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Distinct substrate specificities of the three catalytic subunits of the Trichomonas vaginalis proteasome

P. Fajtova, BM. Hurysz, Y. Miyamoto, MSM. Serafim, Z. Jiang, JM. Vazquez, DF. Trujillo, LJ. Liu, U. Somani, J. Almaliti, SA. Myers, CR. Caffrey, WH. Gerwick, DL. McMinn, CJ. Kirk, E. Boura, L. Eckmann, AJ. O'Donoghue

Fajtova, Pavla
Author Fajtova, Pavla Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague 6, Czech Republic Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, California, USA
Hurysz, Brianna M
Author Hurysz, Brianna M Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, California, USA
Miyamoto, Yukiko
Author Miyamoto, Yukiko Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, California, USA Department of Medicine, University of California San Diego, La Jolla, California, USA
Serafim, Mateus Sá M
Author Serafim, Mateus Sá M Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, California, USA Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
Jiang, Zhenze
Author Jiang, Zhenze Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, California, USA
Vazquez, Julia M
Author Vazquez, Julia M Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, California, USA
Trujillo, Diego F
Author Trujillo, Diego F Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, California, USA
Liu, Lawrence J
Author Liu, Lawrence J Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, California, USA
Somani, Urvashi
Author Somani, Urvashi Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, California, USA
Almaliti, Jehad
Author Almaliti, Jehad Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, California, USA Scripps Institution of Oceanography, University of California San Diego, La Jolla, California, USA
Myers, Samuel A
Author Myers, Samuel A Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, California, USA
Caffrey, Conor R
Author Caffrey, Conor R Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, California, USA
Gerwick, William H
Author Gerwick, William H Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, California, USA Scripps Institution of Oceanography, University of California San Diego, La Jolla, California, USA
McMinn, Dustin L
Author McMinn, Dustin L Kezar Life Sciences, South San Francisco, California, USA
Kirk, Christopher J
Author Kirk, Christopher J Kezar Life Sciences, South San Francisco, California, USA
Boura, Evzen
Author Boura, Evzen Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague 6, Czech Republic
Eckmann, Lars
Author Eckmann, Lars Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, California, USA Department of Medicine, University of California San Diego, La Jolla, California, USA
O'Donoghue, Anthony J
Author O'Donoghue, Anthony J ORCID Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, California, USA

Protein science. 2024 ; 33 (12) : e5225. [pub] -

Protein Sci
ISSN 1469-896X
Medvik
Source

Language English Country United States

Document type Journal Article

Persistent link https://www.medvik.cz/link/bmc25003143

Grant support
St. Baldrick's Foundation
T32GM007752 NIGMS NIH HHS - United States
88887.595578/2020-00 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
R21 AI146387 NIH HHS - United States
88887.684031/2022-00 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
846688 HORIZON EUROPE Marie Sklodowska-Curie Actions
MSM200551901 Akademie Věd České Republiky
DK120515 NIH HHS - United States
R21 AI171824 NIH HHS - United States
Universidade Federal de Minas Gerais
P30 DK120515 NIDDK NIH HHS - United States
R21 AI133393 NIH HHS - United States
R01 AI158612 NIH HHS - United States

Online Full text

NLK Free Medical Journals from 1992 to 1 year ago
PubMed Central from 1992 to 1 year ago
Europe PubMed Central from 1992 to 1 year ago
Medline Complete (EBSCOhost) from 2010-01-01 to 1 year ago
Wiley Free Content from 1996 to 1 year ago

PubMed 39589076
DOI 10.1002/pro.5225
Knihovny.cz E-resources

MeSH
Proteasome Inhibitors pharmacology chemistry MeSH
Catalytic Domain * MeSH
Proteasome Endopeptidase Complex * metabolism chemistry MeSH
Protozoan Proteins chemistry metabolism antagonists & inhibitors genetics MeSH
Substrate Specificity MeSH
Trichomonas vaginalis * enzymology MeSH
Publication type
Journal Article MeSH

The protozoan parasite Trichomonas vaginalis (Tv) causes trichomoniasis, the most common non-viral sexually transmitted infection in the world. Although Tv has been linked to significant health complications, only two closely related 5-nitroimidazole drugs are approved for its treatment. The emergence of resistance to these drugs and lack of alternative treatment options poses an increasing threat to public health, making development of novel anti-Trichomonas compounds an urgent need. The proteasome, a critical enzyme complex found in all eukaryotes has three catalytic subunits, β1, β2, and β5 and has been validated as a drug target to treat trichomoniasis. With the goal of developing tools to study the Tv proteasome, we isolated the enzyme complex and identified inhibitors that preferentially inactivate either one or two of the three catalytic subunits. Using a mass spectrometry-based peptide digestion assay, these inhibitors were used to define the substrate preferences of the β1, β2 and β5 subunits. Subsequently, three model fluorogenic substrates were designed, each specific for one of the catalytic subunits. This novel substrate profiling methodology will allow for individual subunit characterization of other proteasomes of interest. Using the new substrates, we screened a library of 284 peptide epoxyketone inhibitors against Tv and determined the subunits targeted by the most active compounds. The data show that inhibition of the Tv β5 subunit alone is toxic to the parasite. Taken together, the optimized proteasome subunit substrates will be instrumental for understanding the molecular determinants of proteasome specificity and for accelerating drug development against trichomoniasis.

Center for Discovery and Innovation in Parasitic Diseases Skaggs School of Pharmacy and Pharmaceutical Sciences University of California La Jolla California USA

Departamento de Microbiologia Instituto de Ciências Biológicas Universidade Federal de Minas Gerais Belo Horizonte Minas Gerais Brazil

Department of Medicine University of California San Diego La Jolla California USA

Division of Signaling and Gene Expression La Jolla Institute for Immunology La Jolla California USA

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Prague 6 Czech Republic

Kezar Life Sciences South San Francisco California USA

Scripps Institution of Oceanography University of California San Diego La Jolla California USA

Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San Diego La Jolla California USA

References provided by Crossref.org

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