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Cited by 14Renin-Angiotensin System StudiesPeptidase Inhibition and AnalysisProtease and Inhibitor Mechanisms

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Identification and Characterization of Novel Inhibitors of Mammalian Aspartyl Aminopeptidase

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Chen, Yuanyuan, Tang, Hong, Seibel, William, Papoian, Ruben, Oh, Ki, Li, Xiaoyu, Zhang, Jianye, Golczak, Marcin, Palczewski, Krzysztof, Kiser, Philip D.·2014·Molecular Pharmacology
DOI 10.1124/mol.114.093070PMC PMC4127928
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Abstract

Aspartyl aminopeptidase (DNPEP) has been implicated in the control of angiotensin signaling and endosome trafficking, but its precise biologic roles remain incompletely defined. We performed a high-throughput screen of ∼25,000 small molecules to identify inhibitors of DNPEP for use as tools to study its biologic functions. Twenty-three confirmed hits inhibited DNPEP-catalyzed hydrolysis of angiotensin II with micromolar potency. A counter screen against glutamyl aminopeptidase (ENPEP), an enzyme with substrate specificity similar to that of DNPEP, identified eight DNPEP-selective inhibitors. Structure-activity relationships and modeling studies revealed structural features common to the identified inhibitors, including a metal-chelating group and a charged or polar moiety that could interact with portions of the enzyme active site. The compounds identified in this study should be valuable tools for elucidating DNPEP physiology.

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  • LRAT transfers the acyl chain exclusively from phosphatidylcholine onto vitamin A or closely related retinoid-like substrates.

    “Instead, LRAT transfers the acyl chain exclusively from PC onto vitamin A or closely related retinoid-like substrates [40,43].”

    From Molecular Basis for Vitamin A Uptake and Storage in Vertebrates (2016) · cites this paper as [43]

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Metadata

Authors
Chen, Y., Tang, H., Seibel, W., Papoian, R., Oh, K., Li, X., Zhang, J., Golczak, M., Palczewski, K., & Kiser, P. D.
Affiliations
Case Western Reserve University (US)
ORCID
Venue
Molecular Pharmacology
Publisher
Elsevier BV
Published
2014-08
Volume
86
Issue
2
Pages
231-242
ISSN
0026-895X (ISSN-L)
DOI
10.1124/mol.114.093070
PMC
PMC4127928
OpenAlex
W2106600857
Cited by
14
References
0
Citations by year
2025: 3 · 2024: 1 · 2023: 2 · 2021: 1 · 2020: 1 · 2019: 2 · 2017: 1 · 2016: 1 · 2015: 2
FWCI
0.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Pharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Case Western Reserve University
  • School of Medicine, Case Western Reserve University
  • National Institutes of Health (EY008061)
  • National Eye Institute (EY-008061, R01EY008061)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Peptidase Inhibition and Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords
aspartyl aminopeptidase, enzyme inhibitors, glutamyl aminopeptidase, endosomal trafficking, small molecule screening, structure-activity relationship, active site interactions
MeSH terms
Angiotensin II, Animals, Enzyme Inhibitors, Humans, Hydrolysis, Mammals, Structure-Activity Relationship, Spodoptera, Catalytic Domain, Glutamyl Aminopeptidase, Sf9 Cells

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