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Pathway Description
Succinate Signalling
Rattus norvegicus
Category:
Protein Pathway
Sub-Categories:
Immunological
Cellular Response
Created: 2018-09-20
Last Updated: 2019-09-22
The Krebs cycle, also known as the citric acid cycle (CAC) or tricarboxylic acid cycle (TCA cycle) occurs in the mitochondria, and it involves the oxidation of acetyl-CoA from glycolysis to form molecules of ATP, as well as NADH, which will later be used to form more ATP. Intermediates from the Krebs cycle can be used as inflammatory signals in the body, specifically in immune cells such as macrophages. Succinic acid, or its anion succinate, can leave the mitochondria and can directly inhibit the prolyl 4-hydroxylase subunit alpha-3 protein, which then allows for additional activation of the hypoxia-inducible factor 1-alpha (HF-1α). The higher levels of HF-1α enhance the expression of genes, including those for interleukin-1 beta (IL-1β). Succinic acid is also necessary for the succinylation of proteins, leading to changes in their structure and function.
Another intermediate of the Krebs cycle, NAD, activates the NAD-dependent protein deacetylase sirtuin-3, which is involved in the deacetylase of proteins in the cell, regulating ATP levels and promoting mtDNA transcription when needed. Activated sirtuin-3 inhibits NACHT, LRR and PYD domains-containing protein 3, which works to activate the inflammasome, and thus the increase in NAD+ leads to anti-inflammatory actions in the body.
Citric acid is another intermediate of the Krebs cycle, and it activates the production of reactive oxygen species, nitric oxide, which is the precursor for reactive nitrogen species, and prostaglandins. Prostaglandins can act as vasodilators, and as such are involved in the inflammation response.
Finally, glutamine is important for immune cells to carry out their functions, and when LPS binds to the Toll-like receptor 4 (TLR4) on the cell surface, activating this response, extra L-glutamine can be transported into the cell to fill this need. The L-glutamine can then be converted to oxoglutaric acid, which is important in the Krebs cycle, leading to the effects from its intermediates on the rest of the inflammatory response.
References
Succinate Signalling References
Frantz S, Kobzik L, Kim YD, Fukazawa R, Medzhitov R, Lee RT, Kelly RA: Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. J Clin Invest. 1999 Aug;104(3):271-80. doi: 10.1172/JCI6709.
Pubmed: 10430608
Kukkola L, Hieta R, Kivirikko KI, Myllyharju J: Identification and characterization of a third human, rat, and mouse collagen prolyl 4-hydroxylase isoenzyme. J Biol Chem. 2003 Nov 28;278(48):47685-93. doi: 10.1074/jbc.M306806200. Epub 2003 Sep 18.
Pubmed: 14500733
Kietzmann T, Cornesse Y, Brechtel K, Modaressi S, Jungermann K: Perivenous expression of the mRNA of the three hypoxia-inducible factor alpha-subunits, HIF1alpha, HIF2alpha and HIF3alpha, in rat liver. Biochem J. 2001 Mar 15;354(Pt 3):531-7. doi: 10.1042/0264-6021:3540531.
Pubmed: 11237857
Zou AP, Yang ZZ, Li PL, Cowley AW JR: Oxygen-dependent expression of hypoxia-inducible factor-1alpha in renal medullary cells of rats. Physiol Genomics. 2001 Aug 28;6(3):159-68. doi: 10.1152/physiolgenomics.2001.6.3.159.
Pubmed: 11526200
Jourdan T, Godlewski G, Cinar R, Bertola A, Szanda G, Liu J, Tam J, Han T, Mukhopadhyay B, Skarulis MC, Ju C, Aouadi M, Czech MP, Kunos G: Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nat Med. 2013 Sep;19(9):1132-40. doi: 10.1038/nm.3265. Epub 2013 Aug 18.
Pubmed: 23955712
Beirowski B, Gustin J, Armour SM, Yamamoto H, Viader A, North BJ, Michan S, Baloh RH, Golden JP, Schmidt RE, Sinclair DA, Auwerx J, Milbrandt J: Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling. Proc Natl Acad Sci U S A. 2011 Oct 25;108(43):E952-61. doi: 10.1073/pnas.1104969108. Epub 2011 Sep 26.
