Editing Pepsin (section)

== Activity and stability ==

Pepsin is most active in acidic environments between pH 1.5 to 2.5.<ref name="Piper_1965">{{cite journal | vauthors = Piper DW, Fenton BH | title = pH stability and activity curves of pepsin with special reference to their clinical importance | journal = Gut | volume = 6 | issue = 5 | pages = 506–8 | date = October 1965 | pmid = 4158734 | pmc = 1552331 | doi = 10.1136/gut.6.5.506 }}</ref><ref name="urlBRENDA - Information on EC 3.4.23.1 - pepsin A">{{cite web|url=http://www.brenda-enzymes.org/enzyme.php?ecno=3.4.23.1#pH%20OPTIMUM|title=Information on EC 3.4.23.1 - pepsin A|work=[[BRENDA]]-enzymes|access-date=14 Dec 2008}}</ref> Accordingly, its primary site of synthesis and activity is in the stomach ([[pH]] 1.5 to 2). In humans the concentration of pepsin in the stomach reaches 0.5 – 1&nbsp;mg/mL.<ref>{{cite journal | vauthors = Zhu H, Hart CA, Sales D, Roberts NB | title = Bacterial killing in gastric juice--effect of pH and pepsin on Escherichia coli and Helicobacter pylori | journal = Journal of Medical Microbiology | volume = 55 | issue = Pt 9 | pages = 1265–1270 | date = September 2006 | pmid = 16914658 | doi = 10.1099/jmm.0.46611-0 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Brodkorb A, Egger L, Alminger M, Alvito P, Assunção R, Ballance S, Bohn T, Bourlieu-Lacanal C, Boutrou R, Carrière F, Clemente A, Corredig M, Dupont D, Dufour C, Edwards C, Golding M, Karakaya S, Kirkhus B, Le Feunteun S, Lesmes U, Macierzanka A, Mackie AR, Martins C, Marze S, McClements DJ, Ménard O, Minekus M, Portmann R, Santos CN, Souchon I, Singh RP, Vegarud GE, Wickham MS, Weitschies W, Recio I | title = INFOGEST static in vitro simulation of gastrointestinal food digestion | journal = Nature Protocols | volume = 14 | issue = 4 | pages = 991–1014 | date = April 2019 | pmid = 30886367 | doi = 10.1038/s41596-018-0119-1 | doi-access = free | hdl = 11019/1671 | hdl-access = free }}</ref>

Pepsin is inactive at pH 6.5 and above, however pepsin is not fully denatured or irreversibly inactivated until pH 8.0.<ref name="Piper_1965" /><ref name="pmid17417109">{{cite journal | vauthors = Johnston N, Dettmar PW, Bishwokarma B, Lively MO, [[Jamie A. Koufman|Koufman JA]]| title = Activity/stability of human pepsin: implications for reflux attributed laryngeal disease | journal = The Laryngoscope | volume = 117 | issue = 6 | pages = 1036–9 | date = June 2007 | pmid = 17417109 | doi = 10.1097/MLG.0b013e31804154c3 | s2cid = 22124366 }}</ref> Therefore, pepsin in solutions of up to pH 8.0 can be reactivated upon re-acidification. The stability of pepsin at high pH has significant implications on disease attributed to [[laryngopharyngeal reflux]]. Pepsin remains in the larynx following a gastric reflux event.<ref name="pmid15564833">{{cite journal | vauthors = Johnston N, Knight J, Dettmar PW, Lively MO, Koufman J | title = Pepsin and carbonic anhydrase isoenzyme III as diagnostic markers for laryngopharyngeal reflux disease | journal = The Laryngoscope | volume = 114 | issue = 12 | pages = 2129–34 | date = December 2004 | pmid = 15564833 | doi = 10.1097/01.mlg.0000149445.07146.03 | s2cid = 23773155 }}</ref><ref name="pmid16466100">{{cite journal | vauthors = Johnston N, Dettmar PW, Lively MO, Postma GN, Belafsky PC, Birchall M, Koufman JA | title = Effect of pepsin on laryngeal stress protein (Sep70, Sep53, and Hsp70) response: role in laryngopharyngeal reflux disease | journal = The Annals of Otology, Rhinology, and Laryngology | volume = 115 | issue = 1 | pages = 47–58 | date = January 2006 | pmid = 16466100 | doi = 10.1177/000348940611500108 | s2cid = 29939465 }}</ref> At the mean pH of the laryngopharynx (pH = 6.8) pepsin would be inactive  but could be reactivated upon subsequent acid reflux events resulting in damage to local tissues.

Pepsin exhibits a broad cleavage specificity. Pepsin will digest up to 20% of ingested amide bonds.<ref name="Lehninger_5th_ed">{{cite book|last1=Cox|first1=Michael|url=https://archive.org/details/lehningerprincip00lehn_1|title=Lehninger principles of biochemistry|last2=Nelson|first2=David R.|last3=Lehninger|first3=Albert L |publisher=W.H. Freeman|year=2008|isbn=978-0-7167-7108-1|location=San Francisco|url-access=registration |pages = 96}}</ref> Residues in the P1 and P1' positions<ref>The P1 and P1' positions refer to the amino acid residues immediately next to the bond to be cleaved, on the carboxyl and amino side respectively. See {{cite journal | vauthors = Schechter I, Berger A | title = On the active site of proteases. 3. Mapping the active site of papain; specific peptide inhibitors of papain | journal = Biochemical and Biophysical Research Communications | volume = 32 | issue = 5 | pages = 898–902 | date = September 1968 | pmid = 5682314 | doi = 10.1016/0006-291X(68)90326-4 }}</ref> are most important in determining cleavage probability. Generally, hydrophobic amino acids at P1 and P1' positions increase cleavage probability. [[Phenylalanine]], [[leucine]] and [[methionine]] at the P1 position, and [[phenylalanine]], [[tryptophan]] and [[tyrosine]] at the P1' position result in the highest cleavage probability.<ref name="Hamuro_2008" /><ref name="Lehninger_5th_ed" />{{rp|675}} Cleavage is disfavoured by positively charged [[amino acid]]s [[histidine]], [[lysine]] and [[arginine]] at the P1 position.<ref name="Hamuro_2008" />