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Cysteine protease

February 16, 2024

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.[1]

Cysteine peptidase, CA clan
Crystal structure of the cysteine peptidase papain in complex with its covalent inhibitor E-64. Rendered from PDB: 1PE6​
Identifiers
SymbolPeptidase_C1
PfamPF00112
Pfam clanCL0125
InterProIPR000668
SMARTSM00645
PROSITEPDOC00126
MEROPSC1
SCOP21aec / SCOPe / SUPFAM
OPM superfamily355
OPM protein1m6d
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Discovered by Gopal Chunder Roy in 1873, the first cysteine protease to be isolated and characterized was papain, obtained from Carica papaya.[1] Cysteine proteases are commonly encountered in fruits including the papaya, pineapple, fig and kiwifruit. The proportion of protease tends to be higher when the fruit is unripe. In fact, the latex of dozens of different plant families are known to contain cysteine proteases.[2] Cysteine proteases are used as an ingredient in meat tenderizers.

Classification edit

The MEROPS protease classification system counts 14 superfamilies plus several currently unassigned families (as of 2013) each containing many families. Each superfamily uses the catalytic triad or dyad in a different protein fold and so represent convergent evolution of the catalytic mechanism.

For superfamilies, P indicates a superfamily containing a mixture of nucleophile class families, and C indicates purely cysteine proteases. superfamily. Within each superfamily, families are designated by their catalytic nucleophile (C denoting cysteine proteases).

Families of cysteine proteases
Superfamily Families Examples
CA C1, C2, C6, C10, C12, C16, C19, C28, C31, C32, C33, C39, C47, C51, C54, C58, C64,

C65, C66, C67, C70, C71, C76, C78, C83, C85, C86, C87, C93, C96, C98, C101

Papain (Carica papaya),[3] bromelain (Ananas comosus), cathepsin K (liverwort)[4] and calpain (Homo sapiens)[5]
CD C11, C13, C14, C25, C50, C80, C84 Caspase-1 (Rattus norvegicus) and separase (Saccharomyces cerevisiae)
CE C5, C48, C55, C57, C63, C79 Adenain (human adenovirus type 2)
CF C15 Pyroglutamyl-peptidase I (Bacillus amyloliquefaciens)
CL C60, C82 Sortase A (Staphylococcus aureus)
CM C18 Hepatitis C virus peptidase 2 (hepatitis C virus)
CN C9 Sindbis virus-type nsP2 peptidase (sindbis virus)
CO C40 Dipeptidyl-peptidase VI (Lysinibacillus sphaericus)
CP C97 DeSI-1 peptidase (Mus musculus)
PA C3, C4, C24, C30, C37, C62, C74, C99 TEV protease (tobacco etch virus)
PB C44, C45, C59, C69, C89, C95 Amidophosphoribosyltransferase precursor (Homo sapiens)
PC C26, C56 Gamma-glutamyl hydrolase (Rattus norvegicus)
PD C46 Hedgehog protein (Drosophila melanogaster)
PE P1 DmpA aminopeptidase (Brucella anthropi)
unassigned C7, C8, C21, C23, C27, C36, C42, C53, C75

Catalytic mechanism edit

 
Reaction mechanism of the cysteine protease mediated cleavage of a peptide bond.
See also: catalytic triad

The first step in the reaction mechanism by which cysteine proteases catalyze the hydrolysis of peptide bonds is deprotonation of a thiol in the enzyme's active site by an adjacent amino acid with a basic side chain, usually a histidine residue. The next step is nucleophilic attack by the deprotonated cysteine's anionic sulfur on the substrate carbonyl carbon. In this step, a fragment of the substrate is released with an amine terminus, the histidine residue in the protease is restored to its deprotonated form, and a thioester intermediate linking the new carboxy-terminus of the substrate to the cysteine thiol is formed. Therefore, they are also sometimes referred to as thiol proteases. The thioester bond is subsequently hydrolyzed to generate a carboxylic acid moiety on the remaining substrate fragment, while regenerating the free enzyme.[6]

Biological importance edit

Cysteine proteases play multifaceted roles, virtually in every aspect of physiology and development. In plants they are important in growth and development and in accumulation and mobilization of storage proteins such as in seeds. In addition, they are involved in signalling pathways and in the response to biotic and abiotic stresses.[7] In humans and other animals, they are responsible for senescence and apoptosis (programmed cell death), MHC class II immune responses, prohormone processing, and extracellular matrix remodeling important to bone development. The ability of macrophages and other cells to mobilize elastolytic cysteine proteases to their surfaces under specialized conditions may also lead to accelerated collagen and elastin degradation at sites of inflammation in diseases such as atherosclerosis and emphysema.[8] Several viruses (such as polio and hepatitis C) express their entire genome as a single massive polyprotein and use a protease to cleave it into functional units (for example, tobacco etch virus protease).

