Enolase 1 (ENO1), more commonly known as alpha-enolase, is a glycolytic

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

expressed in most tissues, one of the

isozyme In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. dif ...

s of

enolase Phosphopyruvate hydratase, usually known as enolase, is a metalloenzyme () that catalyses the conversion of 2-phosphoglycerate (2-PG) to phosphoenolpyruvate (PEP), the ninth and penultimate step of glycolysis. The chemical reaction is: :2-p ...

. Each isoenzyme is a

homodimer In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...

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 A lens is a transmissive optical device which focuses or disperses a light beam by means of refraction. A simple lens consists of a single piece of transparent material, while a compound lens consists of several simple lenses (''elements ...

protein (

tau Tau (uppercase Τ, lowercase τ, or \boldsymbol\tau; el, ταυ ) is the 19th letter of the Greek alphabet, representing the voiceless dental or alveolar plosive . In the system of Greek numerals, it has a value of 300. The name in English ...

crystallin In anatomy, a crystallin is a water-soluble structural protein found in the lens and the cornea of the eye accounting for the transparency of the structure. It has also been identified in other places such as the heart, and in aggressive breast c ...

) in the

monomer In chemistry, a monomer ( ; '' mono-'', "one" + ''-mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization. Classification ...

ic form. Alternative splicing of this gene results in a shorter isoform that has been shown to bind to the ''

c-myc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' ( MYC), ''l-myc'' ( MYCL), and ''n-myc'' ( MYCN). ''c-myc'' (also sometimes re ...

'' promoter and function as a

tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or re ...

. Several pseudogenes have been identified, including one on the long arm of chromosome 1. Alpha-enolase has also been identified as an

autoantigen In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease". ...

in Hashimoto encephalopathy.

Structure

ENO1 is one of three enolase isoforms, the other two being

ENO2 Gamma-enolase, also known as enolase 2 (ENO2) or neuron specific enolase (NSE), is an enzyme that in humans is encoded by the ''ENO2'' gene. Gamma-enolase is a phosphopyruvate hydratase. Gamma-enolase is one of the three enolase isoenzymes found i ...

(ENO-γ) and

ENO3 Enolase 3 (ENO3), more commonly known as beta-enolase (ENO-β), is an enzyme that in humans is encoded by the ''ENO3'' gene. This gene encodes one of the three enolase isoenzymes found in mammals. This isoenzyme is found in skeletal muscle cells ...

(ENO-β). Each isoform is a protein subunit that can hetero- or

ize to form αα, αβ, αγ, ββ, and γγ dimers. The ''ENO1'' gene spans 18 kb and lacks a

TATA box In molecular biology, the TATA box (also called the Goldberg–Hogness box) is a sequence of DNA found in the core promoter region of genes in archaea and eukaryotes. The bacterial homolog of the TATA box is called the Pribnow box which has ...

while possessing multiple

transcription start site Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules calle ...

s. 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 A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

cells.

Relationship to Myc-binding protein-1

The mRNA transcript of the ''ENO1'' gene can be alternatively translated into a

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...

ic protein, with a

molecular weight A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

of 48

kDa The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...

, or a

nuclear Nuclear may refer to: Physics Relating to the nucleus of the atom: * Nuclear engineering *Nuclear physics *Nuclear power *Nuclear reactor *Nuclear weapon *Nuclear medicine *Radiation therapy *Nuclear warfare Mathematics *Nuclear space *Nuclear ...

protein, with a molecular weight of a 37 kDa. The nuclear form was previously identified as Myc-binding protein-1 (MBP1), which downregulates the protein level of the ''

protooncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

. A start codon at codon 97 of ''ENO1'' and a

Kozak consensus sequence The Kozak consensus sequence (Kozak consensus or Kozak sequence) is a nucleic acid motif that functions as the protein translation initiation site in most eukaryotic mRNA transcripts. Regarded as the optimum sequence for initiating translation in ...

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.

Function

As an enolase, ENO1 is a glycolytic enzyme the catalyzes the conversion of 2-phosphoglycerate to

phosphoenolpyruvate Phosphoenolpyruvate (2-phosphoenolpyruvate, PEP) is the ester derived from the enol of pyruvate and phosphate. It exists as an anion. PEP is an important intermediate in biochemistry. It has the highest-energy phosphate bond found (−61.9 kJ/m ...

. This isozyme is ubiquitously expressed in adult human tissues, including

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...

, and

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

. Within cells, ENO1 predominantly localizes to the

, though an alternatively translated form is localized to the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom * Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...

. Its nuclear form, also known as MBP1, functions solely as a

by binding and inhibiting the ''c-myc'' protooncogene promoter, and lacks the glycolytic enzyme activity of the cytoplasmic form. ENO1 also plays a role in other functions, including a cell surface receptor for

plasminogen Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is encode ...

pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...

s, such as streptococci, and activated immune cells, leading to systemic infection or tissue invasion; an

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

protein in

endothelial The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

cells; a lens

crystalline A crystal or crystalline solid is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered microscopic structure, forming a crystal lattice that extends in all directions. In addition, macros ...

