Neutrophil elastase (, ''leukocyte elastase'', ''ELANE'', ''ELA2'', ''elastase 2'', ''neutrophil'', ''elaszym'', ''serine elastase'', subtype ''human leukocyte elastase (HLE)'') is a serine

proteinase A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products. They do ...

in the same family as

chymotrypsin Chymotrypsin (, chymotrypsins A and B, alpha-chymar ophth, avazyme, chymar, chymotest, enzeon, quimar, quimotrase, alpha-chymar, alpha-chymotrypsin A, alpha-chymotrypsin) is a digestive enzyme component of pancreatic juice acting in the duodenu ...

and has broad substrate specificity. Neutrophil

elastase In molecular biology, elastase is an enzyme from the class of proteases (peptidases) that break down proteins, specifically one that can break down elastin. In other words, the name only refers to the substrate specificity (i.e. what proteins i ...

is secreted by

neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...

s during inflammation, and destroys

bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...

and host tissue. It also localizes to

neutrophil extracellular traps Neutrophil extracellular traps (NETs) are networks of extracellular fibers, primarily composed of DNA from neutrophils, which bind pathogens. Neutrophils are the immune system's first line of defense against infection and have conventionally bee ...

(NETs), via its high affinity for DNA, an unusual property for serine proteases. As with other serine proteinases it contains a charge relay system composed of the

catalytic triad A catalytic triad is a set of three coordinated amino acid residues that can be found in the active site of some enzymes. Catalytic triads are most commonly found in hydrolase and transferase enzymes (e.g. proteases, amidases, esterases, aminoac ...

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...

aspartate Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protein ...

, and

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...

residues that are dispersed throughout the primary sequence of the polypeptide but that are brought together in the three dimensional conformation of the folded protein. The gene encoding neutrophil elastase, ELA2, consists of five

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

s. Neutrophil elastase is closely related to other cytotoxic immune serine proteases, such as the

granzyme Granzymes are serine proteases released by cytoplasmic granules within cytotoxic T cells and natural killer (NK) cells. They induce programmed cell death (apoptosis) in the target cell, thus eliminating cells that have become cancerous or are infe ...

s and

cathepsin G Cathepsin G is a protein that in humans is encoded by the ''CTSG'' gene. It is one of the three serine proteases of the chymotrypsin family that are stored in the azurophil granules, and also a member of the peptidase S1 protein family. Cathepsi ...

. It is more distantly related to the digestive CELA1. The neutrophil form of elastase () is 218

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s long, with two

asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...

-linked

carbohydrate A carbohydrate () is a biomolecule composed of carbon (C), hydrogen (H), and oxygen (O) atoms. The typical hydrogen-to-oxygen atomic ratio is 2:1, analogous to that of water, and is represented by the empirical formula (where ''m'' and ''n'' ...

chains (see ''

glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...

''). It is present in

azurophil An azurophilic granule is a cellular object readily stainable with a Romanowsky stain. In white blood cells and hyperchromatin, staining imparts a burgundy or merlot coloration. Neutrophils in particular are known for containing azurophils load ...

granules in the neutrophil

cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...

. There appear to be two forms of neutrophil elastase, termed IIa and IIb.

Gene

In humans, neutrophil elastase is encoded by the ''ELANE''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

, which resides on chromosome 11.

Function

Elastases form a subfamily of serine proteases that hydrolyze many proteins in addition to elastin. Humans have six elastase genes that encode the structurally similar proteins elastase 1, 2, 2A, 2B, 3A, and 3B. Neutrophil elastase hydrolyzes proteins within specialized neutrophil lysosomes, called

azurophil granules An azurophilic granule is a cellular object readily stainable with a Romanowsky stain. In white blood cells and hyperchromatin, staining imparts a burgundy or merlot coloration. Neutrophils in particular are known for containing azurophils load ...

, as well as proteins of the extracellular matrix following the protein's release from activated neutrophils. Neutrophil elastase may play a role in degenerative and inflammatory diseases by its proteolysis of collagen-IV and elastin of the extracellular matrix. This protein degrades the outer membrane protein A (OmpA) of E. coli as well as the virulence factors of such bacteria as Shigella, Salmonella and Yersinia. Mutations in this gene are associated with

cyclic neutropenia Cyclic neutropenia (CyN) is a rare hematologic disorder and form of congenital neutropenia that tends to occur approximately every three weeks and lasting for few days at a time due to changing rates of neutrophil production by the bone marrow. It ...

(CyN) and

severe congenital neutropenia Severe congenital neutropenia (SCN), also often known as Kostmann syndrome or disease, is a group of rare disorders that affect myelopoiesis, causing a congenital form of neutropenia, usually without other physical malformations. SCN manifests in ...

(SCN). At least 95 disease-causing mutations in this gene have been discovered. This gene is clustered with other serine protease gene family members, azurocidin 1 and proteinase 3 genes, at chromosome 19pter. All 3 genes are expressed coordinately and their protein products are packaged together into

during neutrophil differentiation.

Clinical significance

Neutrophil elastase is an important protease enzyme that when expressed aberrantly can cause

emphysema Emphysema is any air-filled enlargement in the body's tissues. Most commonly emphysema refers to the permanent enlargement of air spaces (alveoli) in the lungs, and is also known as pulmonary emphysema. Emphysema is a lower respiratory tract di ...

or emphysematous changes. This involves breakdown of the lung structure and increased airspaces. Mutations of the ''ELANE'' gene cause cyclic and

severe Severity or Severely may refer to: * ''Severity'' (video game), a canceled video game * "Severely" (song), by South Korean band F.T. Island See also

* * {{disambig ...

congenital

neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...

, which is a failure of neutrophils to mature. In 2019, a study confirmed that ''ELANE'' deletion does not cause neutropenia.

Inhibitors

In order to minimize damage to tissues, there are few inhibitors of neutrophil elastase. One group of inhibitors are the

Serpin Serpins are a superfamily of proteins with similar structures that were first identified for their protease inhibition activity and are found in all kingdoms of life. The acronym serpin was originally coined because the first serpins to be ...

s (Serine Protease Inhibitors). Neutrophil elastase has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...

with

Alpha 2-antiplasmin Alpha 2-antiplasmin (or α2-antiplasmin or plasmin inhibitor) is a serine protease inhibitor (serpin) responsible for inactivating plasmin. Plasmin is an important enzyme that participates in fibrinolysis and degradation of various other proteins ...

, which belongs to the Serpin family of proteins.

References

External links

GeneReviews/NCBI/NIH/UW entry on ELANE-Related Neutropenias
* * {{Portal bar, Biology, border=no EC 3.4.21 Extracellular matrix remodeling enzymes