ENO1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2PSN, 3B97
Identifiers
Aliases	ENO1, ENO1L1, MPB1, NNE, PPH, HEL-S-17, enolase 1
External IDs	OMIM: 172430 MGI: 95393 HomoloGene: 134343 GeneCards: ENO1
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p36.23 Start 8,861,000 bp[1] End 8,879,190 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4 E2|4 81.24 cM Start 150,321,178 bp[2] End 150,333,336 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in nucleus accumbens Achilles tendon renal medulla putamen smooth muscle tissue embryo ascending aorta caudate nucleus amygdala Brodmann area 9 Top expressed in neural tube lens mesencephalon proximal tubule hippocampus proper esophagus rhombencephalon stomach jejunum cerebellar cortex More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding metal ion binding protein binding lyase activity GTPase binding magnesium ion binding RNA binding cadherin binding DNA-binding transcription repressor activity, RNA polymerase II-specific phosphopyruvate hydratase activity protein homodimerization activity RNA polymerase II transcription regulatory region sequence-specific DNA binding Cellular component cytoplasm M band membrane extracellular exosome nucleus extracellular space phosphopyruvate hydratase complex cytosol plasma membrane cell surface cell cortex region Biological process gluconeogenesis regulation of transcription, DNA-templated glycolytic process response to virus transcription, DNA-templated negative regulation of cell growth negative regulation of transcription, DNA-templated negative regulation of transcription by RNA polymerase II positive regulation of plasminogen activation positive regulation of muscle contraction canonical glycolysis negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway positive regulation of ATP biosynthetic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2023 13806 Ensembl ENSG00000074800 ENSMUSG00000063524 UniProt P06733 P17182 RefSeq (mRNA) NM_001201483 NM_001428 NM_001353346 NM_023119 NM_001379127 NM_001379128 RefSeq (protein) NP_001188412 NP_001419 NP_001340275 NP_001366056 NP_001366057 NP_075608 NP_001020559 Location (UCSC) Chr 1: 8.86 – 8.88 Mb Chr 4: 150.32 – 150.33 Mb PubMed search [3] [4]
Wikidata
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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.^[5]

Structure

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

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

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

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.^{[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

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

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

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

Click on genes, proteins and metabolites below to link to respective articles.^{[§ 1]}

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|alt=Glycolysis and Gluconeogenesis edit]]

Glycolysis and Gluconeogenesis edit

1. ^ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".

Interactions

Alpha-enolase has been shown to interact with TRAPPC2.^[26]