Regulation edit

The activity of cysteine proteases is regulated by a few general mechanisms, which includes the production of zymogens, selective expression, pH modification, cellular compartmentalization, and regulation of their enzymatic activity by endogenous inhibitors, which seemingly is the most efficient mechanism associated with the regulation of the activity of cysteine proteases.[6]

Proteases are usually synthesized as large precursor proteins called zymogens, such as the serine protease precursors trypsinogen and chymotrypsinogen, and the aspartic protease precursor pepsinogen. The protease is activated by removal of an inhibitory segment or protein. Activation occurs once the protease is delivered to a specific intracellular compartment (for example the lysosome) or extracellular environment (for example the stomach). This system prevents the cell that produces the protease from being damaged by it.

Protease inhibitors are usually proteins with domains that enter or block a protease active site to prevent substrate access. In competitive inhibition, the inhibitor binds to the active site, thus preventing enzyme-substrate interaction. In non-competitive inhibition, the inhibitor binds to an allosteric site, which alters the active site and makes it inaccessible to the substrate.

Examples of protease inhibitors include:

Uses edit

See also: Papain § Uses, Bromelain § Uses, Ficain, and Chymopapain § Medical applications

Potential pharmaceuticals edit

Currently there is no widespread use of cysteine proteases as approved and effective anthelmintics but research into the subject is a promising field of study. Plant cysteine proteases isolated from these plants have been found to have high proteolytic activities that are known to digest nematode cuticles, with very low toxicity.[9] Successful results have been reported against nematodes such as Heligmosomoides bakeri, Trichinella spiralis, Nippostrongylus brasiliensis, Trichuris muris, and Ancylostoma ceylanicum; the tapeworm Rodentolepis microstoma, and the porcine acanthocephalan parasite Macracanthorhynchus hirundinaceus.[10] A useful property of cysteine proteases is the resistance to acid digestion, allowing possible oral administration. They provide an alternative mechanism of action to current anthelmintics and the development of resistance is thought to be unlikely because it would require a complete change of structure of the helminth cuticle.

In several traditional medicines, the fruits or latex of the papaya, pineapple and fig are widely used for treatment of intestinal worm infections both in humans and livestock.

Other edit

Cysteine proteases are used as feed additives for livestock to improve the digestibility of proteins and amino acids.[11]

