Cathepsin

Last updated
Cathepsin
Cathepsin K 1TU6.png
Structure of Cathepsin K
Identifiers
SymbolCTP
Pfam PF00112
Pfam clan CL0125
InterPro IPR000668
SMART Pept_C1
PROSITE PDOC00126
MEROPS C1
SCOP2 1aec / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Cathepsins (Ancient Greek kata- "down" and hepsein "boil"; abbreviated CTS) are proteases (enzymes that degrade proteins) found in all animals as well as other organisms. There are approximately a dozen members of this family, which are distinguished by their structure, catalytic mechanism, and which proteins they cleave[ citation needed ]. Most of the members become activated at the low pH found in lysosomes. Thus, the activity of this family lies almost entirely within those organelles. There are, however, exceptions such as cathepsin K, which works extracellularly after secretion by osteoclasts in bone resorption. Cathepsins have a vital role in mammalian cellular turnover.

Contents

Classification

Clinical significance

Cathepsins are involved in many physiological processes have been implicated in a number of human diseases. The cysteine cathepsins have attracted significant research effort as drug targets. [1] [2]

Cathepsin A

Deficiencies in this protein are linked to multiple forms of galactosialidosis. The cathepsin A activity in lysates of metastatic lesions of malignant melanoma is significantly higher than in primary focus lysates. Cathepsin A increased in muscles moderately affected by muscular dystrophy and denervating diseases.

Cathepsin B

Cathepsin B may function as a beta-secretase 1, cleaving amyloid precursor protein to produce amyloid beta. [10] Overexpression of the encoded protein, which is a member of the peptidase C1 family, has been associated with esophageal adenocarcinoma and other tumors. [11] Cathepsin B has also been implicated in the progression of various human tumors [3] including ovarian cancer.

Cathepsin D

Cathepsin D (an aspartyl protease) appears to cleave a variety of substrates such as fibronectin and laminin. Unlike some of the other cathepsins, cathepsin D has some protease activity at neutral pH. [12] High levels of this enzyme in tumor cells seems to be associated with greater invasiveness.

Cathepsin K

Cathepsin K is the most potent mammalian collagenase. Cathepsin K is involved in osteoporosis, a disease in which a decrease in bone density causes an increased risk for fracture. Osteoclasts are the bone resorbing cells of the body, and they secrete cathepsin K in order to break down collagen, the major component of the non-mineral protein matrix of the bone. [13] Cathepsin K, among other cathepsins, plays a role in cancer metastasis through the degradation of the extracellular matrix. [14] The genetic knockout for cathepsin S and K in mice with atherosclerosis was shown to reduce the size of atherosclerotic lesions. [15] The expression of cathepsin K in cultured endothelial cells is regulated by shear stress. [16] Cathepsin K has also been shown to play a role in arthritis. [17]

Cathepsin V

Mouse cathepsin L is homologous to human cathepsin V. [18] Mouse cathepsin L has been shown to play a role in adipogenesis and glucose intolerance in mice. Cathepsin L degrades fibronectin, insulin receptor (IR), and insulin-like growth factor 1 receptor (IGF-1R). Cathepsin L-deficient mice were shown to have less adipose tissue, lower serum glucose and insulin levels, more insulin receptor subunits, more glucose transporter (GLUT4) and more fibronectin than wild type controls. [19]

Inhibitors

Five cyclic peptides show inhibitory activity towards human cathepsins L, B, H, and K. [20] Several inhibitors have reached clinical trials, targeting cathepsins K and S as promising therapeutics for osteoporosis, osteoarthritis, and chronic pain. Cathepsin K inhibitors, Relacatib, Balicatib, and Odanacatib, were terminated during clinical trials at phases I, II, and III, respectively, owing to adverse side effects. [21] SAR114137, a Cathepsin S inhibitor, did not progress past phase I for chronic pain. In 2022, STI-1558, a Cathepsin L inhibitor, received FDA clearance to begin phase I studies to treat COVID-19. [22]

