2
  10. HsTIR
Gene Name SARM1
Protein Type Unknown
Biological Properties
General Function Not Available
Specific Function NAD(+) hydrolase, which plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism (PubMed:25908823, PubMed:27671644, PubMed:28334607). Acts as a negative regulator of MYD88- and TRIF-dependent toll-like receptor signaling pathway by promoting Wallerian degeneration, an injury-induced form of programmed subcellular death which involves degeneration of an axon distal to the injury site (PubMed:15123841, PubMed:16964262, PubMed:20306472, PubMed:25908823). Wallerian degeneration is triggered by NAD(+) depletion: in response to injury, SARM1 is activated and catalyzes cleavage of NAD(+) into ADP-D-ribose (ADPR), cyclic ADPR (cADPR) and nicotinamide; NAD(+) cleavage promoting cytoskeletal degradation and axon destruction (PubMed:25908823, PubMed:28334607, PubMed:30333228, PubMed:31128467, PubMed:31439793, PubMed:32049506, PubMed:32828421, PubMed:31439792, PubMed:33053563). Also able to hydrolyze NADP(+), but not other NAD(+)-related molecules (PubMed:29395922). Can activate neuronal cell death in response to stress (PubMed:20306472). Regulates dendritic arborization through the MAPK4-JNK pathway (By similarity). Involved in innate immune response: inhibits both TICAM1/TRIF- and MYD88-dependent activation of JUN/AP-1, TRIF-dependent activation of NF-kappa-B and IRF3, and the phosphorylation of MAPK14/p38 (PubMed:16964262).
Pathways Not Available
Reactions Not Available
GO Classification
Biological Process
signal transduction
NAD catabolic process
regulation of dendrite morphogenesis
nervous system development
innate immune response
cell differentiation
regulation of apoptotic process
response to glucose stimulus
negative regulation of MyD88-independent toll-like receptor signaling pathway
positive regulation of neuron death
regulation of neuron death
response to axon injury
Cellular Component
cytosol
cytoplasm
mitochondrion
dendrite
synapse
extrinsic to mitochondrial outer membrane
axon
microtubule
Molecular Function
NAD+ nucleosidase activity
NAD(P)+ nucleosidase activity
NAD+ nucleotidase, cyclic ADP-ribose generating
signaling adaptor activity
identical protein binding
Cellular Location Not Available
Gene Properties
Chromosome Location Not Available
Locus Not Available
SNPs Not Available
Gene Sequence Not Available
Protein Properties
Number of Residues 724
Molecular Weight 79387.365
Theoretical pI 6.549
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence Not Available
GenBank ID Protein Not Available
UniProtKB/Swiss-Prot ID Q6SZW1
UniProtKB/Swiss-Prot Entry Name SARM1_HUMAN
PDB IDs
GenBank Gene ID Not Available
GeneCard ID Not Available
GenAtlas ID Not Available
HGNC ID Not Available
References
General References
  1. Nagase T, Ishikawa K, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O: Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 1998 Feb 28;5(1):31-9. [PubMed:9628581 ]
  2. Mink M, Fogelgren B, Olszewski K, Maroy P, Csiszar K: A novel human gene (SARM) at chromosome 17q11 encodes a protein with a SAM motif and structural similarity to Armadillo/beta-catenin that is conserved in mouse, Drosophila, and Caenorhabditis elegans. Genomics. 2001 Jun 1;74(2):234-44. doi: 10.1006/geno.2001.6548. [PubMed:11386760 ]
  3. Liberati NT, Fitzgerald KA, Kim DH, Feinbaum R, Golenbock DT, Ausubel FM: Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response. Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6593-8. doi: 10.1073/pnas.0308625101. [PubMed:15123841 ]
  4. Carty M, Goodbody R, Schroder M, Stack J, Moynagh PN, Bowie AG: The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nat Immunol. 2006 Oct;7(10):1074-81. doi: 10.1038/ni1382. Epub 2006 Sep 10. [PubMed:16964262 ]
  5. O'Neill LA: DisSARMing Toll-like receptor signaling. Nat Immunol. 2006 Oct;7(10):1023-5. doi: 10.1038/ni1006-1023. [PubMed:16985498 ]
