Species-selective targeting of pathogens revealed by the
atypical structure and active site of Trypanosoma cruzi histone
deacetylase DAC2

J 2021

Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2

MAREK, Martin, E. RAMOS-MORALES, G.F.A. PICCHI-CONSTANTE, T. BAYER, C. NORSTROM et. al.

Základní údaje

Originální název

Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2

Autoři

MAREK, Martin (203 Česká republika, garant, domácí), E. RAMOS-MORALES, G.F.A. PICCHI-CONSTANTE, T. BAYER, C. NORSTROM, D. HERP, P.A. SALES, E.P. GUERRA-SLOMPO, K. HAUSMANN, A. CHAKRABARTI, T.B. SHAIK, A. MERZ, E. TROESCH, K. SCHMIDTKUNZ, S. GOLDENBERG, R.J. PIERCE, MM MOURAO, M.M. JUNG, J. SCHULTZ, W. SIPPL, N.I.T. ZANCHIN a C. ROMIER

Vydání

Cell Reports, CAMBRIDGE, Cell Press, 2021, 2211-1247

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10601 Cell biology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 9.995

Kód RIV

RIV/00216224:14310/21:00124414

Organizační jednotka

Přírodovědecká fakulta

DOI

http://dx.doi.org/10.1016/j.celrep.2021.110129

UT WoS

000734443900007

Klíčová slova anglicky

LYSINE ACETYLATION; HDAC INHIBITORS; IN-VITRO; PARASITES; POTENT; EPIGENETICS; EXPRESSION; MECHANISM; INSIGHTS; FEATURES

Štítky

rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 16. 5. 2022 12:46, Mgr. Marie Šípková, DiS.

Anotace

V originále

Writing and erasing of posttranslational modifications are crucial to phenotypic plasticity and antigenic variation of eukaryotic pathogens. Targeting pathogens' modification machineries, thus, represents a valid approach to fighting parasitic diseases. However, identification of parasitic targets and the development of selective anti-parasitic drugs still represent major bottlenecks. Here, we show that the zinc-dependent his tone deacetylases (HDACs) of the protozoan parasite Trypanosoma cruzi are key regulators that have significantly diverged from their human counterparts. Depletion of T. cruzi class I HDACs tcDAC1 and tcDAC2 compromises cell-cycle progression and division, leading to cell death. Notably, tcDAC2 displays a deacetylase activity essential to the parasite and shows major structural differences with human HDACs. Specifically, tcDAC2 harbors a modular active site with a unique subpocket targeted by inhibitors showing substantial anti-parasitic effects in cellulo and in vivo. Thus, the targeting of the many atypical HDACs in pathogens can enable anti-parasitic selective chemical impairment.

Citovat

MAREK, Martin, E. RAMOS-MORALES, G.F.A. PICCHI-CONSTANTE, T. BAYER, C. NORSTROM, D. HERP, P.A. SALES, E.P. GUERRA-SLOMPO, K. HAUSMANN, A. CHAKRABARTI, T.B. SHAIK, A. MERZ, E. TROESCH, K. SCHMIDTKUNZ, S. GOLDENBERG, R.J. PIERCE, MM MOURAO, M.M. JUNG, J. SCHULTZ, W. SIPPL, N.I.T. ZANCHIN a C. ROMIER. Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2. Cell Reports. CAMBRIDGE: Cell Press, 2021, roč. 37, č. 12, s. 1-17, "e1-e9", 26 s. ISSN 2211-1247. Dostupné z: https://dx.doi.org/10.1016/j.celrep.2021.110129.

