Biology:Alpha-enolase

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Short description: Protein-coding gene in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Enolase 1 (ENO1), more commonly known as alpha-enolase, is a glycolytic enzyme expressed in most tissues, one of the isozymes of enolase. Each isoenzyme is a homodimer composed of 2 alpha, 2 gamma, or 2 beta subunits, and functions as a glycolytic enzyme. Alpha-enolase, in addition, functions as a structural lens protein (tau-crystallin) in the monomeric form. Alternative splicing of this gene results in a shorter isoform that has been shown to bind to the c-myc promoter and function as a tumor suppressor. Several pseudogenes have been identified, including one on the long arm of chromosome 1. Alpha-enolase has also been identified as an autoantigen in Hashimoto encephalopathy.[1]

Structure

ENO1 is one of three enolase isoforms, the other two being ENO2 (ENO-γ) and ENO3 (ENO-β).[2] Each isoform is a protein subunit that can hetero- or homodimerize to form αα, αβ, αγ, ββ, and γγ dimers.[3] The ENO1 gene spans 18 kb and lacks a TATA box while possessing multiple transcription start sites.[4] A hypoxia-responsive element can be found in the ENO1 promoter and allows the enzyme to function in aerobic glycolysis and contribute to the Warburg effect in tumor cells.[5]

Relationship to Myc-binding protein-1

The mRNA transcript of the ENO1 gene can be alternatively translated into a cytoplasmic protein, with a molecular weight of 48 kDa, or a nuclear protein, with a molecular weight of a 37 kDa.[5][6] The nuclear form was previously identified as Myc-binding protein-1 (MBP1), which downregulates the protein level of the c-myc protooncogene.[6] A start codon at codon 97 of ENO1 and a Kozak consensus sequence were found preceding the 3' region of ENO1 encoding the MBP1 protein. In addition, the N-terminal region of the MBP1 protein it critical to DNA binding and, thus, its inhibitory function.[6]

Function

As an enolase, ENO1 is a glycolytic enzyme the catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate.[2][5][7] This isozyme is ubiquitously expressed in adult human tissues, including liver, brain, kidney, and spleen.[2] Within cells, ENO1 predominantly localizes to the cytoplasm, though an alternatively translated form is localized to the nucleus.[2][5] Its nuclear form, also known as MBP1, functions solely as a tumor suppressor by binding and inhibiting the c-myc protooncogene promoter, and lacks the glycolytic enzyme activity of the cytoplasmic form.[6] ENO1 also plays a role in other functions, including a cell surface receptor for plasminogen on pathogens, such as streptococci, and activated immune cells, leading to systemic infection or tissue invasion; an oxidative stress protein in endothelial cells; a lens crystalline; a heat shock protein; and a binding partner of cytoskeletal and chromatin structures to aid in transcription.[5][6][7][8][9]

Clinical significance

Cancer

ENO1 overexpression has been associated with multiple tumors, including glioma, neuroendocrine tumors, neuroblastoma, pancreatic cancer, prostate cancer, cholangiocarcinoma, thyroid carcinoma, lung cancer, hepatocellular carcinoma, and breast cancer.[2][5][9][10] In many of these tumors, ENO1 promoted cell proliferation by regulating the PI3K/AKT signaling pathway and induced tumorigenesis by activating plasminogen.[2][5] Moreover, ENO1 is expressed on the tumor cell surface during pathological conditions such as inflammation, autoimmunity, and malignancy. Its role as a plasminogen receptor leads to extracellular matrix degradation and cancer invasion.[5][9][10] Due to its surface expression, targeting surface ENO1 enables selective targeting of tumor cells while leaving the ENO1 inside normal cells functional.[5] Moreover, in tumors such as non-Hodgkin lymphomas (NHLs) and breast cancer, inhibition of ENO1 expression decreased tolerance to hypoxia while increasing sensitivity to radiation therapy, thus indicating that ENO1 may have aided chemoresistance.[2][7] Considering these factors, ENO1 holds great potential to serve as an effective therapeutic target for treating many types of tumors in patients.[2][7][9]

ENO1 is located on the 1p36 tumor suppressor locus near MIR34A which is homozygously deleted in Glioblastoma, Hepatocellular carcinoma and Cholangiocarcinoma.[11][12] The co-deletion of ENO1 is a passenger event with the resultant tumor cells being entirely dependent on ENO2 for the execution of glycolysis.[13][14] Tumor cells with such deletions are exceptionally sensitive towards ablation of ENO2.[13][14] Inhibition of ENO2 in ENO1-homozygously deleted cancer cells constitutes an example of synthetic lethality treatment for cancer.

Autoimmune disease

ENO1 has been detected in serum drawn from children diagnosed with juvenile idiopathic arthritis.[15]

Alpha-enolase has been identified as an autoantigen in Hashimoto's encephalopathy.[16] Single studies have also identified it as an autoantigen associated with severe asthma[17] and a putative target antigen of anti-endothelial cell antibody in Behçet's disease.[18] Reduced expression of the enzyme has been found in the corneal epithelium of people suffering from keratoconus.[19][20]

Gastrointestinal disease

CagA protein was found to activate ENO1 expression through activating the Src and MEK/ERK pathways as a mechanism for H. pylori-mediated gastric diseases.[10]

Hemolytic anemia

Enolase deficiency is a rare inborn error of metabolism disease, leads to hemolytic anemia in affected homozygous carriers of loss of function mutations in ENO1.[21] As with other glycolysis enzyme deficiency diseases, the condition is aggravated by redox-cycling agents such as nitrofurantoin.

