Alpha-enolase
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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]
Contents
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 spliced 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 activity of the c-myc protooncogene.[7][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][8] 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 spliced form is localizes 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.[6][5][8][9][10]
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][10][11] 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.[10][11][5] 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's 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][8] Considering these factors, ENO1 holds great potential to serve as an effective therapeutic target for treating many types of tumors in patients.[2][10][8]
Autoimmune disease
ENO1 has been detected in serum drawn from children diagnosed with juvenile idiopathic arthritis.[12]
Alpha-enolase has been identified as an autoantigen in Hashimoto's encephalopathy.[13] Single studies have also identified it as an autoantigen associated with severe asthma[14] and a putative target antigen of anti-endothelial cell antibody in Behçet's disease.[15] Reduced expression of the enzyme has been found in the corneal epithelium of people suffering from keratoconus.[16][17]
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.[11]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: Lua error in package.lua at line 80: module 'strict' not found.
Interactions
Alpha-enolase has been shown to interact with TRAPPC2.[18]
See also
External links
- Alpha-Enolase Linked to Severe Asthma - medscape news report, 25 aug 2006.
References
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.
