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@PHDTHESIS{Flammersfeld:789173,
author = {Flammersfeld, Ansgar},
othercontributors = {Pradel, Gabriele and Antonin, Wolfram and Spehr, Marc},
title = {{F}unktionale {C}harakterisierung der {P}atatin-ähnlichen
{P}hospholipase {PNPLA}1 in den {B}lut- und {S}exualstadien
des humanpathogenen {M}alariaerregers {P}lasmodium
falciparum},
school = {RWTH Aachen University},
type = {Dissertation},
address = {Aachen},
reportid = {RWTH-2020-05048},
pages = {1 Online-Ressource (v, 209 Seiten) : Illustrationen,
Diagramme, Karten},
year = {2020},
note = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
University; Dissertation, RWTH Aachen University, 2020},
abstract = {The malaria pathogen P. falciparum displays a
well-regulated lipid metabolism required to ensure its
survival in the human host as well as in the mosquito
vector. Therefore, proteins involved in synthesis and
acquisition of phospholipids were extensively studied in the
past and represent prime targets for malaria therapeutics.
In contrast, not much is known about phospholipases, which
may have potentially important functions in membrane
dynamics, host cell membrane penetration, cell
proliferation, and cell signaling due to their
phospholipid-hydrolytic activity. In a comprehensive genome
analysis carried out within the scope of this work, a total
of 22 putative phospholipases were identified in the P.
falciparum genome, four of which are annotated as patatin
like phospholipases (PNPLA). PNPLA1, a putative PLA2, is
present in the asexual and sexual blood stages and here
localizes to the cytosol. PNPLA1-deficient parasites showed
normal asexual replication, gametocyte development and
gametogenesis. However, parasites lacking PNPLA1 formed
significantly less gametocyte numbers and showed delayed
development of the five maturation stages, while episomal
overexpression of PNPLA1 promoted gametocyte formation. The
loss of PNPLA1 function also led to a transcriptional
deregulation of genes related to game to cytogenesis,
including the gene encoding the key regulator of sexual
commitment, the transcription factor AP2-G. Comparative
lipidodomic analysis of asexual PNPLA1-deficient parasites
revealed overall increased levels of major phospholipids, in
particular phosphatidylcholine (PC), which is the main
component of plasmodial membranes. PC synthesis is known to
be pivotal for erythrocytic replication, while reduced
availability of PC precursors drives the parasite into game
to cytogenesis. Thus, the higher PC levels due to
PNPLA1-deficiency might prevent the blood stage parasites
from entering the sexual pathway. By the first
characterization of a plasmodial PNPLA, the results of this
thesis contribute to the elucidation of the biochemical and
functional role of phospholipases in the life cycle of the
malaria pathogen and deepen the understanding of the sexual
differentiation pathway.},
cin = {164020 / 160000},
ddc = {570},
cid = {$I:(DE-82)164020_20200124$ / $I:(DE-82)160000_20140620$},
typ = {PUB:(DE-HGF)11},
doi = {10.18154/RWTH-2020-05048},
url = {https://publications.rwth-aachen.de/record/789173},
}
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