Home LiteratureArticle Details
PMID: 4586863 Published · ppublish English Journal Article

Inhibition of cathepsin D-type proteinase of macrophages by pepstatin, a specific pepsin inhibitor, and other substances.

Infection and immunity ·Vol. 7 ·No. 4 ·1973-04-00 ·Pages 655-65

McAdoo MH, Dannenberg AM, Hayes CJ, James SP, Sanner JH

Abstract

The macrophage is the main cell participating in chronic inflammation. It contains an acid-acting, cathepsin D-type proteinase with the specificity of pepsin, which may release mediators of the inflammatory process. To find new pharmaceutical inhibitors of this proteinase, we tested a variety of chemical compounds in vitro. For this survey, the possible inhibitor (at a concentration of 0.4 mg/ml) was assayed with partially purified cathepsin D-type proteinase from beef lung (a macrophage-rich tissue) and hemoglobin as the substrate. Diazophenylbutanone, three acetophenones, two barbiturates, a gold salt, a copper chelate of a substituted nicotinic acid, a hexapeptide containing a d-amino acid, and Pepstatin inhibited this enzyme; over 200 other potential inhibitors did not. By far the most active and specific inhibitor found to date is Pepstatin, a pentapeptide with two gamma-NH linkages, two beta-OH groups, and five branched aliphatic side chains. Banyu Pharmaceutical Co., Tokyo, Japan, produces this nontoxic compound for the treatment of peptic ulcers. In vitro, as little as 4 ng of Pepstatin inhibits the acid-acting cathepsin D-type proteinase purified from beef and rabbit lung as well as the similar proteinase of rabbit peritoneal and pulmonary macrophages.