Cathepsin zymography

Zymography is a type of gel electrophoresis that uses a polyacrylamide gel co-polymerized with a substrate in order to detect enzyme activity. Cathepsin zymography separates different cathepsins based on their migration through a polyacrylamide gel co-polymerized with a gelatin substrate. The electrophoresis takes place in non-reducing conditions, and the enzymes are protected from denaturation using leupeptin. [23] After protein concentration is determined, equal amounts of tissue protein are loaded into a gel. The protein is then allowed to migrate through the gel. After electrophoresis, the gel is put into a renaturing buffer in order to return the cathepsins to their native conformation. The gel is then put into an activation buffer of a specific pH and left to incubate overnight at 37 °C. This activation step allows the cathepsins to degrade the gelatin substrate. When the gel is stained using a Coomassie blue stain, areas of the gel still containing gelatin appear blue. The areas of the gel where cathepsins were active appear as white bands. This cathepsin zymography protocol has been used to detect femtomole quantities of mature cathepsin K. [23] The different cathepsins can be identified based on their migration distance due to their molecular weights: cathepsin K (~37 kDa), V (~35 kDa), S (~25kDa), and L (~20 kDa). Cathepsins have specific pH levels at which they have optimum proteolytic activity. Cathepsin K is able to degrade gelatin at pH 7 and 8, but these pH levels do not allow for cathepsins L and V activity. At a pH 4 cathepsin V is active, but cathepsin K is not. Adjusting the pH of the activation buffer can allow for further identification of cathepsin types. [24]

History

The term cathepsin was coined in 1929 by Richard Willstätter and Eugen Bamann to describe a proteolytic activity of leukocytes and tissues at slightly acidic pH (Willstätter & Bamann (1929) Hoppe-Seylers Z. Physiol. Chemie 180, 127-143). The earliest record of "cathepsin" found in the MEDLINE database (e.g., via PubMed) is from the Journal of Biological Chemistry in 1949. [25] However, references within this article indicate that cathepsins were first identified and named around the turn of the 20th century. Much of this earlier work was done in the laboratory of Max Bergmann, who spent the first several decades of the century defining these proteases. [26]

It is notable that research published in the 1930s (primarily by Bergmann) used the term "catheptic enzymes" to refer to a broad family of proteases that included papain, bromelin, and cathepsin itself. [27] Initial efforts to purify and characterize proteases using hemoglobin transpired at a time when the word "cathepsin" indicated a single enzyme; [28] the existence of multiple, distinct cathepsin family members (e.g. B, H, L) did not appear to be understood at the time. However, by 1937 Bergmann and colleagues began to differentiate cathepsins on the basis of their source in the human body (e.g. liver cathepsin, spleen cathepsin). [26]

Related Research Articles

<span class="mw-page-title-main">Proteolysis</span> Breakdown of proteins into smaller polypeptides or amino acids

Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, but may also occur by intra-molecular digestion.

<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 numerous biological pathways, including digestion of ingested proteins, protein catabolism, and cell signaling.

In biology and biochemistry, protease inhibitors, or antiproteases, are molecules that inhibit the function of proteases. Many naturally occurring protease inhibitors are proteins.

<span class="mw-page-title-main">Calpain</span> Protease enzyme present in mammals and other organisms

A calpain is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan CA in the MEROPS database. The calpain proteolytic system includes the calpain proteases, the small regulatory subunit CAPNS1, also known as CAPN4, and the endogenous calpain-specific inhibitor, calpastatin.

<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.

<span class="mw-page-title-main">Cathepsin S</span> Protein-coding gene in the species Homo sapiens

Cathepsin S is a protein that in humans is encoded by the CTSS gene. Transcript variants utilizing alternative polyadenylation signals exist for this gene.

<span class="mw-page-title-main">Cathepsin O</span> Protein-coding gene in the species Homo sapiens

Cathepsin O is an enzyme that in humans is encoded by the CTSO gene.

<span class="mw-page-title-main">Cathepsin K</span> Protein-coding gene in the species Homo sapiens

Cathepsin K, abbreviated CTSK, is an enzyme that in humans is encoded by the CTSK gene.

<span class="mw-page-title-main">Cathepsin C</span> Human protease (enzyme)

Cathepsin C (CTSC) also known as dipeptidyl peptidase I (DPP-I) is a lysosomal exo-cysteine protease belonging to the peptidase C1 protein family, a subgroup of the cysteine cathepsins. In humans, it is encoded by the CTSC gene.

