Alpha-enolase
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.[5]
Structure
[edit]ENO1 is one of three enolase isoforms, the other two being ENO2 (ENO-γ) and ENO3 (ENO-β).[6] Each isoform is a protein subunit that can hetero- or homodimerize to form αα, αβ, αγ, ββ, and γγ dimers.[7] The ENO1 gene spans 18 kb and lacks a TATA box while possessing multiple transcription start sites.[8] 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.[9]
Relationship to Myc-binding protein-1
[edit]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.[9][10] The nuclear form was previously identified as Myc-binding protein-1 (MBP1), which downregulates the protein level of the c-myc protooncogene.[10] 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.[10]
Function
[edit]As an enolase, ENO1 is a glycolytic enzyme the catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate.[6][9][11] This isozyme is ubiquitously expressed in adult human tissues, including liver, brain, kidney, and spleen.[6] Within cells, ENO1 predominantly localizes to the cytoplasm, though an alternatively translated form is localized to the nucleus.[6][9] 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.[10] 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.[9][10][11][12][13]
Clinical significance
[edit]Cancer
[edit]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.[6][9][13][14] In many of these tumors, ENO1 promoted cell proliferation by regulating the PI3K/AKT signaling pathway and induced tumorigenesis by activating plasminogen.[6][9] 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.[9][13][14] Due to its surface expression, targeting surface ENO1 enables selective targeting of tumor cells while leaving the ENO1 inside normal cells functional.[9] 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.[6][11] Considering these factors, ENO1 holds great potential to serve as an effective therapeutic target for treating many types of tumors in patients.[6][11][13]
ENO1 is located on the 1p36 tumor suppressor locus near MIR34A which is homozygously deleted in Glioblastoma, Hepatocellular carcinoma and Cholangiocarcinoma.[15][16] The co-deletion of ENO1 is a passenger event with the resultant tumor cells being entirely dependent on ENO2 for the execution of glycolysis.[17][18] Tumor cells with such deletions are exceptionally sensitive towards ablation of ENO2.[17][18] Inhibition of ENO2 in ENO1-homozygously deleted cancer cells constitutes an example of synthetic lethality treatment for cancer.
Autoimmune disease
[edit]ENO1 has been detected in serum drawn from children diagnosed with juvenile idiopathic arthritis.[19]
Alpha-enolase has been identified as an autoantigen in Hashimoto's encephalopathy.[20] Single studies have also identified it as an autoantigen associated with severe asthma[21] and a putative target antigen of anti-endothelial cell antibody in Behçet's disease.[22] Reduced expression of the enzyme has been found in the corneal epithelium of people suffering from keratoconus.[23][24]
Gastrointestinal disease
[edit]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.[14]
Hemolytic anemia
[edit]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.[25] As with other glycolysis enzyme deficiency diseases, the condition is aggravated by redox-cycling agents such as nitrofurantoin.
Interactive pathway map
[edit]Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
- ^ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".
Interactions
[edit]Alpha-enolase has been shown to interact with TRAPPC2.[26]
See also
[edit]External links
[edit]- Alpha-Enolase Linked to Severe Asthma - medscape news report, 25 aug 2006.
- Human ENO1 genome location and ENO1 gene details page in the UCSC Genome Browser.
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000074800 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000063524 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "ENO1 enolase 1 (alpha)". NCBI Entrez Gene database.
- ^ a b c d e f g h Zhu X, Miao X, Wu Y, Li C, Guo Y, Liu Y, Chen Y, Lu X, Wang Y, He S (July 2015). "ENO1 promotes tumor proliferation and cell adhesion mediated drug resistance (CAM-DR) in non-Hodgkin lymphomas". Experimental Cell Research. 335 (2): 216–23. doi:10.1016/j.yexcr.2015.05.020. PMID 26024773.
- ^ Kim AY, Lim B, Choi J, Kim J (October 2016). "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. doi:10.1002/mc.22384. PMID 26310886. S2CID 25167240.
- ^ Giallongo A, Venturella S, Oliva D, Barbieri G, Rubino P, Feo S (June 1993). "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. doi:10.1111/j.1432-1033.1993.tb17932.x. PMID 8513787.
- ^ a b c d e f g h i Song Y, Luo Q, Long H, Hu Z, Que T, Zhang X, Li Z, Wang G, Yi L, Liu Z, Fang W, Qi S (March 2014). "Alpha-enolase as a potential cancer prognostic marker promotes cell growth, migration, and invasion in glioma". Molecular Cancer. 13: 65. doi:10.1186/1476-4598-13-65. PMC 3994408. PMID 24650096.
- ^ a b c d e Subramanian A, Miller DM (February 2000). "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. doi:10.1074/jbc.275.8.5958. PMID 10681589.
- ^ a b c d Gao J, Zhao R, Xue Y, Niu Z, Cui K, Yu F, Zhang B, Li S (April 2013). "Role of enolase-1 in response to hypoxia in breast cancer: exploring the mechanisms of action". Oncology Reports. 29 (4): 1322–32. doi:10.3892/or.2013.2269. PMID 23381546.
- ^ Pancholi V (June 2001). "Multifunctional alpha-enolase: its role in diseases". Cellular and Molecular Life Sciences. 58 (7): 902–20. doi:10.1007/pl00000910. PMID 11497239. S2CID 9191423.
- ^ a b c d Hsiao KC, Shih NY, Fang HL, Huang TS, Kuo CC, Chu PY, Hung YM, Chou SW, Yang YY, Chang GC, Liu KJ (2013). "Surface α-enolase promotes extracellular matrix degradation and tumor metastasis and represents a new therapeutic target". PLOS ONE. 8 (7): e69354. Bibcode:2013PLoSO...869354H. doi:10.1371/journal.pone.0069354. PMC 3716638. PMID 23894455.
- ^ a b c Chen S, Duan G, Zhang R, Fan Q (August 2014). "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. doi:10.3892/ijo.2014.2444. PMID 24841372.
- ^ Muller FL, Aquilanti EA, DePinho RA (November 2015). "Collateral Lethality: A new therapeutic strategy in oncology". Trends in Cancer. 1 (3): 161–173. doi:10.1016/j.trecan.2015.10.002. PMC 4746004. PMID 26870836.
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- ^ Srivastava OP, Chandrasekaran D, Pfister RR (December 2006). "Molecular changes in selected epithelial proteins in human keratoconus corneas compared to normal corneas". Molecular Vision. 12: 1615–25. PMID 17200661.
- ^ Nielsen K, Vorum H, Fagerholm P, Birkenkamp-Demtröder K, Honoré B, Ehlers N, Orntoft TF (February 2006). "Proteome profiling of corneal epithelium and identification of marker proteins for keratoconus, a pilot study". Experimental Eye Research. 82 (2): 201–9. doi:10.1016/j.exer.2005.06.009. PMID 16083875.
- ^ Stefanini M (1972). "Chronic hemolytic anemia associated with erythrocyte enolase deficiency exacerbated by ingestion of nitrofurantoin". American Journal of Clinical Pathology. 58 (4): 408–14. doi:10.1093/ajcp/58.5.408. PMID 4640298.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.