MeSH Terms
Acetophenones/pharmacology Animals Ascitic Fluid/cytology Barbiturates/pharmacology Butanones/pharmacology Cathepsins/antagonists & inhibitors Cattle Chelating Agents Copper/pharmacology Gold/pharmacology Hemoglobins Hydrochloric Acid Hydrogen-Ion Concentration Inflammation/drug therapy Lung/cytology,enzymology Macrophages/enzymology Pepsin A/antagonists & inhibitors Peptides/pharmacology Rabbits Urea
Chemicals
Acetophenones Barbiturates Butanones Chelating Agents Hemoglobins Peptides Gold Copper Urea Cathepsins Pepsin A Hydrochloric Acid
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
McAdoo M H
Dannenberg A M
Hayes C J
James S P
Sanner J H
References (60)
60 references, click to expand
  1. A specific antiserum to lysosomal cathepsin D.
    Immunology. 1969 Sep;17(3):421-8 PMID: 4981915
  2. The nature of the binding of inhibitors to pepsin and the kinetics of inhibited peptic hydrolysis of N-acetyl-L-phenylalanyl-L-tyrosine.
    J Biol Chem. 1968 May 25;243(10):2821-8 PMID: 4870743
  3. The side-chain specificity of pepsin.
    Biochemistry. 1969 Oct;8(10):4183-90 PMID: 4899585
  4. Pepsincatalysed transpeptidation of the amino-transfer type.
    Biochem J. 1959 Sep;73:33-41 PMID: 14426702
  5. Inhibition of the renin-angiotensinogen reaction by pepstatin.
    Science. 1972 Feb 11;175(4022):656 PMID: 4109853
  6. On the reaction of diazoacetyl compounds with pepsin.
    J Biol Chem. 1969 Jan 10;244(1):154-60 PMID: 4886428
  7. The inhibition of pepsin-catalysed reactions by products and product analogues. Kinetic evidence for ordered release of products.
    Biochem J. 1969 Jun;113(2):363-8 PMID: 4897199
  8. Comparative studies on the effect of specific inactivators on human gastricsin and pepsin.
    Biochemistry. 1970 Jul 7;9(14):2897-902 PMID: 4918124
  9. Mechanism of inhibition of pepsin by pepstatin.
    J Antibiot (Tokyo). 1972 Apr;25(4):251-5 PMID: 4559274
  10. Macrophage Function in Infectious Disease with Inbred Rabbits.
    Bacteriol Rev. 1965 Dec;29(4):466-76 PMID: 16350185
  11. Action of pepsin on cationic synthetic substrates.
    Biochemistry. 1969 Feb;8(2):575-85 PMID: 4893576
  12. HYDROLYTIC ENZYMES OF RABBIT MONONUCLEAR EXUDATE CELLS. I. QUANTITATIVE ASSAY AND PROPERTIES OF CERTAIN PROTEASES, NON-SPECIFIC ESTERASES, AND LIPASES OF MONONUCLEAR AND POLYMORPHONUCLEAR CELLS AND ERYTHROCYTES.
    J Cell Biol. 1964 Apr;21:1-13 PMID: 14154492
  13. Lysosomal acid proteinase of rabbit liver.
    Biochem J. 1967 Aug;104(2):601-8 PMID: 6058110
  14. Coloured inhibitors of pepsin.
    Biochim Biophys Acta. 1968 Mar 25;151(3):719-21 PMID: 4868993
  15. A chemotactic factor for mononuclear leukocytes.
    Proc Soc Exp Biol Med. 1971 Nov;138(2):387-90 PMID: 5118450
  16. Reversible inhibition of pepsin by polylysine.
    Nature. 1954 May 22;173(4412):998-9 PMID: 13165702
  17. Bifunctional inhibitors of pepsin.
    Proc Natl Acad Sci U S A. 1971 Nov;68(11):2765-8 PMID: 4941985
  18. The specificity and mechanism of pepsin action.
    Adv Enzymol Relat Areas Mol Biol. 1970;33:401-43 PMID: 4916858
  19. Effect of protease inhibitors of actinomycetes on lysosomal peptide-hydrolases from swine liver.
    J Antibiot (Tokyo). 1971 Jul;24(7):488-90 PMID: 5562046
  20. The inhibition of pepsin action.
    Biochemistry. 1968 May;7(5):1611-5 PMID: 4870331
  21. The isolation and properties of a proteolytic enzyme, cathepsin D, from bovine spleen.
    Biochem J. 1960 Mar;74:501-14 PMID: 14434765
  22. Stereochemical investigation of the active center of pepsin using a new inactivator.
    Biochem Biophys Res Commun. 1967 Jul 21;28(2):203-8 PMID: 5340731
  23. The immunocytochemical demonstration of cathepsin D.
    J Histochem Cytochem. 1972 Apr;20(4):261-5 PMID: 4113294
  24. Pepstatin, a new pepsin inhibitor produced by Actinomycetes.
    J Antibiot (Tokyo). 1970 May;23(5):259-62 PMID: 4912600
  25. A neutrophil chemotactic factor from human C'5.
    J Immunol. 1969 Jan;102(1):93-9 PMID: 5765461
  26. Proteolytic enzymes of lung.
    J Biol Chem. 1955 Jul;215(1):45-54 PMID: 14392142
  27. The inactivation of pepsin by diazoacetylnorleucine methyl ester.
    J Biol Chem. 1966 Sep 25;241(18):4295-7 PMID: 5332481
  28. The inhibition of tissue acid proteinases by pepstatin.
    Biochem J. 1972 Apr;127(2):439-41 PMID: 4561921
  29. Antipain, a new protease inhibitor isolated from actinomycetes.
    J Antibiot (Tokyo). 1972 Apr;25(4):263-6 PMID: 4559651
  30. Pepstatin inhibits the digestion of hemoglobin and protein-polysaccharide complex by cathepsin D.
    Biochem Biophys Res Commun. 1972 May 26;47(4):965-70 PMID: 4260317
