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{{Short description|Enzyme}} |
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{{Drugbox |
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{{Infobox enzyme |
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| IUPAC_name = |
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| image = |
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| Name = Chymopapain |
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| EC_number = 3.4.22.6 |
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| CAS_number = |
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| CAS_number = 2593837 |
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| CAS_supplemental = |
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| ATC_prefix = M09 |
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| GO_code = |
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| ATC_suffix = AB01 |
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| image = 1yal.jpg |
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| ATC_supplemental = |
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| width = 200 |
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| PubChem = |
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| caption = Chymopapain's structure |
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| DrugBank = |
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| chemical_formula = |
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| C= | H= | N= | O= |
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| molecular_weight = |
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| smiles = |
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| bioavailability = |
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| protein_bound = |
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| metabolism = |
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| elimination_half-life = |
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| excretion = |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = |
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| pregnancy_category= |
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| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> |
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| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C --> |
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| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
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| legal_status = Rx-only |
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| routes_of_administration = ] into ] |
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}} |
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}} |
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'''Chymopapain''' (trand name '''Chymodiactin''') is a ] isolated from the ] of ] (''Carica papaya''), it is a medication used to treat slipped (]ted) lower ] discs in the spine.<ref></ref> Chymopapain injections should preferably be given under local, rather than general, ]. The dose for a single ] is 2 to 4 nano]s, with a maximum dose per patient of 8 nanokatals. |
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'''Chymopapain''' ({{EC number|3.4.22.6}}, ''chymopapain A'', ''chymopapain B'', ''chymopapain S'', brand name '''Chymodiactin''') is a ] isolated from the ] of ] (''Carica papaya''). It is a ] which belongs to the ] (PLCP) group.<ref name="InterPro" /> Because of its proteolytic activity, it is the main molecule in the process of chemonucleolysis, used in some procedures like the treatment of ]ted lower ] discs in the spine by a nonsurgical method.<ref>{{Cite web |url=http://www.medicinenet.com/chymopapain-injection/article.htm#Uses |title=Chymopapain Injection | work = MedicineNet |access-date=2009-07-21 |archive-url=https://web.archive.org/web/20090804235335/http://www.medicinenet.com/chymopapain-injection/article.htm#Uses |archive-date=2009-08-04 |url-status=dead }}</ref> |
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== Structure == |
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The sale and distribution of chymopapain was discontinued in the United States on January 27, 2003.<ref> </ref> |
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=== Primary structure === |
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==Side effects== |
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Chymopapain's ] is made up of a total of 352 residues, and it has a weight of approximately 23.78kDa.<ref name="Maes_1996">{{cite journal | vauthors = Maes D, Bouckaert J, Poortmans F, Wyns L, Looze Y | title = Structure of chymopapain at 1.7 A resolution | journal = Biochemistry | volume = 35 | issue = 50 | pages = 16292–16298 | date = December 1996 | pmid = 8973203 | doi = 10.1021/bi961491w }}</ref> Three different regions can be distinguished inside the precursor's chain.<ref name="Maes_1996" /> |
