Glutamyl endopeptidase GluV8

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Glutamyl endopeptidase
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EC no. 3.4.21.19
CAS no. 137010-42-5
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Glutamyl endopeptidase (EC 3.4.21.19, SspA, V8 protease, GluV8,endoproteinase Glu-C, staphylococcal serine proteinase) is an extracellular bacterial serine protease of the glutamyl endopeptidase I family that was initially isolated from the Staphylococcus aureus strain V8. The protease is, hence, commonly referred to as "V8 protease", or alternatively SspA from its corresponding gene. [1] [2] [3]

Contents

Genetics

Glutamyl endopeptidase is in S. aureus expressed from the gene sspA within the operon ssp. Downstream of sspA, the operon also includes the genes of the cysteine protease staphopain B (sspB) and of staphostatin B (sspC; specific inhibitor of staphopain B). [4] [5]

Glutamyl endopeptidase is largely co-expressed with the other major proteases of S. aureus: aureolysin, staphopain A, and staphopain B. The transcription of ssp, that occurs via a promoter controlled by "housekeeping" sigma factor σA, is up-regulated by accessory gene regulator agr, while it is repressed by staphylococcal accessory regulator sarA and by alternative sigma factor σB (a stress response modulator of Gram-positive bacteria). ssp expression is highly expressed in post-exponential growth phase. [4] A more complex network of modulators and of environmental conditions affecting ssp expression have been suggested, however. [6] [7]

The sspA gene has a high prevalence in the genome of both commensal- and pathogenic-type S. aureus strains. [8]

Activation

Glutamyl endopeptidase is expressed as a zymogen that, in order to become fully active, has been modified both through autocatalysis and through cleavage by the metalloprotease aureolysin. [1] [4] [9]

Function

Glutamyl endopeptidase proteolytically activates the zymogen of the cysteine protease staphopain B (staphopain A is activated through and independent process). [10] [11] [12]

The bacterial protease has a narrow specificity, with a strict preference for catalyzing hydrolysis of proteins after negatively charged amino acids, especially glutamic acid, and to some extent aspartic acid. [1] [2] [13] Aspartic acid is cleaved mainly when followed by a small amino acid, such as glycine. [13]

Glutamyl endopeptidase has been shown to cleave certain target proteins among human inflammatory regulators and immune components. It can process kininogen into kinin, and cleave immunoglobulins. The protease also cleaves and inactivates α1-antitrypsin, but is successfully inhibited by α2-macroglubulin. [1] Glutamyl endopeptidase can inhibit the activation of targets within the complement system. It is indicated to cause inhibition to all three pathways of complement activation. [14]

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. [15] [16] [17]

Biological significance

An immunization survey of human serum samples suggests that exposure to glutamyl endopeptidase is common, although a correlation to any specific type of infection could not be established. [8] The numerous targets of bacterial proteases, adding the complexity of other virulence factors 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. [1] [14] [18] [19]

Glutamyl endopeptidase is indicated to participate in control and dissemination in bacterial biofilms. [20]

The protease can contribute to infection symptoms, e.g. pain and edema through increased vascular permeability by activating kinin. [1] De-regulation of neutrophil proteases through inactivation of α1-antitrypsin has been suggested as a potential cause of dysfunctional coagulation in sepsis. [21]

Related Research Articles

<span class="mw-page-title-main">Protease</span> Enzyme that cleaves other proteins into smaller peptides

A protease 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 this by cleaving the peptide bonds within proteins by hydrolysis, a reaction where water breaks bonds. Proteases are involved in many biological functions, including digestion of ingested proteins, protein catabolism, and cell signaling.

<i>Staphylococcus aureus</i> Species of Gram-positive bacterium

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 for catalase and nitrate reduction and is a facultative anaerobe that can grow without the need for oxygen. Although S. aureus usually acts as a commensal of the human microbiota, it can also become an opportunistic pathogen, being a common cause of skin infections including abscesses, respiratory infections such as sinusitis, and food poisoning. Pathogenic strains often promote infections by producing virulence factors such as potent protein toxins, and the expression of a cell-surface protein that binds and inactivates antibodies. S. aureus is one of the leading pathogens for deaths associated with antimicrobial resistance and the emergence of antibiotic-resistant strains, such as methicillin-resistant S. aureus (MRSA), is a worldwide problem in clinical medicine. Despite much research and development, no vaccine for S. aureus has been approved.

<span class="mw-page-title-main">Serine protease</span> Class of enzymes

Serine proteases are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. Serine proteases fall into two broad categories based on their structure: chymotrypsin-like (trypsin-like) or subtilisin-like.

<span class="mw-page-title-main">Cysteine protease</span> Class of enzymes

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.