<span class="mw-page-title-main">Cathepsin G</span> Protein-coding gene in the species Homo sapiens

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. Cathepsin G plays an important role in eliminating intracellular pathogens and breaking down tissues at inflammatory sites, as well as in anti-inflammatory response.

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

Aspartic proteases are a catalytic type of protease enzymes that use an activated water molecule bound to one or more aspartate residues for catalysis of their peptide substrates. In general, they have two highly conserved aspartates in the active site and are optimally active at acidic pH. Nearly all known aspartyl proteases are inhibited by pepstatin.

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

Ficain also known as ficin, debricin, or higueroxyl delabarre is a proteolytic enzyme extracted from the latex sap from the stems, leaves, and unripe fruit of the American wild fig tree Ficus insipida.

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

Actinidain is a type of cysteine protease enzyme found in fruits including kiwifruit, pineapple, mango, banana, figs, and papaya. This enzyme is part of the peptidase C1 family of papain-like proteases.

<span class="mw-page-title-main">Cathepsin L1</span> Protein-coding gene in the species Homo sapiens

Cathepsin L1 is a protein that in humans is encoded by the CTSL1 gene. The protein is a cysteine cathepsin, a lysosomal cysteine protease that plays a major role in intracellular protein catabolism.

<span class="mw-page-title-main">Cathepsin Z</span> Protein-coding gene in the species Homo sapiens

Cathepsin Z, also called cathepsin X or cathepsin P, is a protein that in humans is encoded by the CTSZ gene. It is a member of the cysteine cathepsin family of cysteine proteases, which has 11 members. As one of the 11 cathepsins, cathepsin Z contains distinctive features from others. Cathepsin Z has been reported involved in cancer malignancy and inflammation.

<span class="mw-page-title-main">Cathepsin F</span> Protein-coding gene in the species Homo sapiens (Humans)

Cathepsin F is a protein that in humans is encoded by the CTSF gene.

Angiogenesis is the process of forming new blood vessels from existing blood vessels, formed in vasculogenesis. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase domain (ADAM), a disintegrin and metalloproteinase domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.

Cathepsin zymography is a technique for quantifying enzymatic activity of the cathepsin family of cysteine proteases. It is based on SDS-PAGE whereby samples tested for cathepsin activity are loaded into a polyacrylamide gel and then separated by molecular weight. Gelatin is embedded in the gel itself, providing a substrate for the enzymes to hydrolyze.

<span class="mw-page-title-main">Zingibain</span> Cysteine protease enzyme

Zingibain, zingipain, or ginger protease is a cysteine protease enzyme found in ginger rhizomes. It catalyses the preferential cleavage of peptides with a proline residue at the P2 position. It has two distinct forms, ginger protease I (GP-I) and ginger protease II (GP-II).

<span class="mw-page-title-main">Papain-like protease</span> Protein family of cysteine protease enzymes