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Serious side effects from the use of chymopapain include ], ] of the legs, or ].<ref> </ref> |
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* The first 18 aminoacids act as a '''sorting signal''' by indicating the final destination of chymopapain inside the cell when being sorted by the ].<ref name="Maes_1996" /> Although this final destination is not fully studied yet, other PLCPs are contained in ]s and other acidified vesicles and chymopapain is believed to be in these same vesicles as well.<ref name="InterPro">{{cite web|url=http://www.ebi.ac.uk/interpro/entry/IPR000668|title=Peptidase C1A, papain C-terminal (IPR000668) | work = InterPro | publisher = EMBL-EBI | access-date=2018-10-11}}</ref><ref name="National Center for Biotechnology Information (NCBI), National Library of Medicine">{{cite web|url=https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=cd02248|title = Conserved Protein Domain (CDD) Family: Peptidase_C1A| work = National Center for Biotechnology Information (NCBI), National Library of Medicine | publisher = U.S. National Institutes of Health | access-date=2018-10-11}}</ref> Chymopapain is also known to be secreted outside the cell.<ref>{{cite journal | vauthors = Oberg KA, Ruysschaert JM, Azarkan M, Smolders N, Zerhouni S, Wintjens R, Amrani A, Looze Y | display-authors = 6 | title = Papaya glutamine cyclase, a plant enzyme highly resistant to proteolysis, adopts an all-beta conformation | journal = European Journal of Biochemistry | volume = 258 | issue = 1 | pages = 214–222 | date = November 1998 | pmid = 9851712 | doi = 10.1046/j.1432-1327.1998.2580214.x | doi-access = free }}</ref> |
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==See also== |
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* The second region is constituted by residues 19 to 134, which conform a '''propeptide''' that will be removed upon activation once chymopapain reaches its final destination inside the cell.<ref name="Maes_1996" /> This region allows the protein to be properly folded in the ] and to stabilize the chain in different acidity conditions, as its optimum pH varies from 3,5 to 10 depending on the substrate.<ref>{{cite journal| vauthors = Khan I, Polgar L |date=1983-11-08|title=Purification and characterization of a novel proteinase, chymopapain S |journal=Biochimica et Biophysica Acta (BBA) - General Subjects |volume=760 |issue=3 |pages=350–356 |doi=10.1016/0304-4165(83)90372-0 }}</ref> Therefore, the ability to work in low pH conditions supports the idea that chymopapain can be found in ]s.<ref name="InterPro" /><ref name="National Center for Biotechnology Information (NCBI), National Library of Medicine" /> The propeptide is folded in a way that prevents substrates from entering into the ], thus blocking proteolytic activity until it is cleaved.<ref>{{cite web|url=https://www.uniprot.org/uniprot/F6KSW9|title=Chymopapain - Carica papaya (Papaya)| work = UniProt | access-date=2018-10-11}}</ref><ref>{{cite web|url=http://smart.embl.de/smart/do_annotation.pl?DOMAIN=SM00848|title=SMART: Inhibitor_I29 domain annotation| work = Simple Modular Architecture Research Tool (SMART) | publisher = Biobyte Solutions GmbH | access-date=2018-10-11}}</ref> |
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* The rest of the protein -residues 135 to 352- conform to the chymopapain's mature chain.<ref name="Maes_1996" /> Three amino acids can be highlighted in this region, which are Cys159, His293 and Asn313, as they constitute the ] of the enzyme.<ref name="Maes_1996" /> Cys159 and His293 are the two residues that perform the catalysis of the substrate while Asn313 interacts with Cys159 and properly orients its imidazolium ring to allow the reaction to happen, thus bearing an essential function in the catalysis too.<ref name="pmid26147872">{{cite journal | vauthors = López-Iglesias M, Gotor-Fernández V | title = Recent Advances in Biocatalytic Promiscuity: Hydrolase-Catalyzed Reactions for Nonconventional Transformations | journal = Chemical Record | volume = 15 | issue = 4 | pages = 743–759 | date = August 2015 | pmid = 26147872 | doi = 10.1002/tcr.201500008 | hdl-access = free | hdl = 10651/34362 }}</ref> |
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==References== |
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<references/> |
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=== Secondary and tertiary structures === |
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==External links== |
