Distinct substrate specificities of the three catalytic subunits of the Trichomonas vaginalis proteasome
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F24%3A00602601" target="_blank" >RIV/61388963:_____/24:00602601 - isvavai.cz</a>
Result on the web
<a href="https://doi.org/10.1002/pro.5225" target="_blank" >https://doi.org/10.1002/pro.5225</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1002/pro.5225" target="_blank" >10.1002/pro.5225</a>
Alternative languages
Result language
angličtina
Original language name
Distinct substrate specificities of the three catalytic subunits of the Trichomonas vaginalis proteasome
Original language description
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, beta 1, beta 2, and beta 5 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 beta 1, beta 2 and beta 5 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 beta 5 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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Protein Science
ISSN
0961-8368
e-ISSN
1469-896X
Volume of the periodical
33
Issue of the periodical within the volume
12
Country of publishing house
US - UNITED STATES
Number of pages
17
Pages from-to
e5225
UT code for WoS article
001370275200001
EID of the result in the Scopus database
2-s2.0-85210436939