  31. Specific inactivation of pepsin by benzyloxycarbonyl-L-phenylalanyldiazomethane.
    Nature. 1967 Sep 30;215(5109):1492-4 PMID: 4861199
  32. Pepsinogen and pepsin.
    J Gen Physiol. 1962 Mar;45(4)Pt 2:57-76 PMID: 13906833
  33. A reactive aspartyl residue of pepsin.
    Biochem Biophys Res Commun. 1968 Mar 12;30(5):489-95 PMID: 4870410
  34. Effect of pepsin inhibitor from Ascaris lumbricoides on cathepsin D and E.
    Biochim Biophys Acta. 1972 Oct 12;284(2):461-4 PMID: 4564458
  35. Specific inactivation of pepsin by a diazo ketone.
    Proc Natl Acad Sci U S A. 1966 Dec;56(6):1817-22 PMID: 16591425
  36. Macrophage proteinase and inflammation: the production of chemotactic activity from the fifth complement by macrophage proteinase.
    J Immunol. 1972 Oct;109(4):896-8 PMID: 5074336
  37. On the mechanism of action of pepsin.
    Philos Trans R Soc Lond B Biol Sci. 1970 Feb 12;257(813):135-46 PMID: 4399041
  38. Inhibition by pepstatin of human cartilage degradation.
    Biochem J. 1972 Apr;127(2):443-4 PMID: 4263191
  39. The inactivation of pepsin by an equimolar amount of 1-diazo-4-phenylbutanone-2.
    Biochem Biophys Res Commun. 1967 Jan 23;26(2):193-8 PMID: 5339943
  40. Retinol inhibition of some proteolytic enzymes.
    Lipids. 1968 May;3(3):221-4 PMID: 17805859
  41. The pH-dependence of the binding of competitive inhibitors to pepsin.
    Biochem J. 1969 Jun;113(2):343-51 PMID: 4897197
  42. An aspartic acid residue at the active site of pepsin. The isolation and sequence of the heptapeptide.
    Biochem J. 1969 Jun;113(2):377-86 PMID: 4897201
  43. Evidence for an active carboxyl group in pepsin.
    J Biol Chem. 1966 Aug 10;241(15):3638-9 PMID: 5331581
  44. Studies on pulmonary alveolar macrophages from the normal rabbit: a technique to procure them in a high state of purity.
    J Immunol. 1961 Feb;86:128-32 PMID: 13727273
  45. Chemotactic and anaphylatoxic fragment cleaved from the fifth component of guinea pig complement.
    Science. 1968 Oct 18;162(3851):361-3 PMID: 4175690
  46. Inactivation of pepsin by diphenyldiazomethane.
    Proc Natl Acad Sci U S A. 1965 Oct;54(4):1161-7 PMID: 5327254
  47. Identification of the carboxyl group of pepsin reacting with diazoacetamide derivatives.
    Biochem Biophys Res Commun. 1968 Jun 10;31(5):825-30 PMID: 4874970
  48. Studies on the specificity of pepsin.
    Biochemistry. 1967 Jun;6(6):1765-77 PMID: 5340947
  49. Purification and properties of cathepsin D from bovine utrus.
    J Biol Chem. 1971 Apr 10;246(7):1951-60 PMID: 5549596
  50. Renin inhibition by pepstatin.
    Biochem Pharmacol. 1972 Nov 1;21(21):2941-4 PMID: 4567022
  51. SPECIFICITY OF PEPSIN AND ITS DEPENDENCE ON A POSSIBLE 'HYDROPHOBICBINDING SITE'.
    Nature. 1963 Sep 14;199:1094-5 PMID: 14066947
  52. Effect of steric factors on digestibility of peptides containing aromatic amino acids by cathepsin D and pepsin.
    Eur J Biochem. 1968 May;4(4):442-7 PMID: 4873246
  53. Pepsinogen and pepsin: conformational relations, studied by iodination, immunochemical precipitation, and the influence of pepain inhibitor.
    Biochemistry. 1963 Mar-Apr;2:238-46 PMID: 13991805
  54. Structural changes associated with the conversion of pepsinogen to pepsin. I. The N-terminal amino acid residue and amino acid composition of the pepsin inhibitor.
    Biochim Biophys Acta. 1956 Dec;22(3):537-43 PMID: 13382883
  55. The structure of pepstatin.
    J Antibiot (Tokyo). 1970 May;23(5):263-5 PMID: 4912601
  56. Effect of pepstatin on acid proteases.
    J Antibiot (Tokyo). 1971 Oct;24(10):687-94 PMID: 4945810
  57. Action of proteinase I of bovine lung; hydrolysis of the oxidized B chain of insulin; polymer formation from amino acid esters.
    J Biol Chem. 1955 Jul;215(1):55-66 PMID: 14392143
  58. Cathepsin D. Characteristics of immunoinhibition and the confirmation of a role in cartilage breakdown.
    Biochem J. 1971 Jun;123(1):1-13 PMID: 4256870
  59. [Pepsin and pepsinogen. Origin, properties, preparation].
    Pathol Biol (Paris). 1970 Mar;18(5):317-42 PMID: 4911318
  60. A histochemical study of phagocytic and enzymatic functions of rabbit mononuclear and polymorphonuclear exudate cells and alveolar macrophages. I. Survey and quantitation of enzymes, and states of cellular activation.
    J Cell Biol. 1963 Jun;17:465-86 PMID: 14024972
Article Info
Journal
Infection and immunity
Abbr.
Infect Immun
ISSN
0019-9567
DOI
10.1128/iai.7.4.655-665.1973
Published
1973-04-00
Pages
655-65
Language
English
Region
United States
NLM ID
0246127
PMCID
PMC422739
Subset
IM
External Links
PubMed source DOI: 10.1128/iai.7.4.655-665.1973 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2