Evidence map›Paper›PMID 35472493›Full record

SynthesisBiochimica et biophysica acta. General subjects2022

Esomeprazole covalently interacts with the cardiovascular enzyme dimethylarginine dimethylaminohydrolase: Insights into the cardiovascular risk of proton pump inhibitors.

Clyde A Smith, Afshin Ebrahimpour, Lyudmila Novikova, Dominic Farina, Aaron O Bailey, William K Russell, Antrix Jain, Alexander B Saltzman, Anna Malovannaya, B V Venkataram Prasad and 2 more

Abstract readMeta-Analysis
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in Biochimica et biophysica acta. General subjects, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
1.4field-weighted citation impact, top 22% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed, 9 citations in OpenAlex.

  1. Article
  2. Review
  3. Article
  4. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 5 institutions in 1 country.

Clyde A SmithStanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Stanford University, Menlo Park, CA 94025, USA; Department of Chemistry, Stanford University, Stanford, CA 94305, USA. Electronic address: csmith@slac.stanford.edu.
Afshin EbrahimpourDepartment of Radiation Oncology, Baylor College of Medicine, Houston, TX 77030, USA.
Lyudmila NovikovaStanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Stanford University, Menlo Park, CA 94025, USA.
Dominic FarinaStanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Stanford University, Menlo Park, CA 94025, USA.
Aaron O BaileyDepartment of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
William K RussellDepartment of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Antrix JainMass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, TX 77030, USA.
Alexander B SaltzmanMass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, TX 77030, USA.
Anna MalovannayaMass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, TX 77030, USA.
B V Venkataram PrasadVerna and Marrs Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Liya HuVerna and Marrs Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Yohannes T GhebreDepartment of Radiation Oncology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Section on Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: yohannes.ghebre@bcm.edu.
Baylor College of Medicine · USThe University of Texas Medical Branch at Galveston · USSLAC National Accelerator Laboratory · USStanford Synchrotron Radiation Lightsource · USStanford University · US

Funding

Tumor BiologyP30CA125123 · NCI · BAYLOR COLLEGE OF MEDICINE · PI Michael M Ittmann · 2007 to 2026
$73.9M
A Synchrotron Radiation Structural Biology ResourcesP30GM133894 · NIGMS · STANFORD UNIVERSITY · PI Ritimukta Sarangi · 2020 to 2026
$43.3M
ZWITTERION SURFACTANT DDMAB FOR IMPROV STABIL OF PROTEINP41RR001209 · NCRR · STANFORD UNIVERSITY · PI SCOTT, EMILY E · 1985 to 2011
$38.9M
Preclinical and Clincial OutcomesP50HD103555 · NICHD · BAYLOR COLLEGE OF MEDICINE · PI Sandesh Chakravarthy Sreenath Nagamani, David Loren Nelson · 2020 to 2026
$9.9M
RESEARCH TRAINING IN LUNG DISEASET32HL007747 · NHLBI · BAYLOR COLLEGE OF MEDICINE · PI ROSAS, IVAN O. · 1993 to 2020
$5.1M
Combination of PPI and pirfenidone to enhance antifibrotic efficacyR01HL137703 · NHLBI · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI GHEBRE, YOHANNES T · 2017 to 2021
$2.0M
DDAH As a Novel Target in Pulmonary FibrosisK01HL118683 · NHLBI · METHODIST HOSPITAL RESEARCH INSTITUTE · PI GHEBRE, YOHANNES T · 2013 to 2017
$682k
Repurposing esomeprazole for the treatment of sclerodermaR56AR077445 · NIAMS · BAYLOR COLLEGE OF MEDICINE · PI GHEBRE, YOHANNES T · 2020 to 2020
$352k
NCI NIH HHS P30 CA125123NCRR NIH HHS P41 RR001209NHLBI NIH HHS K01 HL118683NHLBI NIH HHS R01 HL137703NHLBI NIH HHS T32 HL007747NIAMS NIH HHS R56 AR077445NICHD NIH HHS P50 HD103555NIGMS NIH HHS P30 GM133894
6 · The paper itself

Abstract

backgroundProton 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).

methodsWe 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.

resultsAnalysis 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.

conclusionsThe 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.

Indexed as

Cardiovascular DiseasesEsomeprazoleAmidohydrolasesCysteineHeart Disease Risk FactorsHumansMolecular Docking SimulationProton Pump InhibitorsRisk FactorsAmidohydrolasesCysteinedimethylargininaseEsomeprazoleProton Pump InhibitorsCardiovascular enzymeDDAHEsomeprazoleMass spectrometryProton pump inhibitorsX-ray crystallography

Identifiers

PMID35472493
PMCPMC12554391
OpenAlexW4224318582

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.