Quantifying tetrahedral adduct formation and stabilization in the cysteine and the serine proteases

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dc.contributor.authorCleary, Jennifer A.-
dc.contributor.authorDoherty, William-
dc.contributor.authorEvans, Paul-
dc.contributor.authorMalthouse, J.Paul G.-
dc.date.accessioned2015-08-06T14:57:47Z-
dc.date.available2016-10-01T01:00:11Z-
dc.date.copyright2015 Elsevieren
dc.date.issued2015-10-
dc.identifier.citationBiochimica et Biophysica Acta (BBA) - Proteins and Proteomicsen
dc.identifier.urihttp://hdl.handle.net/10197/6746-
dc.description.abstractTwo new papain inhibitors have been synthesized where the terminal α-carboxyl groups of Z-Phe-Ala-COOH and Ac-Phe-Gly-COOH have been replaced by a proton to give Z-Phe-Ala-H and Ac-Phe-Gly-H. We show that for papain, replacing the terminal carboxylate group of a peptide inhibitor with a hydrogen atom decreases binding 3–4 fold while replacing an aldehyde or glyoxal group with a hydrogen atom decreases binding by 300,000–1,000,000 fold. Thiohemiacetal formation by papain with aldehyde or glyoxal inhibitors is shown to be ~ 10,000 times more effective than hemiacetal or hemiketal formation with chymotrypsin. It is shown using effective molarities, that for papain, thiohemiacetal stabilization is more effective with aldehyde inhibitors than with glyoxal inhibitors. The effective molarity obtained when papain is inhibited by an aldehyde inhibitor is similar to the effective molarity obtained when chymotrypsin is inhibited by glyoxal inhibitors showing that both enzymes can stabilize tetrahedral adducts by similar amounts. Therefore the greater potency of aldehyde and glyoxal inhibitors with papain is not due to greater thiohemiacetal stabilization by papain compared to the hemiketal and hemiacetal stabilization by chymotrypsin, instead it reflects the greater intrinsic reactivity of the catalytic thiol group of papain compared to the catalytic hydroxyl group of chymotrypsin. It is argued that while the hemiacetals and thiohemiacetals formed with the serine and cysteine proteases respectively can mimic the catalytic tetrahedral intermediate they are also analogues of the productive and non-productive acyl intermediates that can be formed with the cysteine and serine proteases.en
dc.description.sponsorshipIrish Research Councilen
dc.description.sponsorshipUniversity College Dublinen
dc.language.isoenen
dc.publisherElsevieren
dc.rightsThis is the author’s version of a work that was accepted for publication in Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics (VOL 1854, ISSUE 10, Part A, (2015)) DOI: 10.1016/j.bbapap.2015.07.006en
dc.subjectAldehyde inhibitoren
dc.subjectGlyoxal inhibitoren
dc.subjectTetrahedral intermediateen
dc.subjectCysteine proteaseen
dc.subjectSerine proteaseen
dc.titleQuantifying tetrahedral adduct formation and stabilization in the cysteine and the serine proteasesen
dc.typeJournal Articleen
dc.internal.authorcontactotherj.paul.g.malthouse@ucd.ie-
dc.statusPeer revieweden
dc.identifier.volume1854en
dc.identifier.issue10, Part Aen
dc.identifier.startpage1382en
dc.identifier.endpage1391en
dc.identifier.doi10.1016/j.bbapap.2015.07.006-
dc.neeo.contributorCleary|Jennifer A.|aut|-
dc.neeo.contributorDoherty|William|aut|-
dc.neeo.contributorEvans|Paul|aut|-
dc.neeo.contributorMalthouse|J.Paul G.|aut|-
dc.internal.rmsid507228701-
dc.date.updated2015-07-22T10:15:24Z-
item.grantfulltextopen-
item.fulltextWith Fulltext-
Appears in Collections:Conway Institute Research Collection
Biomolecular and Biomedical Science Research Collection
CSCB Research Collection
Chemistry Research Collection
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