Interactive pathway map

Interactions

Alpha-enolase has been shown to interact with TRAPPC2.[22]

See also

External links

References

  1. ↑ "ENO1 enolase 1 (alpha)". NCBI Entrez Gene database. https://www.ncbi.nlm.nih.gov/gene/2023. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 "ENO1 promotes tumor proliferation and cell adhesion mediated drug resistance (CAM-DR) in non-Hodgkin lymphomas". Experimental Cell Research 335 (2): 216–23. July 2015. doi:10.1016/j.yexcr.2015.05.020. PMID 26024773. 
  3. ↑ "The TFG-TEC oncoprotein induces transcriptional activation of the human β-enolase gene via chromatin modification of the promoter region". Molecular Carcinogenesis 55 (10): 1411–23. October 2016. doi:10.1002/mc.22384. PMID 26310886. 
  4. ↑ "Structural features of the human gene for muscle-specific enolase. Differential splicing in the 5'-untranslated sequence generates two forms of mRNA". European Journal of Biochemistry 214 (2): 367–74. June 1993. doi:10.1111/j.1432-1033.1993.tb17932.x. PMID 8513787. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 "Alpha-enolase as a potential cancer prognostic marker promotes cell growth, migration, and invasion in glioma". Molecular Cancer 13: 65. March 2014. doi:10.1186/1476-4598-13-65. PMID 24650096. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "Structural analysis of alpha-enolase. Mapping the functional domains involved in down-regulation of the c-myc protooncogene". The Journal of Biological Chemistry 275 (8): 5958–65. February 2000. doi:10.1074/jbc.275.8.5958. PMID 10681589. 
  7. ↑ 7.0 7.1 7.2 7.3 "Role of enolase-1 in response to hypoxia in breast cancer: exploring the mechanisms of action". Oncology Reports 29 (4): 1322–32. April 2013. doi:10.3892/or.2013.2269. PMID 23381546. 
  8. ↑ "Multifunctional alpha-enolase: its role in diseases". Cellular and Molecular Life Sciences 58 (7): 902–20. June 2001. doi:10.1007/pl00000910. PMID 11497239. 
  9. ↑ 9.0 9.1 9.2 9.3 "Surface α-enolase promotes extracellular matrix degradation and tumor metastasis and represents a new therapeutic target". PLOS ONE 8 (7): e69354. 2013. doi:10.1371/journal.pone.0069354. PMID 23894455. Bibcode: 2013PLoSO...869354H. 
  10. ↑ 10.0 10.1 10.2 "Helicobacter pylori cytotoxin-associated gene A protein upregulates α-enolase expression via Src/MEK/ERK pathway: implication for progression of gastric cancer". International Journal of Oncology 45 (2): 764–70. August 2014. doi:10.3892/ijo.2014.2444. PMID 24841372. 
  11. ↑ "Collateral Lethality: A new therapeutic strategy in oncology". Trends in Cancer 1 (3): 161–173. November 2015. doi:10.1016/j.trecan.2015.10.002. PMID 26870836. 
  12. ↑ "Tumor necrosis factor-alpha in human arterial wall with atherosclerosis". Atherosclerosis 89 (2–3): 247–54. August 1991. doi:10.1016/0021-9150(91)90066-C. PMID 1793452. 
  13. ↑ 13.0 13.1 "SF2312 is a natural phosphonate inhibitor of enolase". Nature Chemical Biology 12 (12): 1053–1058. December 2016. doi:10.1038/nchembio.2195. PMID 27723749. 
  14. ↑ 14.0 14.1 "Passenger deletions generate therapeutic vulnerabilities in cancer". Nature 488 (7411): 337–42. August 2012. doi:10.1038/nature11331. PMID 22895339. Bibcode: 2012Natur.488..337M. 
  15. ↑ "Measurement and evaluation of isotypes of anti-citrullinated fibrinogen and anti-citrullinated alpha-enolase antibodies in juvenile idiopathic arthritis". Clinical and Experimental Rheumatology 32 (5): 740–6. 2014. PMID 25068682. 
  16. ↑ "High prevalence of serum autoantibodies against the amino terminal of alpha-enolase in Hashimoto's encephalopathy". Journal of Neuroimmunology 185 (1–2): 195–200. April 2007. doi:10.1016/j.jneuroim.2007.01.018. PMID 17335908. 
  17. ↑ "Identification of alpha-enolase as an autoantigen associated with severe asthma". The Journal of Allergy and Clinical Immunology 118 (2): 376–81. August 2006. doi:10.1016/j.jaci.2006.04.002. PMID 16890761. 
  18. ↑ "Human alpha-enolase from endothelial cells as a target antigen of anti-endothelial cell antibody in Behçet's disease". Arthritis and Rheumatism 48 (7): 2025–35. July 2003. doi:10.1002/art.11074. PMID 12847697. 
  19. ↑ "Molecular changes in selected epithelial proteins in human keratoconus corneas compared to normal corneas". Molecular Vision 12: 1615–25. December 2006. PMID 17200661. http://www.molvis.org/molvis/v12/a185/. 
  20. ↑ "Proteome profiling of corneal epithelium and identification of marker proteins for keratoconus, a pilot study". Experimental Eye Research 82 (2): 201–9. February 2006. doi:10.1016/j.exer.2005.06.009. PMID 16083875. 
  21. ↑ "Chronic hemolytic anemia associated with erythrocyte enolase deficiency exacerbated by ingestion of nitrofurantoin". American Journal of Clinical Pathology 58 (4): 408–14. 1972. doi:10.1093/ajcp/58.5.408. PMID 4640298. 
  22. ↑ "A novel 16-kilodalton cellular protein physically interacts with and antagonizes the functional activity of c-myc promoter-binding protein 1". Molecular and Cellular Biology 21 (2): 655–62. January 2001. doi:10.1128/MCB.21.2.655-662.2001. PMID 11134351. 

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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