Glutamyl endopeptidase (, ''SspA, V8 protease, GluV8,'' ''endoproteinase Glu-C'', ''staphylococcal serine proteinase'') is an extracellular

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...

l serine protease of the

glutamyl endopeptidase I Glutamyl endopeptidase I is a family of extracellular bacterial serine proteases. The proteases within this family have been identified in species of ''Staphylococcus'', ''Bacillus'', and ''Streptomyces'', among others. The two former are more close ...

family that was initially isolated from the ''

Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often positive ...

'' strain V8. The

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

is, hence, commonly referred to as "V8 protease", or alternatively SspA from its corresponding

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

Genetics

Glutamyl endopeptidase is in ''S. aureus'' expressed from the

''sspA'' within the operon ''ssp''. Downstream of ''sspA'', the operon also includes the genes of the

cysteine protease Cysteine proteases, also known as thiol proteases, are hydrolase enzymes that degrade proteins. These proteases share a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic triad or dyad. Discovered by Gopal Chund ...

staphopain B (''sspB'') and of staphostatin B (''sspC''; specific inhibitor of staphopain B). Glutamyl endopeptidase is largely co-expressed with the other major proteases of ''S. aureus'':

aureolysin Aureolysin (, ''protease III, staphylococcal metalloprotease,'' ''Staphylococcus aureus neutral proteinase'') is an extracellular metalloprotease expressed by ''Staphylococcus aureus''. This protease is a major contributor to the bacterium's virule ...

, staphopain A, and staphopain B. The transcription of ''ssp'', that occurs via a promoter controlled by " housekeeping"

sigma factor A sigma factor (σ factor or specificity factor) is a protein needed for initiation of transcription in bacteria. It is a bacterial transcription initiation factor that enables specific binding of RNA polymerase (RNAP) to gene promoters. It is ho ...

σ^A, is up-regulated by accessory gene regulator ''agr'', while it is repressed by staphylococcal accessory regulator ''sarA'' and by alternative sigma factor σ^B (a stress response modulator of

Gram-positive bacteria In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bact ...

). ''ssp'' expression is highly expressed in post-exponential growth phase. A more complex network of modulators and of environmental conditions affecting ''ssp'' expression have been suggested, however. The ''sspA'' gene has a high prevalence in the genome of both commensal- and

pathogenic 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 ...

-type ''S. aureus'' strains.

Activation

Glutamyl endopeptidase is expressed as a

zymogen In biochemistry, a zymogen (), also called a proenzyme (), is an inactive precursor of an enzyme. A zymogen requires a biochemical change (such as a hydrolysis reaction revealing the active site, or changing the configuration to reveal the active ...

that, in order to become fully active, has been modified both through autocatalysis and through cleavage by the metalloprotease

Function

Glutamyl endopeptidase proteolytically activates the zymogen of the

staphopain B (staphopain A is activated through and independent process). The bacterial protease has a narrow specificity, with a strict preference for catalyzing hydrolysis of proteins after negatively charged amino acids, especially

glutamic acid Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...

, and to some extent

aspartic acid 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. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...

. Glutamyl endopeptidase has been shown to cleave certain target proteins among human inflammatory regulators and immune components. It can process

kininogen Kininogens are precursor proteins for kinins, biologically active polypeptides involved in blood coagulation, vasodilation, smooth muscle contraction, inflammatory regulation, and the regulation of the cardiovascular and renal systems. Types o ...

into kinin, and cleave immunoglobulins. The protease also cleaves and inactivates α₁-antitrypsin, but is successfully inhibited by α₂-macroglubulin. Glutamyl endopeptidase can inhibit the activation of targets within the

complement system The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and at ...

. It is indicated to cause inhibition to all three pathways of complement activation. Glutamyl endopeptidase can furthermore cleave a wide array bacterial surface proteins, including fibronectin-binding proteins and protein A, potentially acting as a self-regulatory mechanism.

Biological significance

immunization Immunization, or immunisation, is the process by which an individual's immune system becomes fortified against an infectious agent (known as the immunogen). When this system is exposed to molecules that are foreign to the body, called ''non-sel ...

survey of human serum samples suggests that exposure to glutamyl endopeptidase is common, although a correlation to any specific type of

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...

could not be established. The numerous targets of bacterial proteases, adding the complexity of other

virulence factors Virulence factors (preferably known as pathogenicity factors or effectors in plant science) are cellular structures, molecules and regulatory systems that enable microbial pathogens (bacteria, viruses, fungi, and protozoa) to achieve the following ...

and their genetic regulation, makes it difficult to attribute a specific role of the protease for the bacteria. ''In vivo'' trials with ''S. aureus'' with inactivation of ''ssp'' or ''sspA controlling'' glutamyl endopeptidase gives a contradictory picture for its importance, although it has shown impact for bacterial survival in human whole blood. It has been suggested, however, that the protease promotes ''S. aureus'' dissemination through cleavage of self-proteins and through kinin-induced vasodilation, simultaneously protecting against immunological responses, i.e. through corruption of the regulation of the complement system and of neutrophil-derived proteases. Glutamyl endopeptidase is indicated to participate in control and dissemination in bacterial biofilms. The protease can contribute to

symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...

s, e.g. pain and edema through increased vascular permeability by activating kinin. De-regulation of neutrophil proteases through inactivation of α₁-antitrypsin has been suggested as a potential cause of dysfunctional

coagulation Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...

sepsis Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...

References

External links

* ''Staphylococcus aureus'' {{Portal bar, Biology, border=no EC 3.4.21 Proteases Hydrolases