View source for Papain

[[Image:papayas.jpg|525px|right|thumb|Papaya<ref>[http://dailyfitnessmagz.com/2011/03/papayas-nutrition-facts/] Papaya's Nutrition Facts</ref>]]
Papain. Meat tenderizer. Old time home remedy for insect, jellyfish, and stingray stings<ref>[http://www.ameriden.com/products/advanced-digestive-enzyme/] Ameridan International</ref>. Who would have thought that a sulfhydryl protease from the latex of the papaya fruit, ''Carica papaya'' and ''Vasconcellea cundinamarcensis'', would have such a practical application beyond Proteopedia?

Papain is a 23.4 kDa, 212 residue cysteine protease, also known as '''papaya proteinase I''', from the peptidase C1 family (E.C. 3.4.22.2).<ref>[http://www.uniprot.org/uniprot/P00784] Uniprot</ref><ref name="9PAP PDB">[http://www.pdb.org/pdb/explore/explore.do?structureId=9PAP] 9PAP PDB</ref> It is the natural product of the [http://en.wikipedia.org/wiki/Carica_papaya Papaya](''Carica papaya'')<ref name="Sigma Aldrich">[http://www.sigmaaldrich.com/life-science/metabolomics/enzyme-explorer/analytical-enzymes/papain.html] Sigma Aldrich</ref>, and may be extracted from the plant's latex, leaves and roots. Papain displays a broad range of functions, acting as an endopeptidase, exopeptidase, amidase, and esterase,<ref name="Worthington">[http://www.worthington-biochem.com/pap/default.html] Worthington</ref> with its optimal activity values for pH lying between 6.0 and 7.0, and its optimal temperature for activity is 65 °C. Its pI values are 8.75 and 9.55, and it is best visualized at a wavelength of 278 nm. <ref name="Sigma Aldrich" />

Papain's enzymatic use was first discovered in 1873 by G.C. Roy who published his results in the Calcutta Medical Journal in the article, "The Solvent Action of Papaya Juice on Nitrogenous Articles of Food." In 1879, Papain was named officially by Wurtz and Bouchut, who managed to partially purify the product from the sap of papaya. It wasn't until the mid-twentieth century that the complete purification and isolation of Papain was achieved. In 1968, Drenth et al. determined the structure of Papain by x-ray crystallography, making it the second enzyme whose structure was successfully determined by x-ray crystallography. Additionally, Papain was the first cysteine protease to have its structure identified.<ref name="Worthington" /> In 1984, Kamphuis et al. determined the geometry of the active site, and the three-dimensional structure was visualized to a 1.65 Angstrom solution.<ref name="Structure">PMID:6502713</ref> Today, studies continue on the stability of Papain, involving changes in environmental conditions as well as testing of inhibitors such as phenylmethanesulfonylfluoride (PMSF), TLCK, TPCK, aplh2-macroglobulin, heavy metals, AEBSF, antipain, cystatin, E-64, leupeptin, sulfhydryl binding agents, carbonyl reagents, and alkylating agents.<ref name="Worthington" />

<StructureSection load='9pap' size='500' side='right' caption='Click on the links to the left to view different structural aspects.[[9pap]]' scene='Papain/Primary_scene/2' >
==Structure==

===General Structural Features===

Papain is a relatively simple enzyme, consisting of a single 212 residue chain.  A majority of papain's residues are <scene name='Papain/Hydrophobicity_papain/1'>hydrophobic</scene> as shown in fuchsia.  As with all proteins, it is primarily the exclusion of these residues by water that leads to papain's assumption of a globular form.  Despite its apparent simplicity and small size, papain folds into two distinct, evenly sized <scene name='Papain/Sk_two_domains/2'>domains</scene>, each with its own <scene name='Papain/Sk_hydrophobic_core/2'>hydrophobic core</scene> (surface residues are transparent, hydrophobic-core residues are colored and opaque, and the remaining are polar, non-surface residues).<ref name="Structure">PMID:6502713</ref>  
These two subunits are held together with <scene name='Papain/Armcrossing/1'>"arm" linkage</scene>, where each protein domain holds the opposite domain. In papain's case the "arm" crossing primarily occurs on or near the surface.<ref>[http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2i.html] Jane S. Richardson</ref>  It is between these two domains that the <scene name='Papain/9pap_bindingpocket_wrtdomains/4'>substrate binding pocket</scene> is situated. The two domains interact with one another via hydrophobic interactions, <scene name='Papain/Twodomainshbonds/2'>hydrogen bonds</scene> (shown in white), and electrostatic interactions in this cleft.  For example, <scene name='Papain/Valine_19/2'>Valine-32</scene> from Domain L hydrophobically interacts with the carbon atoms on residues Lys-174, Ala-162 and Pro-129 of Domain R. <scene name='Papain/Gln_19/2'>Gln-19</scene> hydrogen bonds multiple times with the oxygen atoms of Ser-176.  Electrostatic interactions are seen between <scene name='Papain/Glu_35/1'>Glu-35 and Lys-174</scene> where the carboxyl group of Glu-35 forms an ionic bond with the ammonia group of the Lys-174 residue.  The <scene name='Papain/Twodomainsallncbonds/1'>sum total</scene> of interactions within the cleft between the two domains ensures that the lobes do not move with respect to one another. <ref>[http://books.google.com/books?hl=en&lr=&id=fk1hbZdPTEgC&oi=fnd&pg=PA79&dq=aromatic+residues+in+papain&ots=L8SvlkQaZU&sig=xZ2l8kj52PD7DzuiAQ1zah0CU2M#v=onepage&q=aromatic%20residues%20in%20papain&f=false] The Structure of Papain </ref> 