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Chymopapain's structure was solved by ] techniques.<ref name="Maes_1996">{{cite journal | vauthors = Maes D, Bouckaert J, Poortmans F, Wyns L, Looze Y | title = Structure of chymopapain at 1.7 A resolution | journal = Biochemistry | volume = 35 | issue = 50 | pages = 16292–16298 | date = December 1996 | pmid = 8973203 | doi = 10.1021/bi961491w }}</ref> Analysis of this structure showed chymopapain to have 7 ] regions, 10 ] regions and 2 loop turns.<ref name="Maes_1996" /> These 2 turns are the main difference between chymopapain's structure and other papaya proteinase proteins such as ] or ], which have similar conformations.<ref>{{cite journal | vauthors = Jacquet A, Kleinschmidt T, Schnek AG, Looze Y, Braunitzer G | title = The thiol proteinases from the latex of Carica papaya L. III. The primary structure of chymopapain | journal = Biological Chemistry Hoppe-Seyler | volume = 370 | issue = 5 | pages = 425–434 | date = May 1989 | pmid = 2500950 | doi = 10.1515/bchm3.1989.370.1.425 }}</ref><ref>{{cite journal | vauthors = Watson DC, Yaguchi M, Lynn KR | title = The amino acid sequence of chymopapain from Carica papaya | journal = The Biochemical Journal | volume = 266 | issue = 1 | pages = 75–81 | date = February 1990 | pmid = 2106878 | pmc = 1131098 | doi = 10.1042/bj2660075 }}</ref> |
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*The ] online database for peptidases and their inhibitors: |
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Besides, chymopapain presents 3 ] as post-traducional modifications stablished between residues 156–197, 190–229 and 287–338.<ref name="Maes_1996" /> |
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=== Quaternary structure === |
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Chymopapain presents a ] characterized by the formation of ], which means that two chymopapain chains join each other through ]s to conform one unique biological structure.<ref name="loschmidt.chemi.muni.cz">{{cite web|url=https://loschmidt.chemi.muni.cz/hotspotwizard/?action=results&job=stixf2&analysis=functional&|title=HotSpot Wizard 3.0|website=loschmidt.chemi.muni.cz|access-date=2018-10-11}}</ref> |
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== Function == |
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As well as all the other enzymes in the PLCPs group, chymopapain is a ]. ]s are enzymes that ] ]s between the residues that conform a protein. In every hydrolysis a water molecule is released. Specifically, a cysteine protease is an enzyme which breaks the peptide bond by using the ] group of a cysteine residue as the nucleophile. In order to hydrolyse, the whole ] of the enzyme must be used.<ref name="InterPro" /> This is constituted by a ], the Cys159 residue, a ], the His203 residue, and a third residue, which tends to be an ], specifically the Asn313 residue.<ref>{{cite web|url=http://www.enzyme.chem.msu.ru/hcs/cgi/protein.cgi?id=P14080|title=HCS: Chymopapain| vauthors = Gariev IA |website=www.enzyme.chem.msu.ru|access-date=2018-10-20}}</ref> The functional groups used in the reaction are the thiol group of the cysteine and the ] of a histidine. The asparagine residue works orientating the imidazolium ring of the histidine.<ref name="pmid26147872"/> |
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The mechanism followed is exposed below:<ref name="pmid26147872"/> |
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# The thiol group from the cysteine loses a proton, so it becomes ] and the amino group of the histidine catches a proton, which gives it a ]. |
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# The cysteine makes a bond with the carbon breaking the carbon's ] with oxygen and converting it into a simple bond. |
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# The amino group is attracted by the positive charge of the histidine and a bond between these two is formed. The peptide bond is now broken and the ] is remade. |
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# The NH<sub>2</sub>R group is released from the histidine. The bond between the thiol group from the cysteine and the carbon is broken and a NHR group replaces it. |
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When this two bonds are broken, the catalytic triad from the chymopapain is available to be used again. |
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== Synthesis == |