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. ↑ Novinec, Marko; Lenarčič, Brigita (1 June 2013). "Papain-like peptidases: structure, function, and evolution". BioMolecular Concepts. 4 (3): 287–308. doi: 10.1515/bmc-2012-0054 . PMID   25436581. S2CID   2112616.
  2. ↑ Turk, Vito; Stoka, Veronika; Vasiljeva, Olga; Renko, Miha; Sun, Tao; Turk, Boris; Turk, Dušan (January 2012). "Cysteine cathepsins: From structure, function and regulation to new frontiers". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1824 (1): 68–88. doi:10.1016/j.bbapap.2011.10.002. PMC   7105208 . PMID   22024571.
  3. 1 2 Nomura T, Katunuma N (February 2005). "Involvement of cathepsins in the invasion, metastasis and proliferation of cancer cells" (PDF). J. Med. Invest. 52 (1–2): 1–9. doi: 10.2152/jmi.52.1 . PMID   15751268.
  4. ↑ Lipton P (October 1999). "Ischemic cell death in brain neurons". Physiol. Rev. 79 (4): 1431–568. doi:10.1152/physrev.1999.79.4.1431. PMID   10508238.
  5. ↑ Xu J, Wang H, Ding K, Lu X, Li T, Wang J, Wang C, Wang J (Oct 24, 2013). "Inhibition of cathepsin S produces neuroprotective effects after traumatic brain injury in mice". Mediators of Inflammation. 2013 (2013): 187873. doi: 10.1155/2013/187873 . PMC   3824312 . PMID   24282339.
  6. ↑ Yamashima T (2013). "Reconsider Alzheimer's disease by the 'calpain-cathepsin hypothesis'--a perspective review". Progress in Neurology. 105: 1–23. doi:10.1016/j.pneurobio.2013.02.004. PMID   23499711. S2CID   39292302.
  7. ↑ Raptis SZ, Shapiro SD, Simmons PM, Cheng AM, Pham CT (June 2005). "Serine protease cathepsin G regulates adhesion-dependent neutrophil effector functions by modulating integrin clustering". Immunity. 22 (6): 679–91. doi: 10.1016/j.immuni.2005.03.015 . PMID   15963783.
  8. ↑ Chandran K (2005). "Endosomal Proteolysis of the Ebola Virus Glycoprotein Is Necessary for Infection". Science. 308 (5728): 1643–1645. Bibcode:2005Sci...308.1643C. doi:10.1126/science.1110656. PMC   4797943 . PMID   15831716.
  9. ↑ Im E, Kazlauskas A (March 2007). "The role of cathepsins in ocular physiology and pathology". Exp. Eye Res. 84 (3): 383–8. doi:10.1016/j.exer.2006.05.017. PMID   16893541.
  10. ↑ Hook, Gregory; Hook, Vivian; Kindy, Mark (2011-01-01). "The cysteine protease inhibitor, E64d, reduces brain amyloid-β and improves memory deficits in Alzheimer's disease animal models by inhibiting cathepsin B, but not BACE1, β-secretase activity". Journal of Alzheimer's Disease. 26 (2): 387–408. doi:10.3233/JAD-2011-110101. ISSN   1875-8908. PMC   4317342 . PMID   21613740.
  11. ↑ Habibollahi, Peiman; Figueiredo, Jose-Luiz; Heidari, Pedram; Dulak, Austin M; Imamura, Yu; Bass, Adam J.; Ogino, Shuji; Chan, Andrew T; Mahmood, Umar (2012). "Optical Imaging with a Cathepsin B Activated Probe for the Enhanced Detection of Esophageal Adenocarcinoma by Dual Channel Fluorescent Upper GI Endoscopy". Theranostics. 2 (2): 227–234. doi:10.7150/thno.4088. PMC   3296470 . PMID   22400064.
  12. ↑ Lkhider M, Castino R, Bouguyon E, Isidoro C, Ollivier-Bousquet M (2004). "Cathepsin D released by lactating rat mammary epithelial cells is involved in prolactin cleavage under physiological conditions". Journal of Cell Science . 117 (Pt 21): 5155–5164. doi: 10.1242/jcs.01396 . PMID   15456852.
  13. ↑ Shi GP, Chapman HA, Bhairi SM, DeLeeuw C, Reddy VY, Weiss SJ (January 1995). "Molecular cloning of human cathepsin O, a novel endoproteinase and homologue of rabbit OC2" (PDF). FEBS Lett. 357 (2): 129–34. doi: 10.1016/0014-5793(94)01349-6 . hdl:2027.42/116965. PMID   7805878. S2CID   28099876.
  14. ↑ Gocheva V, Joyce JA (January 2007). "Cysteine cathepsins and the cutting edge of cancer invasion". Cell Cycle. 6 (1): 60–4. doi: 10.4161/cc.6.1.3669 . PMID   17245112.