Virulence factors are cellular structures, molecules and regulatory systems that enable microbial pathogens to achieve the following:

<span class="mw-page-title-main">Panton–Valentine leukocidin</span>

Panton–Valentine leukocidin (PVL) is a cytotoxin—one of the β-pore-forming toxins. The presence of PVL is associated with increased virulence of certain strains (isolates) of Staphylococcus aureus. It is present in the majority of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) isolates studied and is the cause of necrotic lesions involving the skin or mucosa, including necrotic hemorrhagic pneumonia. PVL creates pores in the membranes of infected cells. PVL is produced from the genetic material of a bacteriophage that infects Staphylococcus aureus, making it more virulent.

<span class="mw-page-title-main">Hemolysin</span> Molecule destroying the membrane of red blood cells

Hemolysins or haemolysins are lipids and proteins that cause lysis of red blood cells by disrupting the cell membrane. Although the lytic activity of some microbe-derived hemolysins on red blood cells may be of great importance for nutrient acquisition, many hemolysins produced by pathogens do not cause significant destruction of red blood cells during infection. However, hemolysins are often capable of lysing red blood cells in vitro.

<span class="mw-page-title-main">SprD</span>

In molecular biology SprD is a non-coding RNA expressed on pathogenicity islands in Staphylococcus aureus. It was identified in silico along with a number of other sRNAs (SprA-G) through microarray analysis which were confirmed using a Northern blot. SprD has been found to significantly contribute to causing disease in an animal model.

<span class="mw-page-title-main">Streptococcal pyrogenic exotoxin</span>

Streptococcal pyrogenic exotoxins also known as erythrogenic toxins, are exotoxins secreted by strains of the bacterial species Streptococcus pyogenes. SpeA and speC are superantigens, which induce inflammation by nonspecifically activating T cells and stimulating the production of inflammatory cytokines. SpeB, the most abundant streptococcal extracellular protein, is a cysteine protease. Pyrogenic exotoxins are implicated as the causative agent of scarlet fever and streptococcal toxic shock syndrome. There is no consensus on the exact number of pyrogenic exotoxins. Serotypes A-C are the most extensively studied and recognized by all sources, but others note up to thirteen distinct types, categorizing speF through speM as additional superantigens. Erythrogenic toxins are known to damage the plasma membranes of blood capillaries under the skin and produce a red skin rash. Past studies have shown that multiple variants of erythrogenic toxins may be produced, depending on the strain of S. pyogenes in question. Some strains may not produce a detectable toxin at all. Bacteriophage T12 infection of S. pyogenes enables the production of speA, and increases virulence.

<span class="mw-page-title-main">OmpT</span>

OmpT is an aspartyl protease found on the outer membrane of Escherichia coli. OmpT is a subtype of the family of omptin proteases, which are found on some gram-negative species of bacteria.

Staphopain is an enzyme. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Aureolysin</span>

Aureolysin is an extracellular metalloprotease expressed by Staphylococcus aureus. This protease is a major contributor to the bacterium's virulence, or ability to cause disease, by cleaving host factors of the innate immune system as well as regulating S. aureus secreted toxins and cell wall proteins. To catalyze its enzymatic activities, aureolysin requires zinc and calcium which it obtains from the extracellular environment within the host.

Staphylococcus pseudintermedius is a gram positive coccus bacteria of the genus Staphylococcus found worldwide. It is primarily a pathogen for domestic animals, but has been known to affect humans as well. S. pseudintermedius is an opportunistic pathogen that secretes immune modulating virulence factors, has many adhesion factors, and the potential to create biofilms, all of which help to determine the pathogenicity of the bacterium. Diagnoses of Staphylococcus pseudintermedius have traditionally been made using cytology, plating, and biochemical tests. More recently, molecular technologies like MALDI-TOF, DNA hybridization and PCR have become preferred over biochemical tests for their more rapid and accurate identifications. This includes the identification and diagnosis of antibiotic resistant strains.

<span class="mw-page-title-main">PA clan of proteases</span>

The PA clan is the largest group of proteases with common ancestry as identified by structural homology. Members have a chymotrypsin-like fold and similar proteolysis mechanisms but can have identity of <10%. The clan contains both cysteine and serine proteases. PA clan proteases can be found in plants, animals, fungi, eubacteria, archaea and viruses.

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 closely related, while the Streptomyces-type is treated as a separate family, glutamyl endopeptidase II.

Staphopain A (<i>Staphylococcus aureus</i>)

Staphopain A is a secreted cysteine protease produced by Staphylococcus aureus. It was first identified in the S. aureus V8 strain as a papain-like cysteine protease. The protease distinguishes itself from the other major proteases of S. aureus in its very broad specificity and its ability to degrade elastin.

