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Lansoprazole Inhibits The Cysteine Protease Legumain By Binding To The Active Site

Tatjana Bosnjak, R. Solberg, Paya Diana Hemati, A. Jafari, M. Kassem, H. T. Johansen
Published 2019 · Medicine

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Proton pump inhibitors (PPIs) are prodrugs used in the treatment of peptic ulcer diseases. Once activated by acidic pH, the PPIs subsequently inhibit the secretion of gastric acid by covalently forming disulphide bonds with the SH groups of the parietal proton pump, that is the H+/K+‐ATPase. Long‐term use of PPIs has been associated with numerous adverse effects, including bone fractures. Considering the mechanism of activation, PPIs could also be active in acidic micro‐environments such as in lysosomes, tumours and bone resorption sites. We suggested that the SH group in the active site of cysteine proteases could be susceptible for inhibition by PPIs. In this study, the inhibition by lansoprazole was shown on the cysteine proteases legumain and cathepsin B by incubating purified proteases or cell lysates with lansoprazole at different concentrations and pH conditions. The mechanism of legumain inhibition was shown to be a direct interaction of lansoprazole with the SH group in the active site, and thus blocking binding of the legumain‐selective activity‐based probe MP‐L01. Lansoprazole was also shown to inhibit both legumain and cathepsin B in various cell models like HEK293, monoclonal legumain over‐expressing HEK293 cells (M38L) and RAW264.7 macrophages, but not in human bone marrow‐derived skeletal (mesenchymal) stem cells (hBMSC‐TERT). During hBMSC‐TERT differentiation to osteoblasts, lansoprazole inhibited legumain secretion, alkaline phosphatase activity, but had no effects on in vitro mineralization capacity. In conclusion, lansoprazole acts as a direct covalent inhibitor of cysteine proteases via disulphide bonds with the SH group in the protease active site. Such inhibition of cysteine proteases could explain some of the off‐target effects of PPIs.
This paper references
10.1007/978-1-4615-5833-0_6
Lysosomal metabolism of proteins.
R. Mason (1996)
10.1007/s12032-013-0621-9
Effects of legumain as a potential prognostic factor on gastric cancers
N. Li (2013)
10.1016/0005-2736(91)90238-4
Omeprazole and bafilomycin, two proton pump inhibitors: differentiation of their effects on gastric, kidney and bone H(+)-translocating ATPases.
J. P. Mattsson (1991)
10.3891/acta.chem.scand.43-0587
Chemical Reactions of Omeprazole and Omeprazole Analogues. V. The Reaction of N-Alkylated Derivatives of Omeprazole Analogues with 2-Mercaptoethanol.
Arne Elof Braendstroem (1989)
Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy.
C. Liu (2003)
10.1006/ABIO.1999.4221
Colorimetric and fluorimetric microplate assays for legumain and a staining reaction for detection of the enzyme after electrophoresis.
H. T. Johansen (1999)
10.5056/jnm.2013.19.1.25
Pharmacokinetics and Pharmacodynamics of the Proton Pump Inhibitors
J. Shin (2013)
prostate cancer invasiveness and aggressiveness
Al Bosnjak (2013)
10.1007/s10549-006-9311-z
Legumain expression as a prognostic factor in breast cancer patients
Jessica Gawenda (2006)
FDA Drug Safety Communication: Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors
BOSNJAK (2010)
10.1007/s00198-015-3365-x
Proton-pump inhibitors and risk of fractures: an update meta-analysis
B. Zhou (2015)
Association of legumain expression pattern with | 99 BOSNJAK et Al. prostate cancer invasiveness and aggressiveness
Y Ohno (2013)
10.1021/acs.jmedchem.7b00228
Blockade of Asparagine Endopeptidase Inhibits Cancer Metastasis.
Q. Qi (2017)
Association of legumain expression pattern with | 99
Y Ohno
10.1074/MCP.M111.012138
Temporal Profiling and Pulsed SILAC Labeling Identify Novel Secreted Proteins During Ex Vivo Osteoblast Differentiation of Human Stromal Stem Cells*
L. P. Kristensen (2012)
10.1016/j.bbrc.2013.11.055
Validation of a simple and fast method to quantify in vitro mineralization with fluorescent probes used in molecular imaging of bone.
Martiene J.C. Moester (2014)
10.1359/JBMR.2001.16.10.1804
Osteoclast inhibitory peptide 2 inhibits osteoclast formation via its C-terminal fragment.
S. Choi (2001)
10.1007/s00535-013-0774-5
Inhibition of lysosomal enzyme activities by proton pump inhibitors
Wensheng Liu (2013)
10.1016/j.biochi.2012.11.002
Autoactivation of prolegumain is accelerated by glycosaminoglycans.
L. Berven (2013)
10.1074/jbc.M705761200
Glycosaminoglycans Facilitate Procathepsin B Activation through Disruption of Propeptide-Mature Enzyme Interactions*
Dejan Caglič (2007)
10.1161/01.ATV.0000229695.68416.76
Novel Candidate Genes in Unstable Areas of Human Atherosclerotic Plaques
M. Papaspyridonos (2006)
10.5009/gnl15502
25 Years of Proton Pump Inhibitors: A Comprehensive Review
Daniel S. Strand (2017)
10.1186/1756-9966-29-44
Proton pump inhibitors as anti vacuolar-ATPases drugs: a novel anticancer strategy
E. P. Spugnini (2010)
10.1074/JBC.274.39.27747
