Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:6.4.1.1 (
pyruvate carboxylase
)
1,516
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Toxoplasma gondii
is considered to be one of the most successful intracellular pathogens, because it can reproduce in varied nutritional milieus, encountered in diverse host cell types of essentially any warm-blooded organism. Our earlier work demonstrated that the acute (tachyzoite) stage of
T. gondii
depends on cooperativity of glucose and glutamine catabolism to meet biosynthetic demands. Either of these two nutrients can sustain the parasite survival; however, what determines the metabolic plasticity has not yet been resolved. Here, we reveal two discrete phosphoenolpyruvate carboxykinase (PEPCK) enzymes in the parasite, one of which resides in the
m
i
t
ochondrion (
Tg
PEPCK
mt
), whereas the other protein is
n
ot
e
xpressed in
t
achyzoites (
Tg
PEPCK
net
). Parasites with an intact glycolysis can tolerate genetic deletions of
Tg
PEPCK
mt
as well as of
Tg
PEPCK
net
, indicating their nonessential roles for tachyzoite survival.
Tg
PEPCK
net
can also be ablated in a glycolysis-deficient mutant, while
Tg
PEPCK
mt
is refractory to deletion. Consistent with this, the lytic cycle of a conditional mutant of
Tg
PEPCK
mt
in the glycolysis-impaired strain was aborted upon induced repression of the mitochondrial isoform, demonstrating its essential role for the glucose-independent survival of parasites. Isotope-resolved metabolomics of the conditional mutant revealed defective flux of glutamine-derived carbon into RNA-bound ribose sugar as well as metabolites associated with gluconeogenesis, entailing a critical
nodal
role of PEPCK
mt
in linking catabolism of glucose and glutamine with anabolic pathways. Our data also suggest a homeostatic function of
Tg
PEPCK
mt
in cohesive operation of glycolysis and the tricarboxylic acid cycle in a normal glucose-replete milieu. Conversely, we found that the otherwise integrative enzyme
pyruvate carboxylase
(
Tg
PyC) is dispensable not only in glycolysis-competent but also in glycolysis-deficient tachyzoites despite a mitochondrial localization. Last but not least, the observed physiology of
T. gondii
tachyzoites appears to phenocopy cancer cells, which holds promise for developing common therapeutics against both threats.
...
PMID:A plant/fungal-type phosphoenolpyruvate carboxykinase located in the parasite mitochondrion ensures glucose-independent survival of
Toxoplasma gondii
. 2872 41