<span class="mw-page-title-main">Contact activation system</span>

In the contact activation system or CAS, three proteins in the blood, factor XII (FXII), prekallikrein (PK) and high molecular weight kininogen (HK), bind to a surface and cause blood coagulation and inflammation. FXII and PK are proteases and HK is a non-enzymatic co-factor. The CAS can activate the kinin–kallikrein system and blood coagulation through its ability to activate multiple downstream proteins. The CAS is initiated when FXII binds to a surface and reciprocal activation of FXII and PK occurs, forming FXIIa and PKa. FXIIa can initiate the coagulation cascade by cleaving and activating factor XI (FXI), which leads to formation of a blood clot. Additionally, the CAS can activate the kinin–kallikrein system when PKa cleaves HK to form cHK, releasing a peptide known as bradykinin (BK). BK and its derivatives bind to bradykinin receptors B1 and B2 to mediate inflammation.

<span class="mw-page-title-main">Asparagine endopeptidase</span> Class of enzymes

Asparagine endopeptidase is a proteolytic enzyme from C13 peptidase family which hydrolyses a peptide bond using the thiol group of a cysteine residue as a nucleophile. It is also known as asparaginyl endopeptidase, citvac, proteinase B, hemoglobinase, PRSC1 gene product or LGMN, vicilin peptidohydrolase and bean endopeptidase. In humans it is encoded by the LGMN gene.

Accessory gene regulator (agr) is a complex 5 gene locus that is a global regulator of virulence in Staphylococcus aureus. It encodes a two-component transcriptional quorum-sensing (QS) system activated by an autoinducing, thiolactone-containing cyclic peptide (AIP).

<span class="mw-page-title-main">Papain-like protease</span>

Papain-like proteases are a large protein family of cysteine protease enzymes that share structural and enzymatic properties with the group's namesake member, papain. They are found in all domains of life. In animals, the group is often known as cysteine cathepsins or, in older literature, lysosomal peptidases. In the MEROPS protease enzyme classification system, papain-like proteases form Clan CA. Papain-like proteases share a common catalytic dyad active site featuring a cysteine amino acid residue that acts as a nucleophile.