  15. ↑ Lutgens E, Lutgens SP, Faber BC, Heeneman S, Gijbels MM, de Winther MP, Frederik P, van der Made I, Daugherty A, Sijbers AM, Fisher A, Long CJ, Saftig P, Black D, Daemen MJ, Cleutjens KB (January 2006). "Disruption of the cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation". Circulation. 113 (1): 98–107. doi: 10.1161/CIRCULATIONAHA.105.561449 . PMID   16365196.
  16. ↑ Platt MO, Ankeny RF, Shi GP, Weiss D, Vega JD, Taylor WR, Jo H (March 2007). "Expression of cathepsin K is regulated by shear stress in cultured endothelial cells and is increased in endothelium in human atherosclerosis". Am. J. Physiol. Heart Circ. Physiol. 292 (3): H1479–86. doi:10.1152/ajpheart.00954.2006. PMID   17098827.
  17. ↑ Salminen-Mankonen HJ, Morko J, Vuorio E (February 2007). "Role of cathepsin K in normal joints and in the development of arthritis". Curr Drug Targets. 8 (2): 315–23. doi:10.2174/138945007779940188. PMID   17305509.
  18. ↑ Brömme D, Li Z, Barnes M, Mehler E (February 1999). "Human cathepsin V functional expression, tissue distribution, electrostatic surface potential, enzymatic characterization, and chromosomal localization". Biochemistry. 38 (8): 2377–85. doi:10.1021/bi982175f. PMID   10029531.
  19. ↑ Yang M, Zhang Y, Pan J, Sun J, Liu J, Libby P, Sukhova GK, Doria A, Katunuma N, Peroni OD, Guerre-Millo M, Kahn BB, Clement K, Shi GP (August 2007). "Cathepsin L activity controls adipogenesis and glucose tolerance". Nat. Cell Biol. 9 (8): 970–7. doi:10.1038/ncb1623. PMC   3065497 . PMID   17643114.
  20. ↑ Bratkovič, et al. (2005). "Affinity selection to papain yields potent peptide inhibitors of cathepsins L, B, H, and K.". Biochemical and Biophysical Research Communications. 332 (3): 897–903. doi:10.1016/j.bbrc.2005.05.028. PMID   15913550.
  21. ↑ Mullard, Asher (2016-10-01). "Merck & Co. drops osteoporosis drug odanacatib". Nature Reviews Drug Discovery. 15 (10): 669. doi: 10.1038/nrd.2016.207 . ISSN   1474-1784. PMID   27681784. S2CID   10186583.
  22. ↑ Cooley, Brian (July 19, 2022). ""Sorrento Therapeutics Announces the FDA IND Clearance of STI-1558, An Oral M(pro) and Cathepsin L Inhibitor to Treat COVID-19"". Sorrento Therapeutics, Inc. Retrieved September 1, 2022.
  23. 1 2 Li WA, Barry ZT, Cohen JD, Wilder CL, Deeds RJ, Keegan PM, Platt MO (June 2010). "Detection of femtomole quantities of mature cathepsin K with zymography". Anal. Biochem. 401 (1): 91–8. doi:10.1016/j.ab.2010.02.035. PMID   20206119.
  24. ↑ Wilder CL, Park KY, Keegan PM, Platt MO (December 2011). "Manipulating substrate and pH in zymography protocols selectively distinguishes cathepsins K, L, S, and V activity in cells and tissues". Arch. Biochem. Biophys. 516 (1): 52–7. doi:10.1016/j.abb.2011.09.009. PMC   3221864 . PMID   21982919.
  25. ↑ Maver ME, Greco AE (December 1949). "The hydrolysis of nucleoproteins by cathepsins from calf thymus". J. Biol. Chem. 181 (2): 853–60. doi: 10.1016/S0021-9258(18)56608-4 . PMID   15393803.
  26. 1 2 Bergmann M, Fruton JS (July 1936). "Regarding the general nature of catheptic enzymes". Science. 84 (2169): 89–90. Bibcode:1936Sci....84...89B. doi:10.1126/science.84.2169.89. PMID   17748131.
  27. ↑ Bergmann M, Fruton JS (June 1, 1937). "On proteolytic enzymes XV. Regarding the general nature of intracellular proteolytic enzymes". The Journal of Biological Chemistry. 119: 35–46. doi: 10.1016/S0021-9258(18)74429-3 .
  28. ↑ Anson, M. L. (September 1936). "The estimation of cathepsin with hemoglobin and the partial purification of cathepsin". The Journal of General Physiology. 20 (4): 565–574. doi:10.1085/jgp.20.4.565. PMC   2141516 . PMID   19873011.
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