See also edit

References edit

  1. ^ a b Rawat, Aadish; Roy, Mrinalini; Jyoti, Anupam; Kaushik, Sanket; Verma, Kuldeep; Srivastava, Vijay Kumar (August 2021). "Cysteine proteases: Battling pathogenic parasitic protozoans with omnipresent enzymes". Microbiological Research. 249: 126784. doi:10.1016/j.micres.2021.126784. ISSN 1618-0623. PMID 33989978. S2CID 234597200.
  2. ^ Domsalla A, Melzig MF (June 2008). "Occurrence and properties of proteases in plant latices". Planta Medica. 74 (7): 699–711. doi:10.1055/s-2008-1074530. PMID 18496785.
  3. ^ Mitchel RE, Chaiken IM, Smith EL (July 1970). "The complete amino acid sequence of papain. Additions and corrections". The Journal of Biological Chemistry. 245 (14): 3485–92. doi:10.1016/S0021-9258(18)62954-0. PMID 5470818.
  4. ^ Sierocka I, Kozlowski LP, Bujnicki JM, Jarmolowski A, Szweykowska-Kulinska Z (June 2014). "Female-specific gene expression in dioecious liverwort Pellia endiviifolia is developmentally regulated and connected to archegonia production". BMC Plant Biology. 14: 168. doi:10.1186/1471-2229-14-168. PMC 4074843. PMID 24939387.
  5. ^ Sorimachi H, Ohmi S, Emori Y, Kawasaki H, Saido TC, Ohno S, et al. (May 1990). "A novel member of the calcium-dependent cysteine protease family". Biological Chemistry Hoppe-Seyler. 371 Suppl: 171–6. PMID 2400579.
  6. ^ a b Roy, Mrinalini; Rawat, Aadish; Kaushik, Sanket; Jyoti, Anupam; Srivastava, Vijay Kumar (May 2022). "Endogenous cysteine protease inhibitors in upmost pathogenic parasitic protozoa". Microbiological Research. 261: 127061. doi:10.1016/j.micres.2022.127061. PMID 35605309. S2CID 248741177.
  7. ^ Grudkowska M, Zagdańska B (2004). "Multifunctional role of plant cysteine proteinases". Acta Biochimica Polonica. 51 (3): 609–24. doi:10.18388/abp.2004_3547. PMID 15448724.
  8. ^ Chapman HA, Riese RJ, Shi GP (1997). "Emerging roles for cysteine proteases in human biology". Annual Review of Physiology. 59: 63–88. doi:10.1146/annurev.physiol.59.1.63. PMID 9074757.
  9. ^ Stepek G, Behnke JM, Buttle DJ, Duce IR (July 2004). "Natural plant cysteine proteinases as anthelmintics?". Trends in Parasitology. 20 (7): 322–7. doi:10.1016/j.pt.2004.05.003. PMID 15193563.
  10. ^ Behnke JM, Buttle DJ, Stepek G, Lowe A, Duce IR (September 2008). "Developing novel anthelmintics from plant cysteine proteinases". Parasites & Vectors. 1 (1): 29. doi:10.1186/1756-3305-1-29. PMC 2559997. PMID 18761736.
  11. ^ O'Keefe, Terrence (6 April 2012). "Protease enzymes improve amino acid digestibility". Wattagnet. Retrieved 6 January 2018.

External links edit

  • The MEROPS online database for peptidases and their inhibitors: Cysteine Peptidases
  • Cysteine+endopeptidases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