Pubmed: 21949390
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Pubmed: 15489334
De Smet C, Nishimori H, Furnari FB, Bogler O, Huang HJ, Cavenee WK: A novel seven transmembrane receptor induced during the early steps of astrocyte differentiation identified by differential expression. J Neurochem. 2002 May;81(3):575-88. doi: 10.1046/j.1471-4159.2002.00847.x.
Pubmed: 12065666
Gibbs RA, Weinstock GM, Metzker ML, Muzny DM, Sodergren EJ, Scherer S, Scott G, Steffen D, Worley KC, Burch PE, Okwuonu G, Hines S, Lewis L, DeRamo C, Delgado O, Dugan-Rocha S, Miner G, Morgan M, Hawes A, Gill R, Celera, Holt RA, Adams MD, Amanatides PG, Baden-Tillson H, Barnstead M, Chin S, Evans CA, Ferriera S, Fosler C, Glodek A, Gu Z, Jennings D, Kraft CL, Nguyen T, Pfannkoch CM, Sitter C, Sutton GG, Venter JC, Woodage T, Smith D, Lee HM, Gustafson E, Cahill P, Kana A, Doucette-Stamm L, Weinstock K, Fechtel K, Weiss RB, Dunn DM, Green ED, Blakesley RW, Bouffard GG, De Jong PJ, Osoegawa K, Zhu B, Marra M, Schein J, Bosdet I, Fjell C, Jones S, Krzywinski M, Mathewson C, Siddiqui A, Wye N, McPherson J, Zhao S, Fraser CM, Shetty J, Shatsman S, Geer K, Chen Y, Abramzon S, Nierman WC, Havlak PH, Chen R, Durbin KJ, Egan A, Ren Y, Song XZ, Li B, Liu Y, Qin X, Cawley S, Worley KC, Cooney AJ, D'Souza LM, Martin K, Wu JQ, Gonzalez-Garay ML, Jackson AR, Kalafus KJ, McLeod MP, Milosavljevic A, Virk D, Volkov A, Wheeler DA, Zhang Z, Bailey JA, Eichler EE, Tuzun E, Birney E, Mongin E, Ureta-Vidal A, Woodwark C, Zdobnov E, Bork P, Suyama M, Torrents D, Alexandersson M, Trask BJ, Young JM, Huang H, Wang H, Xing H, Daniels S, Gietzen D, Schmidt J, Stevens K, Vitt U, Wingrove J, Camara F, Mar Alba M, Abril JF, Guigo R, Smit A, Dubchak I, Rubin EM, Couronne O, Poliakov A, Hubner N, Ganten D, Goesele C, Hummel O, Kreitler T, Lee YA, Monti J, Schulz H, Zimdahl H, Himmelbauer H, Lehrach H, Jacob HJ, Bromberg S, Gullings-Handley J, Jensen-Seaman MI, Kwitek AE, Lazar J, Pasko D, Tonellato PJ, Twigger S, Ponting CP, Duarte JM, Rice S, Goodstadt L, Beatson SA, Emes RD, Winter EE, Webber C, Brandt P, Nyakatura G, Adetobi M, Chiaromonte F, Elnitski L, Eswara P, Hardison RC, Hou M, Kolbe D, Makova K, Miller W, Nekrutenko A, Riemer C, Schwartz S, Taylor J, Yang S, Zhang Y, Lindpaintner K, Andrews TD, Caccamo M, Clamp M, Clarke L, Curwen V, Durbin R, Eyras E, Searle SM, Cooper GM, Batzoglou S, Brudno M, Sidow A, Stone EA, Venter JC, Payseur BA, Bourque G, Lopez-Otin C, Puente XS, Chakrabarti K, Chatterji S, Dewey C, Pachter L, Bray N, Yap VB, Caspi A, Tesler G, Pevzner PA, Haussler D, Roskin KM, Baertsch R, Clawson H, Furey TS, Hinrichs AS, Karolchik D, Kent WJ, Rosenbloom KR, Trumbower H, Weirauch M, Cooper DN, Stenson PD, Ma B, Brent M, Arumugam M, Shteynberg D, Copley RR, Taylor MS, Riethman H, Mudunuri U, Peterson J, Guyer M, Felsenfeld A, Old S, Mockrin S, Collins F: Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature. 2004 Apr 1;428(6982):493-521. doi: 10.1038/nature02426.
Pubmed: 15057822
This pathway was propagated using PathWhiz -
Pon, A. et al. Pathways with PathWhiz (2015) Nucleic Acids Res. 43(Web Server issue): W552–W559.
Propagated from SMP0083294
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