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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.
Succinate Signalling References
Sauter KS, Brcic M, Franchini M, Jungi TW: Stable transduction of bovine TLR4 and bovine MD-2 into LPS-nonresponsive cells and soluble CD14 promote the ability to respond to LPS. Vet Immunol Immunopathol. 2007 Jul 15;118(1-2):92-104. doi: 10.1016/j.vetimm.2007.04.017. Epub 2007 May 3.Pubmed: 17559944
Hara S, Kobayashi C, Imura N: Molecular cloning of cDNAs encoding hypoxia-inducible factor (HIF)-1alpha and -2alpha of bovine arterial endothelial cells. Biochim Biophys Acta. 1999 May 14;1445(2):237-43. doi: 10.1016/s0167-4781(99)00048-2.Pubmed: 10320777
Leong SR, Flaggs GM, Lawman M, Gray PW: The nucleotide sequence for the cDNA of bovine interleukin-1 beta. Nucleic Acids Res. 1988 Sep 26;16(18):9054. doi: 10.1093/nar/16.18.9054.Pubmed: 3262866
Maliszewski CR, Baker PE, Schoenborn MA, Davis BS, Cosman D, Gillis S, Cerretti DP: Cloning, sequence and expression of bovine interleukin 1 alpha and interleukin 1 beta complementary DNAs. Mol Immunol. 1988 May;25(5):429-37. doi: 10.1016/0161-5890(88)90162-9.Pubmed: 3261832
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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