February 16, 2024
cysteine, protease, also, known, thiol, proteases, hydrolase, enzymes, that, degrade, proteins, these, proteases, share, common, catalytic, mechanism, that, involves, nucleophilic, cysteine, thiol, catalytic, triad, dyad, cysteine, peptidase, clancrystal, stru. 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 1 Cysteine peptidase CA clanCrystal structure of the cysteine peptidase papain in complex with its covalent inhibitor E 64 Rendered from PDB 1PE6 IdentifiersSymbolPeptidase C1PfamPF00112Pfam clanCL0125InterProIPR000668SMARTSM00645PROSITEPDOC00126MEROPSC1SCOP21aec SCOPe SUPFAMOPM superfamily355OPM protein1m6dAvailable protein structures Pfam structures ECOD PDBRCSB PDB PDBe PDBjPDBsumstructure summaryDiscovered by Gopal Chunder Roy in 1873 the first cysteine protease to be isolated and characterized was papain obtained from Carica papaya 1 Cysteine proteases are commonly encountered in fruits including the papaya pineapple fig and kiwifruit The proportion of protease tends to be higher when the fruit is unripe In fact the latex of dozens of different plant families are known to contain cysteine proteases 2 Cysteine proteases are used as an ingredient in meat tenderizers Contents 1 Classification 2 Catalytic mechanism 3 Biological importance 4 Regulation 5 Uses 5 1 Potential pharmaceuticals 5 2 Other 6 See also 7 References 8 External linksClassification editThe MEROPS protease classification system counts 14 superfamilies plus several currently unassigned families as of 2013 each containing many families Each superfamily uses the catalytic triad or dyad in a different protein fold and so represent convergent evolution of the catalytic mechanism For superfamilies P indicates a superfamily containing a mixture of nucleophile class families and C indicates purely cysteine proteases superfamily Within each superfamily families are designated by their catalytic nucleophile C denoting cysteine proteases Families of cysteine proteases Superfamily Families ExamplesCA C1 C2 C6 C10 C12 C16 C19 C28 C31 C32 C33 C39 C47 C51 C54 C58 C64 C65 C66 C67 C70 C71 C76 C78 C83 C85 C86 C87 C93 C96 C98 C101 Papain Carica papaya 3 bromelain Ananas comosus cathepsin K liverwort 4 and calpain Homo sapiens 5 CD C11 C13 C14 C25 C50 C80 C84 Caspase 1 Rattus norvegicus and separase Saccharomyces cerevisiae CE C5 C48 C55 C57 C63 C79 Adenain human adenovirus type 2 CF C15 Pyroglutamyl peptidase I Bacillus amyloliquefaciens CL C60 C82 Sortase A Staphylococcus aureus CM C18 Hepatitis C virus peptidase 2 hepatitis C virus CN C9 Sindbis virus type nsP2 peptidase sindbis virus CO C40 Dipeptidyl peptidase VI Lysinibacillus sphaericus CP C97 DeSI 1 peptidase Mus musculus PA C3 C4 C24 C30 C37 C62 C74 C99 TEV protease tobacco etch virus PB C44 C45 C59 C69 C89 C95 Amidophosphoribosyltransferase precursor Homo sapiens PC C26 C56 Gamma glutamyl hydrolase Rattus norvegicus PD C46 Hedgehog protein Drosophila melanogaster PE P1 DmpA aminopeptidase Brucella anthropi unassigned C7 C8 C21 C23 C27 C36 C42 C53 C75Catalytic mechanism edit nbsp Reaction mechanism of the cysteine protease mediated cleavage of a peptide bond See also catalytic triad The first step in the reaction mechanism by which cysteine proteases catalyze the hydrolysis of peptide bonds is deprotonation of a thiol in the enzyme s active site by an adjacent amino acid with a basic side chain usually a histidine residue The next step is nucleophilic attack by the deprotonated cysteine s anionic sulfur on the substrate carbonyl carbon In this step a fragment of the substrate is released with an amine terminus the histidine residue in the protease is restored to its deprotonated form and a thioester intermediate linking the new carboxy terminus of the substrate to the cysteine thiol is formed Therefore they are also sometimes referred to as thiol proteases The thioester bond is subsequently hydrolyzed to generate a carboxylic acid moiety on the remaining substrate fragment while regenerating the free enzyme 6 Biological importance editCysteine proteases play multifaceted roles virtually in every aspect of physiology and development In plants they are important in growth and development and in accumulation and mobilization of storage proteins such as in seeds In addition they are involved in signalling pathways and in the response to biotic and abiotic stresses 7 In humans and other animals they are responsible for senescence and apoptosis programmed cell death MHC class II immune responses prohormone processing and extracellular matrix remodeling important to bone development The ability of macrophages and other cells to mobilize elastolytic cysteine proteases to their surfaces under specialized conditions may also lead to accelerated collagen and elastin degradation at sites of inflammation in diseases such as atherosclerosis and emphysema 8 Several viruses such as polio and hepatitis C express their entire genome as a single massive polyprotein and use a protease to cleave it into functional units for example tobacco etch virus protease Regulation editThe activity of cysteine proteases is regulated by a few general mechanisms which includes the production of zymogens selective expression pH modification cellular compartmentalization and regulation of their enzymatic activity by endogenous inhibitors which seemingly is the most efficient mechanism associated with the regulation of