TY - JOUR
T1 - Esomeprazole covalently interacts with the cardiovascular enzyme dimethylarginine dimethylaminohydrolase
T2 - Insights into the cardiovascular risk of proton pump inhibitors
AU - Smith, Clyde A.
AU - Ebrahimpour, Afshin
AU - Novikova, Lyudmila
AU - Farina, Dominic
AU - Bailey, Aaron O.
AU - Russell, William K.
AU - Jain, Antrix
AU - Saltzman, Alexander B.
AU - Malovannaya, Anna
AU - Prasad, B. V.Venkataram
AU - Hu, Liya
AU - Ghebre, Yohannes T.
N1 - Publisher Copyright:
© 2022
PY - 2022/8
Y1 - 2022/8
N2 - Background: Proton pump inhibitors (PPIs) are widely prescribed drugs for the treatment of gastroesophageal reflux disease (GERD). Several meta-analysis studies have reported associations between prolonged use of PPIs and major adverse cardiovascular events. However, interaction of PPIs with biological molecules involved in cardiovascular health is incompletely characterized. Dimethylarginine dimethylaminohydrolase (DDAH) is a cardiovascular enzyme expressed in cardiomyocytes, and other somatic cell types in one of two isotypes (DDAH1 and DDAH2) to metabolize asymmetric dimethylarginine (ADMA); a cardiovascular risk factor and competitive inhibitor of nitric oxide synthases (NOSs). Methods: We performed high throughput drug screening of over 130,000 small molecules to discover human DDAH1 inhibitors and found that PPIs directly inhibit DDAH1. We expressed and purified the enzyme for structural and mass spectrometry proteomics studies to understand how a prototype PPI, esomeprazole, interacts with DDAH1. We also performed molecular docking studies to model the interaction of DDAH1 with esomeprazole. X-ray crystallography was used to determine the structure of DDAH1 alone and bound to esomeprazole at resolutions ranging from 1.6 to 2.9 Å. Results: Analysis of the enzyme active site shows that esomeprazole interacts with the active site cysteine (Cys273) of DDAH1. The structural studies were corroborated by mass spectrometry which indicated that cysteine was targeted by esomeprazole to inactivate DDAH1. Conclusions: The inhibition of this important cardiovascular enzyme by a PPI may help explain the reported association of PPI use and increased cardiovascular risk in patients and the general population. General significance: Our study calls for pharmacovigilance studies to monitor adverse cardiovascular events in chronic PPI users.
AB - Background: Proton pump inhibitors (PPIs) are widely prescribed drugs for the treatment of gastroesophageal reflux disease (GERD). Several meta-analysis studies have reported associations between prolonged use of PPIs and major adverse cardiovascular events. However, interaction of PPIs with biological molecules involved in cardiovascular health is incompletely characterized. Dimethylarginine dimethylaminohydrolase (DDAH) is a cardiovascular enzyme expressed in cardiomyocytes, and other somatic cell types in one of two isotypes (DDAH1 and DDAH2) to metabolize asymmetric dimethylarginine (ADMA); a cardiovascular risk factor and competitive inhibitor of nitric oxide synthases (NOSs). Methods: We performed high throughput drug screening of over 130,000 small molecules to discover human DDAH1 inhibitors and found that PPIs directly inhibit DDAH1. We expressed and purified the enzyme for structural and mass spectrometry proteomics studies to understand how a prototype PPI, esomeprazole, interacts with DDAH1. We also performed molecular docking studies to model the interaction of DDAH1 with esomeprazole. X-ray crystallography was used to determine the structure of DDAH1 alone and bound to esomeprazole at resolutions ranging from 1.6 to 2.9 Å. Results: Analysis of the enzyme active site shows that esomeprazole interacts with the active site cysteine (Cys273) of DDAH1. The structural studies were corroborated by mass spectrometry which indicated that cysteine was targeted by esomeprazole to inactivate DDAH1. Conclusions: The inhibition of this important cardiovascular enzyme by a PPI may help explain the reported association of PPI use and increased cardiovascular risk in patients and the general population. General significance: Our study calls for pharmacovigilance studies to monitor adverse cardiovascular events in chronic PPI users.
KW - Cardiovascular enzyme
KW - DDAH
KW - Esomeprazole
KW - Mass spectrometry
KW - Proton pump inhibitors
KW - X-ray crystallography
UR - http://www.scopus.com/inward/record.url?scp=85129368754&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85129368754&partnerID=8YFLogxK
U2 - 10.1016/j.bbagen.2022.130149
DO - 10.1016/j.bbagen.2022.130149
M3 - Article
C2 - 35472493
AN - SCOPUS:85129368754
SN - 0304-4165
VL - 1866
JO - Biochimica et Biophysica Acta - General Subjects
JF - Biochimica et Biophysica Acta - General Subjects
IS - 8
M1 - 130149
ER -