In addition to hydrophobic residues, papain contains a variety of <scene name='Papain/Sk_polar_residues/2'>polar residues</scene>, some carrying a <scene name='Papain/Sk_acidic_residues/2'>negative charge</scene>, shown in gray at physiological pH, and are therefore acidic; others a <scene name='Papain/Sk_basic_residues/2'>positive charge</scene>, shown in purple, and are therefore basic. The rest of the <scene name='Papain/Sk_basic_residues/3'>polar residues</scene>, shown in a light gray, are neutral.  As expected, the charged <scene name='Papain/Termini/3'>termini</scene> face outward due to their hydrophilic nature.

Papain's secondary structure is composed of 21% <scene name='Papain/Ke_betasheets/2'>beta sheets</scene> (45 residues comprising 17 sheets) and 25% <scene name='Papain/Ke_alphahelices/2'>alpha helices</scene> (51 residues comprising 7 helices).  The rest of the residues, accounting for over 50% of the enzymes structure, make up ordered non-repetative sequences.<ref name="RSCB PDB">[http://www.rcsb.org/pdb/explore/explore.do?structureId=9PAP] RCSB PDB</ref>  These secondary structures may be traced from the N- to C-terminus by means of <scene name='Papain/Lm_elemental/2'>differential coloration</scene>.  As shown in this scene, the red end begins the protein at the N-terminus, and can be traced through the colors of the rainbow to the blue end at the C-terminus.  These secondary structures form as a result of favorable hydrogen bonding interactions within the polypeptide backbone.  Meanwhile, secondary structures are kept in place by hydrophobic interactions and hydrogen bonds between sidechains of adjacent structures.  For example, the <scene name='Papain/Papain_sam_centralhelix/1'>first helix</scene> (residues 25-42) is maintained as a result of <scene name='Papain/Papain_sb_helix1_hbonds/1'>hydrogen bonds</scene> between backbone carbonyl atoms and the hydrogen on the amide nitrogen four residues away.  However, <scene name='Papain/Papain_sam_nohbondswhelix1/1'>no hydrogen bonds</scene> are present between this helix and the rest of the protein, suggesting that this helix is coordinated primarily by hydrophobic interactions.  This is reasonable given its central location in the enzyme.  As expected, the helix contains many <scene name='Papain/Papain_sb_helix1_hydrophobic/1'>hydrophobic residues</scene> (red residues are hydrophilic).  

<scene name='Papain/Ke_salt_bridges/2'>Salt bridges</scene> strongly contribute to the tertiary structure of papain.<ref name="Sigma Aldrich" /> In this particular image, clarification of residue coordination is demonstrated by color: paired residues are shown in the same color, oxygen is shown in red, and nitrogen is shown in blue.  The tertiary structure of papain is also maintained by three <scene name='Papain/9pap_sam_disulfides/1'>disulfide bonds</scene>, which connect <scene name='Papain/9pap_sam_disulfides_22-63/1'>Cys-22 to Cys63</scene>, <scene name='Papain/9pap_sam_disulfides_56-95/1'>Cys-56 to Cys-95</scene>, and <scene name='Papain/9pap_sam_disulfides_153-200/1'>Cys-153 to Cys-200</scene><ref name="9PAP PDB" />.  These disulfide bonds are likely important in conserving the structural integrity of the enzyme as it operates in extracellular environments at high temperatures.