the activity of cysteine proteases 6 Proteases are usually synthesized as large precursor proteins called zymogens such as the serine protease precursors trypsinogen and chymotrypsinogen and the aspartic protease precursor pepsinogen The protease is activated by removal of an inhibitory segment or protein Activation occurs once the protease is delivered to a specific intracellular compartment for example the lysosome or extracellular environment for example the stomach This system prevents the cell that produces the protease from being damaged by it Protease inhibitors are usually proteins with domains that enter or block a protease active site to prevent substrate access In competitive inhibition the inhibitor binds to the active site thus preventing enzyme substrate interaction In non competitive inhibition the inhibitor binds to an allosteric site which alters the active site and makes it inaccessible to the substrate Examples of protease inhibitors include Serpins Stefins IAPsUses editSee also Papain Uses Bromelain Uses Ficain and Chymopapain Medical applications Potential pharmaceuticals edit Currently there is no widespread use of cysteine proteases as approved and effective anthelmintics but research into the subject is a promising field of study Plant cysteine proteases isolated from these plants have been found to have high proteolytic activities that are known to digest nematode cuticles with very low toxicity 9 Successful results have been reported against nematodes such as Heligmosomoides bakeri Trichinella spiralis Nippostrongylus brasiliensis Trichuris muris and Ancylostoma ceylanicum the tapeworm Rodentolepis microstoma and the porcine acanthocephalan parasite Macracanthorhynchus hirundinaceus 10 A useful property of cysteine proteases is the resistance to acid digestion allowing possible oral administration They provide an alternative mechanism of action to current anthelmintics and the development of resistance is thought to be unlikely because it would require a complete change of structure of the helminth cuticle In several traditional medicines the fruits or latex of the papaya pineapple and fig are widely used for treatment of intestinal worm infections both in humans and livestock Other edit Cysteine proteases are used as feed additives for livestock to improve the digestibility of proteins and amino acids 11 See also editProtease Serine protease Threonine protease Aspartic protease Metalloprotease Enzyme Proteolysis Catalytic triad Convergent evolution PA clan The Proteolysis Map Protease inhibitor pharmacology Protease inhibitor biology TopFIND database of protease specificity substrates products and inhibitors MEROPS database of protease evolutionary groupsReferences edit a b Rawat Aadish Roy Mrinalini Jyoti Anupam Kaushik Sanket Verma Kuldeep Srivastava Vijay Kumar August 2021 Cysteine proteases Battling pathogenic parasitic protozoans with omnipresent enzymes Microbiological Research 249 126784 doi 10 1016 j micres 2021 126784 ISSN 1618 0623 PMID 33989978 S2CID 234597200 Domsalla A Melzig MF June 2008 Occurrence and properties of proteases in plant latices Planta Medica 74 7 699 711 doi 10 1055 s 2008 1074530 PMID 18496785 Mitchel RE Chaiken IM Smith EL July 1970 The complete amino acid sequence of papain Additions and corrections The Journal of Biological Chemistry 245 14 3485 92 doi 10 1016 S0021 9258 18 62954 0 PMID 5470818 Sierocka I Kozlowski LP Bujnicki JM Jarmolowski A Szweykowska Kulinska Z June 2014 Female specific gene expression in dioecious liverwort Pellia endiviifolia is developmentally regulated and connected to archegonia production BMC Plant Biology 14 168 doi 10 1186 1471 2229 14 168 PMC 4074843 PMID 24939387 Sorimachi H Ohmi S Emori Y Kawasaki H Saido TC Ohno S et al May 1990 A novel member of the calcium dependent cysteine protease family Biological Chemistry Hoppe Seyler 371 Suppl 171 6 PMID 2400579 a b Roy Mrinalini Rawat Aadish Kaushik Sanket Jyoti Anupam Srivastava Vijay Kumar May 2022 Endogenous cysteine protease inhibitors in upmost pathogenic parasitic protozoa Microbiological Research 261 127061 doi 10 1016 j micres 2022 127061 PMID 35605309 S2CID 248741177 Grudkowska M Zagdanska B 2004 Multifunctional role of plant cysteine proteinases Acta Biochimica Polonica 51 3 609 24 doi 10 18388 abp 2004 3547 PMID 15448724 Chapman HA Riese RJ Shi GP 1997 Emerging roles for cysteine proteases in human biology Annual Review of Physiology 59 63 88 doi 10 1146 annurev physiol 59 1 63 PMID 9074757 Stepek G Behnke JM Buttle DJ Duce IR July 2004 Natural plant cysteine proteinases as anthelmintics Trends in Parasitology 20 7 322 7 doi 10 1016 j pt 2004 05 003 PMID 15193563 Behnke JM Buttle DJ Stepek G Lowe A Duce IR September 2008 Developing novel anthelmintics from plant cysteine proteinases Parasites amp Vectors 1 1 29 doi 10 1186 1756 3305 1 29 PMC 2559997 PMID 18761736 O Keefe Terrence 6 April 2012 Protease enzymes improve amino acid digestibility Wattagnet Retrieved 6 January 2018 External links editThe MEROPS online database for peptidases and their inhibitors Cysteine Peptidases Cysteine endopeptidases at the U S National Library of Medicine Medical Subject Headings MeSH Portal nbsp Biology Retrieved from https en wikipedia org w index php title Cysteine protease amp oldid 1188163155, wikipedia, wiki, book, books, library,

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