Papain: Difference between revisions

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<StructureSection load='9pap' size='400' side='left' caption='Click on the links to the right to view different scenes of the inhibition of Papain.' scene='Papain/9pap_bindingpocket_wrtdomains/4' >
<StructureSection load='9pap' size='400' side='left' caption='Click on the links to the right to view different scenes of the inhibition of Papain.' scene='Papain/9pap_bindingpocket_wrtdomains/4' >


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




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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.  
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===
==='''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 11 different residues 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 seven residues 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>  
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 11 different residues 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 seven residues 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'''===


<scene name='Papain/Cathepsin_l/2'>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/1'>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='Sandbox_34/Clik148_inhibitor/2'>Clik-148</scene>.<ref> PMID:10600517 </ref> It forms a <scene name='Sandbox_34/Clik148_inhibit_cys25/1'>covalent ligand-bound cysteine protease complex</scene> with Cys-25. Five other residues 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='Sandbox_34/Clik148ringstacking/2'>aromatic ring-stacking</scene>, and hydrogen bonding 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>.<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 residues 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 hydrogen bonding that effectively fill up the cleft between the two domains of papain.<ref> PMID:18598021 </ref>


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