; a

heat shock protein Heat shock proteins (HSP) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including expo ...

; and a binding partner of

cytoskeletal The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compo ...

and

chromatin Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...

structures to aid in

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

Clinical significance

Cancer

ENO1 overexpression has been associated with multiple tumors, including

glioma A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours. Signs and symptoms ...

neuroendocrine Neuroendocrine cells are cells that receive neuronal input (through neurotransmitters released by nerve cells or neurosecretory cells) and, as a consequence of this input, release messenger molecules (hormones) into the blood. In this way they bri ...

tumors,

neuroblastoma Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in th ...

, pancreatic cancer, prostate cancer, cholangiocarcinoma, thyroid carcinoma,

lung cancer Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung. Lung carcinomas derive from transformed, malign ...

, hepatocellular carcinoma, and

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...

. In many of these tumors, ENO1 promoted cell proliferation by regulating the

PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

AKT Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tran ...

signaling pathway and induced

tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...

by activating plasminogen. Moreover, ENO1 is expressed on the tumor cell surface during pathological conditions such as

inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

autoimmunity In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...

, and

malignancy Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...

. Its role as a plasminogen receptor leads to

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...

degradation and cancer invasion. Due to its surface expression, targeting surface ENO1 enables selective targeting of tumor cells while leaving the ENO1 inside normal cells functional. Moreover, in tumors such as

non-Hodgkin lymphoma Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tirednes ...

s (NHLs) and breast cancer, inhibition of ENO1 expression decreased tolerance to hypoxia while increasing sensitivity to

radiation therapy Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Radi ...

, thus indicating that ENO1 may have aided chemoresistance. Considering these factors, ENO1 holds great potential to serve as an effective therapeutic target for treating many types of tumors in patients. ENO1 is located on the 1p36 tumor suppressor locus near

MIR34A MicroRNA 34a (miR-34a) is a MicroRNA that in humans is encoded by the ''MIR34A'' gene. Function microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular or ...

which is homozygously deleted in

Glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ...

, Hepatocellular carcinoma and Cholangiocarcinoma. The co-deletion of ENO1 is a passenger event with the resultant tumor cells being entirely dependent on

for the execution of glycolysis. Tumor cells with such deletions are exceptionally sensitive towards ablation of ENO2. Inhibition of ENO2 in ENO1-homozygously deleted cancer cells constitutes an example of

synthetic lethality Synthetic lethality is defined as a type of genetic interaction where the combination of two genetic events results in cell death or death of an organism. Although the foregoing explanation is wider than this, it is common when referring to synthet ...

treatment for cancer.

Autoimmune disease

ENO1 has been detected in serum drawn from children diagnosed with

juvenile idiopathic arthritis Juvenile idiopathic arthritis (JIA) is the most common, chronic rheumatic disease of childhood, affecting approximately one per 1,000 children. ''Juvenile'', in this context, refers to disease onset before 16 years of age, while ''idiopathic'' r ...

. Alpha-enolase has been identified as an

Hashimoto's encephalopathy Hashimoto's encephalopathy, also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), is a neurological condition characterized by encephalopathy, thyroid autoimmunity, and good clinical response to cortico ...

. Single studies have also identified it as an autoantigen associated with severe

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...

and a putative target antigen of anti-endothelial cell antibody in

Behçet's disease Behçet's disease (BD) is a type of inflammatory disorder which affects multiple parts of the body. The most common symptoms include painful sores on the mucous membranes of the mouth and other parts of the body, inflammation of parts of the ey ...

. Reduced expression of the enzyme has been found in the

corneal epithelium The corneal epithelium (epithelium corneæ anterior layer) is made up of epithelial tissue and covers the front of the cornea. It acts as a barrier to protect the cornea, resisting the free flow of fluids from the tears, and prevents bacteria fro ...

of people suffering from keratoconus.

Gastrointestinal disease

CagA ''Helicobacter pylori'' virulence factor CagA (cytotoxin-associated gene A) is a 120–145kDa protein encoded on the 40kb ''cag'' pathogenicity island (PAI). ''H. pylori'' strains can be divided into CagA positive or negative strains. Approximately ...

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

Hemolytic anemia

Enolase deficiency Enolase Deficiency is a rare genetic disorder of glucose metabolism. Partial deficiencies have been observed in several caucasian families. The deficiency is transmitted through an autosomal dominant inheritance pattern. The gene for Enolase 1 h ...

is a rare inborn error of metabolism disease, leads to

hemolytic anemia Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonly ...

in affected homozygous carriers of loss of function mutations in ENO1. As with other glycolysis enzyme deficiency diseases, the condition is aggravated by redox-cycling agents such as

nitrofurantoin Nitrofurantoin is an antibacterial medication used to treat urinary tract infections, but it is not as effective for kidney infections. It is taken by mouth. Common side effects include nausea, loss of appetite, diarrhea, and headaches. Rarely ...

Interactive pathway map

Interactions

Alpha-enolase has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with TRAPPC2.

External links

Alpha-Enolase Linked to Severe Asthma
- medscape news report, 25 aug 2006. *

References

{{NLM content Enzymes Glycolysis