The decapping enzyme of parasitic eukaryotes has unusual properties
20 04 2026
ALPH1 is the atypical enzyme that trypanosomes use for mRNA decapping (in place of the usual decapping enzyme of eukaryotes, Dcp2). We study T. brucei ALPH1 as a potential target for antiparasitic drugs that could help combat African trypanosomiasis (sleeping sickness), Chagas disease, and also leishmaniases (caused by related Leishmania parasites).
Here, we characterise the enzymatic activity of ALPH1 using several orthogonal activity assays and reach surprising conclusions:
- ALPH1 prefers RNAs without m7G methylation, despite the heavy methylation of trypanosomal mRNA (cap 4)
- Cleavage by ALPH1 produces ppRNA (whereas Dcp2 produces pRNA).
- The C-terminal domain of ALPH1 is essential in vivo and increases decapping activity in vitro.
In conclusion, ALPH1 retains some characteristics of its prokaryotic homolog ApaH. ALPH1 likely trades enzymatic efficiency for additional regulatory capabilities to work on eukaryotic mRNA substrates.
This work was supported mainly by the trilateral DFG/GACR/NCN funding agreement WEAVE:
National Science Centre, Poland [WEAVE UNISONO grant 22022/04/Y/NZ1/00114 to MWG]
Deutsche Forschungsgemeinschaft [KR4017/12-1 to SK], GACR [24-14298L to MZ]
Leticia Pereira, Dawid A Dzadz, Paula A C Londoño, Marcin Warminski, Joanna Kowalska, Nicole Seifert, Silke Braune, Fabiola Holetz, Martin Zoltner, Susanne Kramer, Maria W Górna
The trypanosome mRNA decapping enzyme ALPH1 prefers caps without m7G methylation and produces diphosphate RNA
Nucleic Acids Research, Volume 54, Issue 6, gkag322
https://doi.org/10.1093/nar/gkag322