===Substrate Binding===

Papain has a relatively small <scene name='Papain/Active_site/1'>active site</scene> consisting of three residues: Cys-25, His-159, and Asn-175. The sulfhydryl group on Cys-25 often forms covalent bonds with substrates. His-159 supports Cys-25, and while Arg-175 does not directly participate in the catalytic mechanism, it keeps histidine-159 in its stabilized imidazole form. In addition to the active site, sometimes referred to as the catalytic site, Papain consists of many <scene name='Papain/Substrate_binding_sites/2'>substrate binding subsites.</scene> Subsites are defined as the regions on the enzyme surface which interact with one amino acid residue of the substrate. In the case of Papain, there are seven subsites labeled as follows: S1, S2, S3, S4, located on the amino side of the catalytic site; S1', S2', and S3', located on the carboxyl side of the catalytic site. The binding sites of a substrate are labeled according to how they fit into the binding cleft. P1 associates with S1, P2 with S2, etc. All seven of Papain's subsites hydrogen bond to the corresponding substrate P subsites. The following <scene name='Papain/Substrate_binding_sites/3'>subsites</scene> of Papain have been identified as follows: S1 - His-159; S2 - Trp-177; S3 - Gln-19; S4 - Gly-23; S2' - Asp-158; and S3' - Asp-64. Unfortunately, S1' has yet to be identified. 

The seven subsites of Papain have various preferences for substrate residues. Through a variety of experiments, Berger & Schechter<ref>PMID:4399049</ref>, were able to show that S1 binds alanine better than glycine, and the larger side chains of lysine, arginine, leucine, and phenylalanine better than alanine. Thus showing that binding in S1 is predominantly hydrophobic. S2 prefers a phenylalanine or a valine residue. Interestingly enough, S2 binds to hydrophobic residues of both short and long peptide chains. They were able to show that subsites S1' and S2' are strongly stereospecific. The conclusion of their research was that Papain's binding site residues show a strong stereospecificity, special interactions, and space limitations.<ref>PMID:4399049</ref>

===Catalytic Mechanism===
It was once thought that cysteine proteases, like serine proteases, contained a <scene name='Papain/Catalytic_triad/1'>catalytic triad</scene>, consisting of Cys-25, His-159, and Arg-175 <ref> PMID:8140097</ref>.  However, site-directed mutagenesis-based studies have demonstrated that Arg-175 is not directly involved in catalysis.  Although Arg-175 is clearly important for the enzyme's activity (an Arg175Ala mutation reduces its activity to undetectable levels), this residue neither reacts with the substrate nor modulates the pKa of reacting residues, and therefore cannot be considered catalytic.<ref name="Shokhen">[http://www.ncbi.nlm.nih.gov/pubmed/19688822]Shokhen M, N Khazanov, and A Albeck. 2009. Challenging a paradigm: theoretical calculations of the protonation state of the Cys25-His159 catalytic diad in free papain. Proteins. 77(4):916-26.</ref><ref name="Noble">[http://www.ncbi.nlm.nih.gov/pubmed/11042128]Noble MA, Gul S, Verma CS, Brocklehurst K. 2000. Ionization characteristics and chemical influences of aspartic acid residue 158 of papain and caricain determined by structure-related kinetic and computational techniques: multiple electrostatic modulators of active-centre chemistry. Biochem J. 2000 351: 723-33.</ref> Arg-175 is believed to keep histidine-159 in its stabilized imidazole form, while both histidine-159 and cysteine-25 take part in the actual catalytic mechanism.<ref name="U Maine">[http://chemistry.umeche.maine.edu/CHY431/Peptidase10.html] University of Maine</ref> Despite this, the basic mechanism of papain-catalyzed proteolysis proceeds much like that of serine proteases.  The mechanism begins when a peptide binds to the active site. Cys-25 is then deprotonated by His-159 and attacks the substrate carbonyl carbon. This forms a covalent, tetrahedral intermediate that is stabilized by an <scene name='Papain/Oxyanion_hole/1'>oxyanion hole</scene>, formed in large part by Gln-19. Next, His-159 acts as a general acid, protonating the nitrogen in the peptide bond, which acts as a leaving group as the carbonyl reforms. This now free C-terminal portion of the peptide is released. Water then enters the active site and attacks the carbonyl carbon while it is deprotonated by His-159, again forming an oxyanion hole-stabilized tetradral covalent intermediate. Finally, the carbonyl reforms and the Cys-25 sulfur acts as a leaving group, releasing the N-terminal portion of the peptide and regenerating the enzyme.  This entire mechanism is shown below<ref name="Harrison">[http://pubs.acs.org/doi/abs/10.1021/ja9711472] Harrison, M.J., N.A. Burton, and I.H. Hillier. 1997. Catalytic Mechanism of the Enzyme Papain: Predictions with a Hybrid Quantum Mechanical/Molecular Mechanical Potential. J. Am. Chem. Soc. 119: 12285-12291</ref>.:
[[Image:Papainmech6.jpg|400px|center|thumb| General mechanism of papain catalysis <ref name="U Maine" />.  Arg-175, which orients His 159, and Gln-19, which contributes to the formation of the oxyanion hole, are not shown.]]