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Chymopapain is no longer used as a standard method to treat chronic low back pain because of its potential side effects.<ref>{{cite journal | vauthors = Deeb ZL, Schimel S, Daffner RH, Lupetin AR, Hryshko FG, Blakley JB | title = Intervertebral disk-space infection after chymopapain injection | journal = AJR. American Journal of Roentgenology | volume = 144 | issue = 4 | pages = 671–674 | date = April 1985 | pmid = 3156470 | doi = 10.2214/ajr.144.4.671 | s2cid = 18909656 }}</ref><ref>{{cite journal | vauthors = Sussman BJ | title = Inadequacies and hazards of chymopapain injections as treatment for intervertebral disc disease | journal = Journal of Neurosurgery | volume = 42 | issue = 4 | pages = 389–396 | date = April 1975 | pmid = 123576 | doi = 10.3171/jns.1975.42.4.0389 }}</ref> Therefore, there is no need to synthesize it artificially. In fact, the sale and distribution of this protein was discontinued in the US in 2003. |
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Despite the huge amount of successful use to treat herniated disk disease, chymopapain use was discontinued not because of hazards or inadequacies but rather because it is no longer available due to a decision by its sole manufacturer to stop production.<ref name="pmid28377858">{{cite journal | vauthors = Wardlaw D | title = Sciatica caused by disc herniation: Why is Chymopapain Chemonucleolysis denied to our patients? | journal = International Journal of Spine Surgery | volume = 10 | issue = | pages = 44 | date = 2016 | pmid = 28377858 | pmc = 5374990 | doi = 10.14444/3044 }}</ref> |
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However, several studies have demonstrated different successful methods to extract and isolate the protease, which vary among authors.<ref>{{cite journal| vauthors = Monti R, Basilio CA, Trevisan HC, Contiero J |date=2000|title=Purification of papain from fresh latex of Carica papaya|journal=Brazilian Archives of Biology and Technology|volume=43|issue=5|pages=501–507|doi=10.1590/S1516-89132000000500009|issn=1516-8913|doi-access=free|hdl=11449/20106|hdl-access=free}}</ref><ref>{{cite journal | vauthors = Buttle DJ, Barrett AJ | title = Chymopapain. Chromatographic purification and immunological characterization | journal = The Biochemical Journal | volume = 223 | issue = 1 | pages = 81–88 | date = October 1984 | pmid = 6437389 | pmc = 1144267 | doi = 10.1042/bj2230081 }}</ref> The most common procedure is the one described by Baines & Brocklehurst in 1979.<ref>{{cite journal | vauthors = Baines BS, Brocklehurst K | title = A necessary modification to the preparation of papain from any high-quality latex of Carica papaya and evidence for the structural integrity of the enzyme produced by traditional methods | journal = The Biochemical Journal | volume = 177 | issue = 2 | pages = 541–548 | date = February 1979 | pmid = 435250 | pmc = 1186404 | doi = 10.1042/bj1770541 }}</ref> |
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In order to obtain the protein, Carica Papaya fruits are used, as chymopapain is found in its latex. The papayas should be just in the previous step before maturation, which implies an average diameter of 6–10 cm.<ref>{{cite report | vauthors = Aguirre E, Castillo P |date=2009-09-15|title=Extracción y estudio comparativo de las enzimas proteolíticas del fruto toronche (carica-stipulata) y de la papaya (carica-papaya) y su aplicación en la industria alimenticia |url=http://www.dspace.espol.edu.ec/handle/123456789/7532}}</ref> |
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Some longitudinal incisions of 2mm of depth have to be made through the skin to proceed to the extraction of latex, which can be collected in solid form some minutes after the extraction. The proteases present in the latex of the fruit are inactive ] that are activated once the papaya is wounded.<ref name="Azarkan_2003">{{cite journal | vauthors = Azarkan M, El Moussaoui A, van Wuytswinkel D, Dehon G, Looze Y | title = Fractionation and purification of the enzymes stored in the latex of Carica papaya | journal = Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences | volume = 790 | issue = 1–2 | pages = 229–238 | date = June 2003 | pmid = 12767335 | doi = 10.1016/s0021-9673(02)01534-0 }}</ref> In 0.3 ml of latex there are about 15 mg of chymopapain.<ref name="Buttle_1984">{{cite journal | vauthors = Buttle DJ, Barrett AJ | title = Chymopapain. Chromatographic purification and immunological characterization | journal = The Biochemical Journal | volume = 223 | issue = 1 | pages = 81–88 | date = October 1984 | pmid = 6437389 | pmc = 1144267 | doi = 10.1042/bj2230081 }}</ref> |
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If we want to conserve the proteolytic properties, latex has to be preserved with ] and stored at a low temperature of about -10 °C.<ref name="Andrade-Mahecha_2013">{{cite report | vauthors = Andrade-Mahecha MM, Morales-Rodriguez O, Martinez-Correa HA | url = http://bdigital.unal.edu.co/30068/11/28818-169899-1-PB.pdf | title = Study of the extraction process of papain from latex of papaya ( Carica papaya L . ) fruits cv . Maradol. | date = 2013 }}</ref> If used immediately after the incisions, a buffer is added to extract the proteins: ], ] or ] all with a concentration of 0.5 mM and a pH of 7. |