References

  1. 1 2 3 4 5 6 Dubin G (2002-07-01). "Extracellular proteases of Staphylococcus spp". Biological Chemistry. 383 (7–8): 1075–1086. doi:10.1515/BC.2002.116. PMID   12437090. S2CID   23295763.
  2. 1 2 Stennicke HR, Breddam K (2013-01-01). Rawlings ND, Salvesen G (eds.). Handbook of Proteolytic Enzymes. Academic Press. pp. 2534–2538. doi:10.1016/b978-0-12-382219-2.00561-5. ISBN   9780123822192.
  3. ↑ Birktoft JJ, Breddam K (1994). "Chapter 8: Glutamyl endopeptidases". Methods in Enzymology. Vol. 244. pp. 114–126. doi:10.1016/0076-6879(94)44010-7. ISBN   9780121821456. PMID   7845201.
  4. 1 2 3 Shaw L, Golonka E, Potempa J, Foster SJ (January 2004). "The role and regulation of the extracellular proteases of Staphylococcus aureus". Microbiology. 150 (Pt 1): 217–228. doi: 10.1099/mic.0.26634-0 . PMID   14702415.
  5. ↑ Filipek R, Rzychon M, Oleksy A, Gruca M, Dubin A, Potempa J, Bochtler M (October 2003). "The Staphostatin-staphopain complex: a forward binding inhibitor in complex with its target cysteine protease". The Journal of Biological Chemistry. 278 (42): 40959–40966. doi: 10.1074/jbc.M302926200 . PMID   12874290.
  6. ↑ Oscarsson J, Tegmark-Wisell K, Arvidson S (October 2006). "Coordinated and differential control of aureolysin (aur) and serine protease (sspA) transcription in Staphylococcus aureus by sarA, rot and agr (RNAIII)". International Journal of Medical Microbiology. 296 (6): 365–380. doi:10.1016/j.ijmm.2006.02.019. PMID   16782403.
  7. ↑ Lindsay JA, Foster SJ (September 1999). "Interactive regulatory pathways control virulence determinant production and stability in response to environmental conditions in Staphylococcus aureus". Molecular & General Genetics. 262 (2): 323–331. doi:10.1007/s004380051090. PMID   10517329. S2CID   29491620.
  8. 1 2 Zdzalik M, Karim AY, Wolski K, Buda P, Wojcik K, Brueggemann S, et al. (November 2012). "Prevalence of genes encoding extracellular proteases in Staphylococcus aureus - important targets triggering immune response in vivo". FEMS Immunology and Medical Microbiology. 66 (2): 220–229. doi: 10.1111/j.1574-695X.2012.01005.x . PMID   22762789.
  9. ↑ Nickerson NN, Prasad L, Jacob L, Delbaere LT, McGavin MJ (November 2007). "Activation of the SspA serine protease zymogen of Staphylococcus aureus proceeds through unique variations of a trypsinogen-like mechanism and is dependent on both autocatalytic and metalloprotease-specific processing". The Journal of Biological Chemistry. 282 (47): 34129–34138. doi: 10.1074/jbc.M705672200 . PMID   17878159.
  10. ↑ Nickerson N, Ip J, Passos DT, McGavin MJ (January 2010). "Comparison of Staphopain A (ScpA) and B (SspB) precursor activation mechanisms reveals unique secretion kinetics of proSspB (Staphopain B), and a different interaction with its cognate Staphostatin, SspC". Molecular Microbiology. 75 (1): 161–177. doi: 10.1111/j.1365-2958.2009.06974.x . PMID   19943908.
  11. ↑ Rice K, Peralta R, Bast D, de Azavedo J, McGavin MJ (January 2001). "Description of staphylococcus serine protease (ssp) operon in Staphylococcus aureus and nonpolar inactivation of sspA-encoded serine protease". Infection and Immunity. 69 (1): 159–169. doi:10.1128/IAI.69.1.159-169.2001. PMC   97868 . PMID   11119502.
  12. ↑ Massimi I, Park E, Rice K, Muller-Esterl W, Sauder D, McGavin MJ (November 2002). "Identification of a novel maturation mechanism and restricted substrate specificity for the SspB cysteine protease of Staphylococcus aureus". The Journal of Biological Chemistry. 277 (44): 41770–41777. doi: 10.1074/jbc.M207162200 . PMID   12207024.
  13. 1 2 Houmard J, Drapeau GR (December 1972). "Staphylococcal protease: a proteolytic enzyme specific for glutamoyl bonds". Proceedings of the National Academy of Sciences of the United States of America. 69 (12): 3506–3509. Bibcode:1972PNAS...69.3506H. doi: 10.1073/pnas.69.12.3506 . PMC   389807 . PMID   4509307.
  14. 1 2 Jusko M, Potempa J, Kantyka T, Bielecka E, Miller HK, Kalinska M, et al. (2014-01-01). "Staphylococcal proteases aid in evasion of the human complement system". Journal of Innate Immunity. 6 (1): 31–46. doi:10.1159/000351458. PMC   3972074 . PMID   23838186.
  15. ↑ Karlsson A, Saravia-Otten P, Tegmark K, Morfeldt E, Arvidson S (August 2001). "Decreased amounts of cell wall-associated protein A and fibronectin-binding proteins in Staphylococcus aureus sarA mutants due to up-regulation of extracellular proteases". Infection and Immunity. 69 (8): 4742–4748. doi:10.1128/IAI.69.8.4742-4748.2001. PMC   98560 . PMID   11447146.
  16. ↑ McGavin MJ, Zahradka C, Rice K, Scott JE (July 1997). "Modification of the Staphylococcus aureus fibronectin binding phenotype by V8 protease". Infection and Immunity. 65 (7): 2621–2628. doi:10.1128/iai.65.7.2621-2628.1997. PMC   175371 . PMID   9199429.
  17. ↑ Kolar SL, Ibarra JA, Rivera FE, Mootz JM, Davenport JE, Stevens SM, et al. (February 2013). "Extracellular proteases are key mediators of Staphylococcus aureus virulence via the global modulation of virulence-determinant stability". MicrobiologyOpen. 2 (1): 18–34. doi:10.1002/mbo3.55. PMC   3584211 . PMID   23233325.
  18. ↑ Potempa J, Pike RN (2009-01-01). "Corruption of innate immunity by bacterial proteases". Journal of Innate Immunity. 1 (2): 70–87. doi:10.1159/000181144. PMC   2743019 . PMID   19756242.
  19. ↑ Koziel J, Potempa J (February 2013). "Protease-armed bacteria in the skin". Cell and Tissue Research. 351 (2): 325–337. doi:10.1007/s00441-012-1355-2. PMC   3560952 . PMID   22358849.
  20. ↑ Chen C, Krishnan V, Macon K, Manne K, Narayana SV, Schneewind O (October 2013). "Secreted proteases control autolysin-mediated biofilm growth of Staphylococcus aureus". The Journal of Biological Chemistry. 288 (41): 29440–29452. doi: 10.1074/jbc.M113.502039 . PMC   3795244 . PMID   23970550.
  21. ↑ Potempa J, Watorek W, Travis J (October 1986). "The inactivation of human plasma alpha 1-proteinase inhibitor by proteinases from Staphylococcus aureus". The Journal of Biological Chemistry. 261 (30): 14330–14334. doi: 10.1016/S0021-9258(18)67022-X . PMID   3533918.
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