== <scene name='Papain/9pap_bindingpocket_wrtdomains/4'>Inhibitors</scene>==

==='''Leupeptin'''===

<scene name='Papain/Leupeptin/4'>Leupeptin</scene> is a commonly studied broad-spectrum competitive protease inhibitor first crystallized by Schröder et. al.  It inhibits by binding and interacting with the active site which allows it to block the enzyme's desired protein substrate from binding.  There are many <scene name='Papain/Leupeptin_residues/4'>ligand contacts</scene> that interact with Leupeptin, which are predominantly <scene name='Papain/1pop_sam_leupeptin_hydrophobic/4'>hydrophobic</scene> (shown in blue). These residues include tyrosine, tryptophan, and valine, which coordinate the bound Leuptin. Some of the enzyme's residues also make <scene name='Papain/Leupeptin_hbonds/2'>hydrogen bonds</scene>.  These hydrogen bonds, shown in white, include interactions between hydrogens on both Gln-19 and the amide nitrogen of the catalytic Cys-25 with the arginal carbanion, forming the catalytically important oxyanion hole.  In addition, Gly-66 interacts with the second leucine in Leupeptin while Asp-158 interacts with a hydrogen on the arginal.  These interactions further stabilize and orient the substrate in the binding pocket<ref name="Schroder">[http://www.sciencedirect.com/science/article/pii/001457939381128M] Schröder, E., C. Phillips, E. Garman, K. Harlos, C. Crawford. 1997. X-ray crystallographic structure of a papain-leupeptin complex. FEBS Letters 315: 38-42</ref>.

A recent study has shown that Leupeptin forms a covalent bond between its <scene name='Papain/Leupeptin_carbonyl_carbon/1'>carbonyl carbon</scene> and the hydrogen in Cys-25. The inhibitor has the structure Ac-Leu-Leu-Arginal, where Ac is an acetyl group attached to the nitrogen of the first leucine.  Cysteine-25, which acts as a catalytic nucleophile, attacks the arginal aldehyde forming a tight-binding transition state from which the normal catalytic mechanism cannot proceed due to this carbonyl having no potential leaving groups bonded to it. 

==='''Cathepsin K'''===

The goal of research for the development of an inhibitor for <scene name='Papain/Cathepsin_k/2'>Cathepsin K</scene> is the hope to develop a treatment for osteoporosis. In two different Cathepsin K inhibitors, <scene name='Papain/Cathkaldinhibit/1'>an aldehyde inhibitor</scene>, [[1bp4]], and <scene name='Papain/Cathkketoinhibition/2'>a keto inhibitor</scene>, [[1bqi]]. 1BP4, N-[(benzyloxy)carbonyl]-L-leucyl-N-[(2S)-1-hydroxy-4-methylpentan-2-yl]-L-leucinamide, inhibits by interacting with <scene name='Papain/Cathkaldinhibit/2'>11 different residues</scene> on papain: Gln-19, Gly-20, Ser-21, Gly-23, Asn-64, Gly-65, Gln-142, Asp-158, His-159, Trp-177, and Trp-181. These interactions range from hydrophobic, electrostatic, and hydrogen bonding, to <scene name='Papain/Cathkaldinhibitpistacking/2'>ring stacking</scene>, illustrated in blue, between the aromatic ring of the carbobenzyl group on 1BP4, and Trp-177 of papain. The inhibition of papain by IBQI, carbobenzyloxy-(L)-leucinyl-(L)leucinyl methoxymethylketone, is quite similar to that of IBP4, although it does not bind quite as tightly. It binds to <scene name='Papain/Cathkketoinhibition/3'>seven residues</scene> of papain: Gln-19, Gly-23, Gly-65, Gln-142, His-159, Trp-177, Trp-181. Additionally, it has similar <scene name='Papain/Cathkketoinhibitionringstackin/3'>ring stacking</scene>, shown in blue, between the Cbz ring on the inhibitor and Trp-177.<ref> PMID:9804696 </ref> 