Identification of Human Asparaginyl Endopeptidase (Legumain) as an Inhibitor of Osteoclast Formation and Bone Resorption*
S. Choi (1999)
Chapter 6 : Lysosomal metabolism of proteins
E Dall (1996)
10.1515/BC.2001.093
Activation of Progelatinase A by Mammalian Legumain, a Recently Discovered Cysteine Proteinase
J. M. Chen (2001)
10.1016/j.biochi.2015.09.022
Structure and function of legumain in health and disease.
E. Dall (2016)
10.1111/cas.12202
Selective ablation of tumor‐associated macrophages suppresses metastasis and angiogenesis
Y. Lin (2013)
The absorption of calcium carbon
LP Kristensen (1967)
10.1080/14728222.2016.1182990
Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases
Zhentao Zhang (2016)
10.1111/jgh.13737
Proton pump inhibitors: Risks of long‐term use
L. Eusebi (2017)
10.1002/stem.2955
TAFA2 Induces Skeletal (Stromal) Stem Cell Migration Through Activation of Rac1‐p38 Signaling
A. Jafari (2019)
10.1016/j.atherosclerosis.2016.11.026
Increased levels of legumain in plasma and plaques from patients with carotid atherosclerosis.
Ngoc Nguyen Lunde (2017)
10.1016/0003-2697(76)90527-3
A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.
M. M. Bradford (1976)
10.1161/CIRCRESAHA.116.308807
Proton Pump Inhibitors Accelerate Endothelial Senescence.
Gautham Yepuri (2016)
10.1038/nrd1010
A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole
L. Olbe (2003)
10.1136/archdischild-2017-314026
Toxicity of long-term use of proton pump inhibitors in children
Pauline De Bruyne (2017)
Chemical‐reactions of omeprazole and omeprazole analogs
A Brandstrom (1989)
10.1016/0167-4889(85)90054-0
Reversal of antisecretory activity of omeprazole by sulfhydryl compounds in isolated rabbit gastric glands.
W. B. Im (1985)
10.1111/bcpt.13059
Basic & Clinical Pharmacology & Toxicology Policy for Experimental and Clinical studies.
P. Tveden-Nyborg (2018)
10.1016/j.ebiom.2015.11.024
Lansoprazole Upregulates Polyubiquitination of the TNF Receptor-Associated Factor 6 and Facilitates Runx2-mediated Osteoblastogenesis
K. Mishima (2015)
10.1089/scd.2010.0093
Human mesenchymal stem cells efficiently manage oxidative stress.
A. Valle-Prieto (2010)
10.1007/s00223-006-0021-7
Proton Pump Inhibitors, Histamine H2 Receptor Antagonists, and Other Antacid Medications and the Risk of Fracture
P. Vestergaard (2006)
10.1152/ajprenal.1994.266.6.F868
H(+)-ATPases of renal cortical and medullary endosomes are differentially sensitive to Sch-28080 and omeprazole.
I. Sabolic (1994)
10.1111/febs.12478
Dose‐dependent inhibitory effects of proton pump inhibitors on human osteoclastic and osteoblastic cell activity
J. Costa-Rodrigues (2013)
10.1007/s00280-017-3426-2
Repositioning of proton pump inhibitors in cancer therapy
Zhen-Ning Lu (2017)
10.1038/nbt0602-592
Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells
J. L. Simonsen (2002)
10.1074/jbc.RA118.002154
Structural and functional analysis of cystatin E reveals enzymologically relevant dimer and amyloid fibril states
E. Dall (2018)
10.1016/j.stemcr.2017.01.003
Legumain Regulates Differentiation Fate of Human Bone Marrow Stromal Cells and Is Altered in Postmenopausal Osteoporosis
A. Jafari (2017)
10.1016/S0167-4838(02)00209-1
Legumain from bovine kidney: its purification, molecular cloning, immunohistochemical localization and degradation of annexin II and vitamin D-binding protein.
T. Yamane (2002)
10.1016/j.chembiol.2016.05.020
Counter Selection Substrate Library Strategy for Developing Specific Protease Substrates and Probes.
M. Poręba (2016)
10.1111/bcpt.13023
Side Effects of Long‐Term Proton Pump Inhibitor Use: A Review
P. Haastrup (2018)
10.1046/J.1365-2125.1998.T01-1-00702.X
Pharmacokinetics and effect on caffeine metabolism of the proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole.
T. Andersson (1998)
10.1002/stem.2013
Pharmacological Inhibition of Protein Kinase G1 Enhances Bone Formation by Human Skeletal Stem Cells Through Activation of RhoA-Akt Signaling.
A. Jafari (2015)
10.1371/journal.pone.0052980
Nuclear Legumain Activity in Colorectal Cancer
M. H. Haugen (2013)
10.1001/JAMA.296.24.2947
Long-term proton pump inhibitor therapy and risk of hip fracture.
Yu-Xiao Yang (2006)
10.1007/s00345-012-0977-z
Association of legumain expression pattern with prostate cancer invasiveness and aggressiveness
Y. Ohno (2012)
10.1016/0006-2952(91)90719-L
Inhibitions of acid secretion by E3810 and omeprazole, and their reversal by glutathione.
H. Fujisaki (1991)
10.1007/BF01352010
Effect of omeprazole, an inhibitor of H+, K+-ATPase, on bone resorption in humans
K. Mizunashi (2005)
10.1016/j.biochi.2012.07.026
Intra- and extracellular regulation of activity and processing of legumain by cystatin E/M.
R. Smith (2012)
10.7326/0003-4819-66-5-917
The absorption of calcium carbonate.
P. Ivanovich (1967)
10.1074/JBC.M302742200
Biosynthetic Processing of Cathepsins and Lysosomal Degradation Are Abolished in Asparaginyl Endopeptidase-deficient Mice*
Kanae Shirahama-Noda (2003)
10.1146/annurev-physiol-021014-071649
Lysosomal physiology.
Haoxing Xu (2015)



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