Papain: Difference between revisions
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==='''Cathepsin K'''=== | ==='''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>, [[ | 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'''=== | ==='''Cathepsin L'''=== | ||
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<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. | <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>.<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> | 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'''=== | ==='''Stefin B'''=== | ||
<scene name='Papain/Stefin_b/4'>Stefin B</scene> 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. | <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. | 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. | ||
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==3D Structures of Papain== | ==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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