@article{1841382,
   author = {Marek, Martin and RamosandMorales, E. and PicchiandConstante, G.F.A. and Bayer, T. and Norstrom, C. and Herp, D. and Sales, P.A. and GuerraandSlompo, E.P. and Hausmann, K. and Chakrabarti, A. and Shaik, T.B. and Merz, A. and Troesch, E. and Schmidtkunz, K. and Goldenberg, S. and Pierce, R.J. and Mourao, MM and Jung, M.M. and Schultz, J. and Sippl, W. and Zanchin, N.I.T. and Romier, C.},
   article_location = {CAMBRIDGE},
   article_number = {12},
   doi = {http://dx.doi.org/10.1016/j.celrep.2021.110129},
   keywords = {LYSINE ACETYLATION; HDAC INHIBITORS; IN-VITRO; PARASITES; POTENT; EPIGENETICS; EXPRESSION; MECHANISM; INSIGHTS; FEATURES},
   language = {eng},
   issn = {2211-1247},
   journal = {Cell Reports},
   title = {Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2},
   url = {https://www.sciencedirect.com/science/article/pii/S2211124721016259?via%3Dihub},
   volume = {37},
   year = {2021}
}

TY  - JOUR
ID  - 1841382
AU  - Marek, Martin - Ramos-Morales, E. - Picchi-Constante, G.F.A. - Bayer, T. - Norstrom, C. - Herp, D. - Sales, P.A. - Guerra-Slompo, E.P. - Hausmann, K. - Chakrabarti, A. - Shaik, T.B. - Merz, A. - Troesch, E. - Schmidtkunz, K. - Goldenberg, S. - Pierce, R.J. - Mourao, MM - Jung, M.M. - Schultz, J. - Sippl, W. - Zanchin, N.I.T. - Romier, C.
PY  - 2021
TI  - Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2
JF  - Cell Reports
VL  - 37
IS  - 12
SP  - 1-17, "e1-e9"
EP  - 1-17, "e1-e9"
PB  - Cell Press
SN  - 22111247
KW  - LYSINE ACETYLATION
KW  - HDAC INHIBITORS
KW  - IN-VITRO
KW  - PARASITES
KW  - POTENT
KW  - EPIGENETICS
KW  - EXPRESSION
KW  - MECHANISM
KW  - INSIGHTS
KW  - FEATURES
UR  - https://www.sciencedirect.com/science/article/pii/S2211124721016259?via%3Dihub
N2  - Writing and erasing of posttranslational modifications are crucial to phenotypic plasticity and antigenic variation of eukaryotic pathogens. Targeting pathogens' modification machineries, thus, represents a valid approach to fighting parasitic diseases. However, identification of parasitic targets and the development of selective anti-parasitic drugs still represent major bottlenecks. Here, we show that the zinc-dependent his tone deacetylases (HDACs) of the protozoan parasite Trypanosoma cruzi are key regulators that have significantly diverged from their human counterparts. Depletion of T. cruzi class I HDACs tcDAC1 and tcDAC2 compromises cell-cycle progression and division, leading to cell death. Notably, tcDAC2 displays a deacetylase activity essential to the parasite and shows major structural differences with human HDACs. Specifically, tcDAC2 harbors a modular active site with a unique subpocket targeted by inhibitors showing substantial anti-parasitic effects in cellulo and in vivo. Thus, the targeting of the many atypical HDACs in pathogens can enable anti-parasitic selective chemical impairment.
ER  -

MAREK, Martin, E. RAMOS-MORALES, G.F.A. PICCHI-CONSTANTE, T. BAYER, C. NORSTROM, D. HERP, P.A. SALES, E.P. GUERRA-SLOMPO, K. HAUSMANN, A. CHAKRABARTI, T.B. SHAIK, A. MERZ, E. TROESCH, K. SCHMIDTKUNZ, S. GOLDENBERG, R.J. PIERCE, MM MOURAO, M.M. JUNG, J. SCHULTZ, W. SIPPL, N.I.T. ZANCHIN a C. ROMIER. Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2. \textit{Cell Reports}. CAMBRIDGE: Cell Press, 2021, roč.~37, č.~12, s.~1-17, ''e1-e9'', 26 s. ISSN~2211-1247. Dostupné z: https://dx.doi.org/10.1016/j.celrep.2021.110129.

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