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It is also important to block the thiol functions to avoid air oxidation and the loss of proteolytic activity.<ref name="Azarkan_2003" /> |
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To eliminate organic and insoluble molecules, the sample is first filtered and afterwards centrifuged at 11000g for 30min.<ref name="Buttle_1984" /> The pellet is discarded and the supernatant added to 96% alcohol with a ratio of 1:3.<ref name="Andrade-Mahecha_2013" /> Impurities precipitate and can be eliminated by filtration. Afterwards, (NH<sub>4</sub>)<sub>2</sub>SO<sub>4</sub> fractioning is done by addition of this substance at a concentration of 0.472 mg/ml.<ref name="Buttle_1984" /> Chymopapain precipitates and can be retrieved through another centrifugation, again at 11000g for 30min. The supernatant is discarded and the ion exchange chromatography can be carried out, with a linear gradient of 100mM (Na<sup>+</sup>) and different volumes of elution. Studying A<sub>280</sub> chymopapain is found in the fraction of 750-1000 ml.<ref name="Azarkan_2003" /> |
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Once chymopapain has been isolated, it can be crystallized through the gradual addition of ] at pH 2.0, which can take up to 4 days.<ref>{{cite journal | vauthors = Ebata M, Yasunobu KT | title = Chymopapain. I. Isolation, crystallization, and preliminary characterization | journal = The Journal of Biological Chemistry | volume = 237 | pages = 1086–1094 | date = April 1962 | pmid = 13888995 | doi = 10.1016/S0021-9258(18)60289-3 | doi-access = free }}</ref> |
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==Medical applications == |
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] |
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{{Infobox drug |
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| Verifiedfields = changed |
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| verifiedrevid = 477380130 |
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| IUPAC_name = |
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| image = |
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<!-- Clinical data --> |
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| tradename = |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = |
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| pregnancy_category = |
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| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled --> |
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| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C --> |
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| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
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| legal_status = Rx-only |
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| routes_of_administration = ] into ] |
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<!-- Pharmacokinetic data --> |
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| bioavailability = |
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<!-- Identifiers --> |
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| CAS_number_Ref = {{cascite|correct|CAS}} |
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| CAS_number = 9001-09-6 |
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| ATC_prefix = M09 |
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| ATC_suffix = AB01 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = 1UK146T40N |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = 1201626 |
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| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} |
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<!-- Chemical data --> |
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| chemical_formula = | C= | H= | N= | O=| molecular_weight = |
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Chymopapain is one of the substracts used in chemonucleolysis (a type of ]).<ref>{{cite web|url=http://www.scielo.br/pdf/clin/v62n2/v62n2a13.pdf|title=Chemonucleolysis|last=|first=|date=|website=Couto JMC, Castilho EA de, Menezes PR. Chemonucleolysis in lumbar disc herniation: a meta-analysis. Clinics. 2007;62(2):175-80|archive-url=|archive-date=|access-date=}}</ref> This method was a new proposal to treat primary lumbar ] disease using a nonsurgical method. As a matter of fact, the treatment consists on an injection of proteolytic enzymes to dissolve the herniated nucleus pulposus of the intervertebral discs. Purified chymopapain is the main component of the injection, composed basically of 20 mg in five millilitres. It is provided in vials containing 10.000 units of the ] agent with 0.37 mg of disodium edetate,<ref>{{cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/EDTA_disodium_salt#section=Top|title=Edetate disodium | work = PubChem | publisher = U.S. National Library of Medicine }}</ref> 3.5 mg of cysteine hydrochloride monohydrate and 1.0 mg of bisulfide. All of them work as stabilisers and activators. Sodium hydroxide is in charge of adjusting the PH of the solution. Then, the injection is rehydrated with 5 milliliters of sterile water. |
