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Faculty
 Choukri Ben Mamoun
Associate Professor of
Genetics and Developmental Biology
choukri@up.uchc.edu
Areas of Interest:
Membrane Biogenesis and Malaria Chemotherapy
Plasmodium falciparum is an important intraerythrocytic protozoan
pathogen responsible for the most severe form of human malaria. The
rapid spread of drug-resistant parasites and lack of an effective
malaria vaccine result in an urgent need for alternative approaches to
prevent malaria infection and pathogenesis. The rapid multiplication of
P. falciparum in human erythrocytes requires active synthesis of new
membranes. Our laboratory uses molecular, biochemical, genomic and
biophysical analyses to understand lipid biogenesis in this parasite.
The long-term goal of our research program is to design new drugs that
can stop P. falciparum proliferation and clear malaria infection.
Yeast as a Model System for Malaria Chemotherapy
Our laboratory uses the baker yeast Saccharomyces cerevisiae as a
surrogate system to functionally characterize malarial genes involved in
membrane biogenesis, determine the mode of action of various
anti-malarial drugs and design target-specific new drugs.
Lab Rotation Projects:
Project 1: Characterize the biological function of membrane proteins of
the Pns1 family.
The yeast Pns1p is a member of a large family of membrane proteins
with a 10-transmembrane helical model conserved among eukaryotes and
highly expressed in the central nervous system in humans; but whose
physiological function is not yet known. The goal of this research
project is to investigate the effect of suppression or overexpression of
Pns1 and its homologs in yeast mutants affected in various metabolic
pathways in order to understand its primary function. The student will
learn various Molecular (cloning, PCR..), genetic (promoter exchange,
genetic cross, tetrad dissection) and biochemical (pulse-chase and thin
layer chromatography) approaches during the period of this research.
Project 2: To establish a biochemical screen for inhibitors of the
malarial phosphoethanolamine methyltransferase.
Research in my lab identified a novel pathway for phosphatidylcholine
biosynthesis in the human malaria parasite Plasmodium falciparum (Pessi
et al., PNAS, 2004; Pessi et al., JBC 2005). This pathway named SDPM
initiates from serine either transported from host serum or resulting
from degradation of human hemoglobin and leads to the synthesis of the
phosphatidylcholine precursor, phosphocholine via the activity of a
malarial expressed phosphoethanolamine methyltransferase, Pfpmt. Genetic
studies in P. falciparum suggest that PfPMT gene is essential for
parasite development and survival and thus is a good target for
development of novel antimalarial drugs. The goal of this research
project is to develop a biochemical assay that can be used to screen
chemical libraries to search for drugs that target Pfpmt activity and
inhibit parasite proliferation.
Project 3: Investigate the role of monomethyl- and
dimethylphosphoethanolamine in the transcription regulation of
sphingolipid genes.
Research in my lab provided genetic evidence that the intermediates
of phosphatidylethanolamine transmethylation regulate the expression of
genes involved in sphingolipid metabolism. The goal of this project is
to perform genetic studies in yeast to characterize the regulation of
the ELO3 gene encoding the Elo3 protein necessary for synthesis of
C26-CoA, which is a source of C26 fatty acyls found in the ceramide
moieties of all sphingolipids. An ELO3-lacZ transcriptional fusion has
been constructed in the lab and its expression has been shown to be
differentially expressed in mutants affected in phosphatidylethanolamine
transmethylation. The student will take advantage of this construct to
attempt to identify the transcription factors involved in this
regulation by screening mutants lacking various transcription factors.
Selected Publications:
Gabriella Pessi, Jae-Yeon Choi, Jennifer M. Reynolds, Dennis R.
Voelker and Choukri Ben Mamoun. In vivo Evidence for the Specificity of
Plasmodium falciparum Phosphoethanolamine Methyltransferase and its
Coupling to the Kennedy Pathway. J. Biol. Chem. (2005) 280:12461-12466.
Rachel Zufferey and Choukri Ben Mamoun. The Initial Step of
Glycerolipid Metabolism in Leishmania major Promastigotes Involves a
Single Glycerol-3-Phosphate Acyltransferase Enzyme Important for the
Synthesis of Triacylglycerol but not Essential for Virulence. Molecular
Microbiology. (2005) 56, 800 - 810.
Gabriella Pessi, Guillermo Kociubinski and Choukri Ben Mamoun. A
Pathway for Phosphatidylcholine Biosynthesis in Plasmodium falciparum
Involving Phosphoethanolamine Methylation. Proc. Natl. Acad. Sci. USA.
(2004) 101, 6206 – 6211.
Rodolphe Roggero, Rachel Zufferey, Mihaela MINCA, Eric Richier,
Michele Calas, Henri Vial and Choukri Ben Mamoun. Unraveling the Mode of
Action of the Anti-Malarial Choline Analog G25 in Plasmodium and Yeast.
Antimicrob. Agents Chemother. (2004) 48, 2816 – 2824.
Teresa C. Santiago, Rachel Zufferey, Rajendra S. Mehra, Rosalind, A.
Coleman and Choukri Ben Mamoun. The Plasmodium falciparum PfGatp is an
Endoplasmic Reticulum Membrane Protein Important for the Initial Step of
Malarial Glycerolipid Synthesis. J. Biol. Chem. (2004) 279, 9222-9232.
Rachel Zufferey, Teresa C. Santiago, Valerie Brachet and Choukri Ben
Mamoun. Reexamining the Role of Choline Transporter-Like (CTL) Proteins
in Choline Transport. Neurochem. Res. (2004) 29, 461-467.
Teresa C. Santiago and Choukri Ben Mamoun. Genome Expression Analysis
in Yeast Reveals Novel Transcriptional Regulations by Inositol and
Choline and New Regulatory Functions for Opi1p, Ino2p and Ino4p. J.
Biol. Chem. (2003) 278, 38723-38730.
Rachel Zuffereyand Choukri Ben Mamoun. Choline transport in
Leishmania major promastigotes and its inhibition by choline and
phosphocholine analogs. Mol. Biochem. Parasitol. (2002) 125, 105-112.
Links
http://genetics.uchc.edu/
http://cmp.uchc.edu/Ben_Mamoun_Lab/ben_mamoun_lab.html
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