aconitate decarboxylase 1 | Itaconate biosynthesis | IUPHAR Guide to IMMUNOPHARMACOLOGY

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aconitate decarboxylase 1

  Target has curated data in GtoImmuPdb

Target id: 3018

Nomenclature: aconitate decarboxylase 1

Abbreviated Name: IRG1

Family: Itaconate biosynthesis

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 481 13q22.3 ACOD1 aconitate decarboxylase 1
Mouse - 488 14 E2.3; 14 51.67 cM Acod1 aconitate decarboxylase 1
Rat - 488 15q23 Acod1 aconitate decarboxylase 1
Previous and Unofficial Names
immune-responsive gene 1 | immunoresponsive gene 1 | IRG1 | cis-aconitate decarboxylase (CAD)
Database Links
BRENDA
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 4.1.1.6
Description Reaction Reference
Generates itaconic acid via decarboxylation of cis-aconitate (a TCA cycle intermediate). Cis-aconitate <=> itaconate + CO(2) 4
Immunopharmacology Comments
Itaconate (itaconic acid) is generated from the citric acid (TCA) cycle intermediate cis-aconitic acid which is produced by mitochondria. Itaconate is synthesised by the enzyme aconitate decarboxylase 1 (referred to as immunoresponsive gene 1 or IRG1). Its synthesis links metabolism to immunity and it plays an important role in the macrophage-based immune response [2-3]. In the cancer setting, tumour cells alter the metabolic state of macrophages and induce their itaconate production. This itaconate potentiates tumour growth, at least as demonstrated in peritoneal tumours [5]. Itaconate-mediated tumour growth may be associated with this metabolite's ability to induce tolerance in human monocytes [3]. As the primary source of itaconate in cells, IRG1 is therefore a target for novel anti-cancer therapeutic design and development. Modulation of immune cell activity by itaconate and/or itaconate derivatives (e.g. dimethyl itaconate) has been suggested as a tractable mechanistic approach for the treatment of IL-17-driven autoimmune diseases [1].
Cell Type Associations
Immuno Cell Type:  Macrophages & monocytes
Cell Ontology Term:   macrophage (CL:0000235)
Comment:  Expressed by macrophages.
References:  6
Immuno Process Associations
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 2 GO processes
GO:0034136 negative regulation of toll-like receptor 2 signaling pathway ISS
GO:0034144 negative regulation of toll-like receptor 4 signaling pathway ISS
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 5 GO processes
GO:0032480 negative regulation of type I interferon production ISS
GO:0035458 cellular response to interferon-beta ISS
GO:0071346 cellular response to interferon-gamma ISS
GO:0071347 cellular response to interleukin-1 ISS
GO:0071356 cellular response to tumor necrosis factor ISS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 5 GO processes
GO:0002760 positive regulation of antimicrobial humoral response IDA
GO:0034136 negative regulation of toll-like receptor 2 signaling pathway ISS
GO:0034144 negative regulation of toll-like receptor 4 signaling pathway ISS
GO:0045824 negative regulation of innate immune response ISS
GO:0050728 negative regulation of inflammatory response ISS
Immuno Process:  Immune system development
GO Annotations:  Associated to 1 GO processes
GO:0072573 tolerance induction to lipopolysaccharide IDA
Immuno Process:  Inflammation
GO Annotations:  Associated to 6 GO processes, IEA only
GO:0034136 negative regulation of toll-like receptor 2 signaling pathway ISS
GO:0034144 negative regulation of toll-like receptor 4 signaling pathway ISS
GO:0045824 negative regulation of innate immune response ISS
GO:0050728 negative regulation of inflammatory response ISS
GO:0071346 cellular response to interferon-gamma ISS
click arrow to show/hide IEA associations
GO:0006954 inflammatory response IEA

References

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1. Bambouskova M, Gorvel L, Lampropoulou V, Sergushichev A, Loginicheva E, Johnson K, Korenfeld D, Mathyer ME, Kim H, Huang LH et al.. (2018) Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis. Nature, 556 (7702): 501-504. [PMID:29670287]

2. Cordes T, Michelucci A, Hiller K. (2015) Itaconic Acid: The Surprising Role of an Industrial Compound as a Mammalian Antimicrobial Metabolite. Annu. Rev. Nutr., 35: 451-73. [PMID:25974697]

3. Domínguez-Andrés J, Novakovic B, Li Y, Scicluna BP, Gresnigt MS, Arts RJW, Oosting M, Moorlag SJCFM, Groh LA, Zwaag J et al.. (2019) The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity. Cell Metab., 29 (1): 211-220.e5. [PMID:30293776]

4. Strelko CL, Lu W, Dufort FJ, Seyfried TN, Chiles TC, Rabinowitz JD, Roberts MF. (2011) Itaconic acid is a mammalian metabolite induced during macrophage activation. J. Am. Chem. Soc., 133 (41): 16386-9. [PMID:21919507]

5. Weiss JM, Davies LC, Karwan M, Ileva L, Ozaki MK, Cheng RY, Ridnour LA, Annunziata CM, Wink DA, McVicar DW. (2018) Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors. J. Clin. Invest., 128 (9): 3794-3805. [PMID:29920191]

6. Xiao W, Wang L, Xiao R, Wu M, Tan J, He Y. (2011) Expression profile of human immune-responsive gene 1 and generation and characterization of polyclonal antiserum. Mol. Cell. Biochem., 353 (1-2): 177-87. [PMID:21424586]

How to cite this page

Itaconate biosynthesis: aconitate decarboxylase 1. Last modified on 22/10/2018. Accessed on 16/09/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=3018.