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A surgeon injects the solution directly into the herniated disc on the spine to dissolve part of it and ease the pain. This process is under fluoroscopic control. Chymopapain is responsible for catalysis, both in vivo and in vitro, a rapid reduction in the viscosity and, as a consequence, the weight of the ]. In fact, it is a ] of the chondromucoprotein<ref>{{cite web|url=https://medical-dictionary.thefreedictionary.com/chondromucoprotein |title=Description of chondromucoprotein| work = The Free Dictionary }}</ref> and a decrease in the ability of a disk to imbibe fluid. The dose for a single ] is 2 to 4 nano]s, with a maximum dose per patient of 8 nanokatals. Chymopapain injections are normally given under local, rather than general, ]. |
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This enzyme has been studied by universities departments around the world.<ref name="pmid13888995">{{cite journal | vauthors = Ebata M, Yasunobu KT | title = Chymopapain. I. Isolation, crystallization, and preliminary characterization | journal = The Journal of Biological Chemistry | volume = 237 | issue = | pages = 1086–94 | date = April 1962 | pmid = 13888995 | doi = 10.1016/S0021-9258(18)60289-3| url = http://www.jbc.org/content/237/4/1086.full.pdf | doi-access = free }}</ref> |
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<ref>{{cite journal | vauthors = Knezevic NN, Mandalia S, Raasch J, Knezevic I, Candido KD | title = Treatment of chronic low back pain - new approaches on the horizon | language = English | journal = Journal of Pain Research | volume = 10 | pages = 1111–1123 | date = May 2017 | pmid = 28546769 | pmc = 5436786 | doi = 10.2147/jpr.s132769 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Wardlaw D | title = Sciatica caused by disc herniation: Why is Chymopapain Chemonucleolysis denied to our patients? | journal = International Journal of Spine Surgery | volume = 10 | pages = 44 | year = 2016 | pmid = 28377858 | pmc = 5374990 | doi = 10.14444/3044 }}</ref> It was tested as much in animals as in humans and, very rarely, did it cause serious side effects including ] of the legs and ].<ref name = "MayoClinic">{{cite web | title = Chymopapain | url = http://www.mayoclinic.com/health/drug-information/DR600373 | publisher = The Mayo Clinic }}</ref> It could also cause ], but it was only seen in 1% of the patients who received the medication. |
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The sale and distribution of chymopapain was discontinued in the United States on January 27, 2003, after the company producing it decided to stop selling it worldwide.<ref name = "MayoClinic" /><ref>{{Cite web |url=http://www.sciatica.com/physician--information/scientific-articles/file/24-the-current-status-of-chymopapain.html |title=The Current Status of Chymopapain |access-date=2013-04-01 |archive-url=https://web.archive.org/web/20160121193139/http://www.sciatica.com/physician--information/scientific-articles/file/24-the-current-status-of-chymopapain.html |archive-date=2016-01-21 |url-status=dead }}</ref> |
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== See also == |
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*] |
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{{clear}} |
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== References == |
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{{reflist}} |
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== Further reading == |
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*The ] online database for peptidases and their inhibitors: |
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{{Other drugs for disorders of the musculo-skeletal system}} |
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{{Cysteine proteases}} |
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{{Enzymes}} |
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|
{{Portal bar|Biology|border=no}} |
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|
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] |
|
{{musculoskeletal-drug-stub}} |
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] |
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{{enzyme-stub}} |
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] |