==='''Cathepsin L'''===

<scene name='Papain/Cathepsin_l/1'>Cathepsin L</scene>, another inhibitor of Papain, is an endosomal cysteine protease that is believed to have both physiological and pathophysiological effects on the human body. It has been indicated not only in cancer, rhematoid  and osteo arthritis, and Alzheimer's, but its mechanism also appears similar to that of Ebola, SARS, Leishmania, malaria, Chagas' disease, African trypanosomiasis, toxoplasmosis, and amoebiasis.<ref> PMID:20920298 </ref>  Understanding the mechanism of inhibition through the use of papain is therefore crucial to developing treatments for such diseases.<ref> PMID:18499453 </ref> Cathepsin L interacts with the <scene name='Papain/Cathepsin_l_interaction_w_pap/2'>residues</scene> Gln-19, Cys-25, Gly-66, Asp-158, and Trp-177 by hydrogen bonding them (Cathepsin L is illustrated in CPK coloring while the interacting sites of Papain are also shown in CPK). In addition to hydrogen bonding, hydrophobic interactions exist to exclude water, allowing the papain enzyme and Cathepsin L to associate even closer.  

An interesting inhibitor for Cathepsin L developed using papain as the model protease is that of <scene name='Papain/Ke_clik148_inhibitor/4'>Clik-148</scene>, [[1cvz]].<ref> PMID:10600517 </ref> It forms a <scene name='Papain/Ke_clik148_inhibit_cys25/2'>covalent ligand-bound cysteine protease complex</scene> with Cys-25. Five other <scene name='Papain/Ke_clik148_inhibit_cys25/3'>residues</scene>, labeled in white, are also involved in the bonding of Clik-148 to papain: Gln-19, Gly-66, Asp-158, Trp-177, and Ser-205. These participate in hydrophobic, <scene name='Papain/Keclik148ringstacking/2'>aromatic ring stacking</scene>, and <scene name='Papain/Cathepsin_l_interaction_w_pap/3'>hydrogen bonding</scene> that effectively fill up the cleft between the two domains of papain.<ref> PMID:18598021 </ref>

==='''Stefin B'''===

<scene name='Papain/Stefin_b/4'>Stefin B</scene>, [[1stf]] acts as a competitive inhibitor to cysteine proteases - it binds tightly but reversibly to the Papain active site. Its interaction is much more complicated than many other cysteine protease inhibitors, such as those illustrated above.  Stefin inhibitors are characterized by an M<sub>r</sub> of about 11,000, with no disulfide bonds and no associated carbohydrates.

Stefin B consists of five beta sheets wrapped around a five-stranded beta sheet wrapped around a single alpha helix. In Stefin B, the Gly-9 residue along with <scene name='Papain/Stefin_b_hairpin_loops/1'>two hairpin loops</scene>, illustrated in magenta, form a "wedge" complementary to the active site groove of Papain.  This wedge makes extensive and tight interactions with Papain which involves the embedding of 16% of Stefin B into Papain with a total of 128 intermolecular atom-atom interactions occurring. <scene name='Papain/Stefin_b/3'>Residue segments</scene> Met-6 - Pro-11, Gln-53 - Asn-59, Gln-101 - His-104, Tyr-124 and Phe-125 on the wedge all have some interaction with the enzyme, though Cys-25 is the only one to form a direct contact.  All residues from the base of Stefin B, shown in ball-and-stick form, and both sides of the <scene name='Papain/Stefin_b_active_site_interacti/1'>active site cleft</scene>, shown in gray, are involved in the complex with the inhibitor.