  6. Kim Y, Zhou P, Qian L, Chuang JZ, Lee J, Li C, Iadecola C, Nathan C, Ding A: MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival. J Exp Med. 2007 Sep 3;204(9):2063-74. doi: 10.1084/jem.20070868. Epub 2007 Aug 27. [PubMed:17724133 ]
  7. Peng J, Yuan Q, Lin B, Panneerselvam P, Wang X, Luan XL, Lim SK, Leung BP, Ho B, Ding JL: SARM inhibits both TRIF- and MyD88-mediated AP-1 activation. Eur J Immunol. 2010 Jun;40(6):1738-47. doi: 10.1002/eji.200940034. [PubMed:20306472 ]
  8. Panneerselvam P, Singh LP, Ho B, Chen J, Ding JL: Targeting of pro-apoptotic TLR adaptor SARM to mitochondria: definition of the critical region and residues in the signal sequence. Biochem J. 2012 Mar 1;442(2):263-71. doi: 10.1042/BJ20111653. [PubMed:22145856 ]
  9. Gerdts J, Brace EJ, Sasaki Y, DiAntonio A, Milbrandt J: SARM1 activation triggers axon degeneration locally via NAD(+) destruction. Science. 2015 Apr 24;348(6233):453-7. doi: 10.1126/science.1258366. Epub 2015 Apr 23. [PubMed:25908823 ]
  10. Summers DW, Gibson DA, DiAntonio A, Milbrandt J: SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate injury-induced SARM1 activation. Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):E6271-E6280. doi: 10.1073/pnas.1601506113. Epub 2016 Sep 26. [PubMed:27671644 ]
  11. Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J: The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD(+) Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron. 2017 Mar 22;93(6):1334-1343.e5. doi: 10.1016/j.neuron.2017.02.022. [PubMed:28334607 ]
  12. Essuman K, Summers DW, Sasaki Y, Mao X, Yim AKY, DiAntonio A, Milbrandt J: TIR Domain Proteins Are an Ancient Family of NAD(+)-Consuming Enzymes. Curr Biol. 2018 Feb 5;28(3):421-430.e4. doi: 10.1016/j.cub.2017.12.024. Epub 2018 Jan 25. [PubMed:29395922 ]
  13. Zhao ZY, Xie XJ, Li WH, Liu J, Chen Z, Zhang B, Li T, Li SL, Lu JG, Zhang L, Zhang LH, Xu Z, Lee HC, Zhao YJ: A Cell-Permeant Mimetic of NMN Activates SARM1 to Produce Cyclic ADP-Ribose and Induce Non-apoptotic Cell Death. iScience. 2019 May 31;15:452-466. doi: 10.1016/j.isci.2019.05.001. Epub 2019 May 4. [PubMed:31128467 ]
  14. Wan L, Essuman K, Anderson RG, Sasaki Y, Monteiro F, Chung EH, Osborne Nishimura E, DiAntonio A, Milbrandt J, Dangl JL, Nishimura MT: TIR domains of plant immune receptors are NAD(+)-cleaving enzymes that promote cell death. Science. 2019 Aug 23;365(6455):799-803. doi: 10.1126/science.aax1771. [PubMed:31439793 ]
  15. Loring HS, Icso JD, Nemmara VV, Thompson PR: Initial Kinetic Characterization of Sterile Alpha and Toll/Interleukin Receptor Motif-Containing Protein 1. Biochemistry. 2020 Mar 3;59(8):933-942. doi: 10.1021/acs.biochem.9b01078. Epub 2020 Feb 17. [PubMed:32049506 ]
  16. Loring HS, Parelkar SS, Mondal S, Thompson PR: Identification of the first noncompetitive SARM1 inhibitors. Bioorg Med Chem. 2020 Sep 15;28(18):115644. doi: 10.1016/j.bmc.2020.115644. Epub 2020 Jul 17. [PubMed:32828421 ]
  17. Sporny M, Guez-Haddad J, Lebendiker M, Ulisse V, Volf A, Mim C, Isupov MN, Opatowsky Y: Structural Evidence for an Octameric Ring Arrangement of SARM1. J Mol Biol. 2019 Sep 6;431(19):3591-3605. doi: 10.1016/j.jmb.2019.06.030. Epub 2019 Jul 3. [PubMed:31278906 ]
  18. Horsefield S, Burdett H, Zhang X, Manik MK, Shi Y, Chen J, Qi T, Gilley J, Lai JS, Rank MX, Casey LW, Gu W, Ericsson DJ, Foley G, Hughes RO, Bosanac T, von Itzstein M, Rathjen JP, Nanson JD, Boden M, Dry IB, Williams SJ, Staskawicz BJ, Coleman MP, Ve T, Dodds PN, Kobe B: NAD(+) cleavage activity by animal and plant TIR domains in cell death pathways. Science. 2019 Aug 23;365(6455):793-799. doi: 10.1126/science.aax1911. [PubMed:31439792 ]
  19. Jiang Y, Liu T, Lee CH, Chang Q, Yang J, Zhang Z: The NAD(+)-mediated self-inhibition mechanism of pro-neurodegenerative SARM1. Nature. 2020 Dec;588(7839):658-663. doi: 10.1038/s41586-020-2862-z. Epub 2020 Oct 14. [PubMed:33053563 ]