Editing Pepsin (section)

== Inhibitors ==

Pepsin may be inhibited by high pH (see [[#Activity_and_stability|Activity and stability]]) or by inhibitor compounds. [[Pepstatin]] is a low molecular weight compound and potently inhibitor specific for acid proteases with an inhibitory dissociation constant (Ki) of about 10<sup>−10</sup> M for pepsin. The statyl residue of pepstatin is thought to be responsible for pepstatin inhibition of pepsin; [[statine]] is a potential analog of the [[transition state]] for catalysis by pepsin and other acid proteases. Pepstatin does not covalently bind pepsin and inhibition of pepsin by pepstatin is therefore reversible.<ref name="pmid339690">{{cite book | vauthors = Marciniszyn J, Hartsuck JA, Tang J | title = Acid Proteases: Structure, Function, and Biology | chapter = Pepstatin Inhibition Mechanism | series = Advances in Experimental Medicine and Biology | volume = 95 | pages = 199–210 | year = 1977 | pmid = 339690 | doi = 10.1007/978-1-4757-0719-9_12 | isbn = 978-1-4757-0721-2 }}</ref> 1-bis(diazoacetyl)-2-phenylethane reversibly inactivates pepsin at pH 5, a reaction which is accelerated by the presence of Cu(II).<ref name="pmid4941985">{{cite journal | vauthors = Husain SS, Ferguson JB, Fruton JS | title = Bifunctional inhibitors of pepsin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 68 | issue = 11 | pages = 2765–8 | date = November 1971 | pmid = 4941985 | pmc = 389520 | doi = 10.1073/pnas.68.11.2765 | bibcode = 1971PNAS...68.2765H | doi-access = free }}</ref>

Porcine pepsin is inhibited by pepsin inhibitor-3 (PI-3) produced by the large roundworm of pig (''[[Ascaris suum]]'').<ref name="Ng_2000">{{cite journal | vauthors = Ng KK, Petersen JF, Cherney MM, Garen C, Zalatoris JJ, Rao-Naik C, Dunn BM, Martzen MR, Peanasky RJ, James MN | title = Structural basis for the inhibition of porcine pepsin by Ascaris pepsin inhibitor-3 | journal = Nature Structural Biology | volume = 7 | issue = 8 | pages = 653–7 | date = August 2000 | pmid = 10932249 | doi = 10.1038/77950 | s2cid = 39440342 }}</ref> PI-3 occupies the active site of pepsin using its N-terminal residues and thereby blocks [[Substrate (chemistry)|substrate]] binding. Amino acid residues 1 - 3 (Gln-Phe-Leu) of mature PI-3 bind to P1' - P3' positions of pepsin. The N-terminus of PI-3 in the PI-3:pepsin complex is positioned by [[hydrogen bond]]s which form an eight-stranded [[Beta sheet|β-sheet]], where three strands are contributed by pepsin and five by PI-3.<ref name="Ng_2000" />

A product of protein digestion by pepsin inhibits the reaction.<ref name="Northrop_1932">{{cite journal|vauthors=Northrop HJ|year=1932|title=The story of the isolation of crystalline pepsin and trypsin|journal=[[The Scientific Monthly]]|volume=35|issue=4|pages=333–340|bibcode=1932SciMo..35..333N}}</ref><ref name="pmid4897199">{{cite journal | vauthors = Greenwell P, Knowles JR, Sharp H | title = The inhibition of pepsin-catalysed reactions by products and product analogues. Kinetic evidence for ordered release of products | journal = The Biochemical Journal | volume = 113 | issue = 2 | pages = 363–8 | date = June 1969 | pmid = 4897199 | pmc = 1184643 | doi = 10.1042/bj1130363 }}</ref>

[[Sucralfate]], a drug used to treat stomach ulcers and other pepsin-related conditions, also inhibits pepsin activity.<ref>{{cite journal | vauthors = Samloff IM, O'Dell C | title = Inhibition of peptic activity by sucralfate | journal = The American Journal of Medicine | volume = 79 | issue = 2C | pages = 15–8 | date = August 1985 | pmid = 3929601 | doi = 10.1016/0002-9343(85)90566-2 }}</ref>