There are a small number of <scene name='Papain/Stefin_b_hbonds/2'>direct hydrogen bonds</scene> (labeled in <scene name='Papain/Stefin_b_hbonds/1'>this scene</scene>, between Stefin B and Papain, however there are many more polar interactions mediated by <scene name='Papain/Stefin_b_polar_residue_interac/2'>solvent bridges</scene>.  Thirteen solvent molecules bridge polar residues of the enzyme and inhibitor.  Seventeen hydrogen bonds are made with a solvent molecule and Stefin B.  Fourteen of these bridges form a Papain contact.  The rest of the interactions are largely hydrophobic-- involving apolar <scene name='Papain/Stefin_b_vdw/2'>Van der Waals forces</scene>.<ref> PMID:2347312 </ref>

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</StructureSection>

==Common Uses==


[[Image:RX2.jpg|200px|right|thumb|<ref>[http://www.123rf.com/photo_10020414_medical-symbol-rx.html] RX </ref>]]
===Medicinal===

Papain has been used for a plethora of medicinal purposes including treating inflammation, shingles, diarrhea, psoriasis, parasites, and many others.<ref name="Web MD">[http://www.webmd.com/vitamins-supplements/ingredientmono-69-PAPAIN.aspx?activeIngredientId=69&activeIngredientName=PAPAIN] Web MD </ref> One major use is the treatment of cutaneous ulcers including diabetic ulcers and pressure ulcers. Pressures ulcers plague many bed bound individuals and are a major source of pain and discomfort.  Two papain based topical drugs are Accuzyme and Panafil, which can be used to treat wounds like cutaneous ulcers.<ref>[http://www.pbm.va.gov/Clinical%20Guidance/Drug%20Monographs/Papain%20Urea.pdf] National PBM Drug Monograph </ref>

A recent New York Times article featured papain and other digestive enzymes. With the number of individuals suffering from irritable bowel syndrome and other gastrointestinal issues, many people are turning toward natural digestive aid supplements like papain.  The author even talks about the use of papain along with a pineapple enzyme, bromelain, in cosmetic facial masks.  Dr. Adam R. Kolker (a plastic surgeon) is quoted in the article saying that "For skin that is sensitive, enzymes are wonderful."  He bases these claims off the idea that proteases like papain help to break peptide bonds holding dead skin cells to the live skin cells.<ref> [http://www.nytimes.com/2012/02/23/fashion/enzymes-once-sidelined-try-to-grab-the-spotlight.html] Enzymes Try to Grab the Spotlight </ref>


===Commercial and Biomedical===
Papain digests most proteins, often more extensively than pancreatic proteases. It has a very broad specificity and is known to cleave peptide bonds of basic amino acids and leucine and glycine residues, but prefers amino acids with large hydrophobic side chains. This non-specific nature of papain's hydrolase activity has led to its use in many and varied commercial products.  It is often used as a meat tenderizer because it can hydrolyze the peptide bonds of collagen, elastin, and actomyosin.  It is also used in contact lens solution to remove protein deposits on the lenses and marketed as a digestive supplement.  <ref name="Web MD">  Finally, papain has several common uses in general biomedical research, including a gentle cell isolation agent, production of glycopeptides from purified proteoglycans, and solubilization of integral membrane proteins.  It is also notable for its ability to specifically cleave IgG and IgM antibodies above and below the disulfide bonds that join the heavy chains and that is found between the light chain and heavy chain. This generates two monovalent Fab segments, that each have a single antibody binding sites, and an intact Fc fragment.<ref name="Worthington" /> 

==Fun Trivia==

Remember the 2002 SARS (Severe Acute Respiratory Syndrome) epidemic that placed global health, particularly in Southeast Asia, in a precarious state? On-going research is happening to further understand the mechanisms of this coronavirus, so that future steps can be taken for prevention. Its been found that the replication of RNA for this virus is mediated by two viral proteases that have many papain-like characteristics. <ref>PMID: 16306590 </ref>  

Despite a low percentage of sequence identities, inhibition and sequence analyses have increasingly been drawing parallels between L proteinases, that involve the foot-and-mouth disease virus and equine rhinovirus 1, and papain. With a similar overall fold to papain and identifiable regions that resemble papain's five alpha-helices and seven beta-sheets, L proteinases of foot-and-mouth disease virus and of equine rhinovirus 1 reveal a mode of operation that is very papain-like.<ref>PMID: 9472614 </ref>  

==References== 

<references />
<ref group="xtra">PMID:8140097</ref>

==3D Structures of Papain==

[[3lfy]], [[1khp]], [[1khq]], [[1cvz]], [[1bqi]], [[1bp4]], [[1ppn]], [[1ppp]], [[1pip]], [[1pop]], [[1pe6]], [[9pap]], [[1ppd]], [[1pad]], [[2pad]], [[4pad]], [[5pad]], [[6pad]]- ''Carica papaya''

[[3ima]] - ''Colocasia esculenta''

[[1stf]] - ''Homo sapiens''

[[2cio]] - ''Trypanosoma brucei''

[[3e1z]] - ''Trypanosoma cruzi''






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