trans

CARBOHYDRATE METABOLISM 157
essential nutrients across multiple membrane
barriers, including the host cell plasma membrane,
the parasitophorous vacuole, and the
plasma membrane of the parasite. The predominant
pathway for hexose uptake into normal
human erythrocytes is through an archetypal
member of the major facilitator superfamily
of integral membrane transporters, the Homo
sapiens glucose transporter 1 (GLUT1) (Figure
7.6). This protein mediates the simple and rapid
equilibration of glucose between the extracellular
and intracellular media. GLUT1 is present
on the erythrocyte membrane at high density,
insuring that the intraerythrocytic glucose concentration
is not rate limiting. Indeed, the
capacity of GLUT1 exceeds the rate of glucose
consumption by normal (uninfected) erythrocytes
by orders of magnitude, providing sufficient
glucose for even a P. falciparum-infected
cell. Removing glucose from the medium or
inhibiting GLUT1 by treatment with the fungal
metabolite cytochalasin B causes an immediate
decline in ATP levels within both the host cell
and the parasite.
Another potential avenue for glucose uptake
from the extracellular medium is provided by
a parasite-induced increase in the permeability
of the host-cell membrane. This phenomenon,
known as the new permeation pathways
(NPP), mediates the uptake of a variety of low
molecular-weight solutes into infected red
blood cells. Given the potency of GLUT1, the
contribution of the NPP to glucose transport is
probably small in human erythrocytes, but this
pathway could be essential for malaria parasites
infecting species where glucose uptake
into the red cell is substantially lower (such as
mice or birds).
After transport across the host-cell plasma
membrane, the next potential barrier for glucose
entry is provided by the parasitophorous
vacuole membrane (PVM), which surrounds
the dividing parasites. The PVM is endowed
with a large number of high capacity, nonselective
pores, of sufficient size to accommodate
molecules up to 1400 Da. Although
the passage of glucose through these channels
has not been measured directly, the similarlysized
gluconate is freely diffusible across the
PVM, suggesting that glucose in the erythrocyte
cytoplasm should gain easy access to the
parasite plasma membrane.
Goodyer and colleagues provided evidence
for a facilitative, cytochalasin B-sensitive activity
that is required for glucose transport directly
into P. falciparum parasites, indicating that
a transporter similar to human GLUT1 is
expressed on the parasite plasma membrane.
The recently published sequence of P. falciparum
chromosome 2 includes a homolog of
GLUT1, designated P. falciparum hexose transporter
1 (PfHT1) that localizes to the parasite
plasma membrane. Recombinant expression
of PfHT1 in a heterologous system provides
evidence for a stereospecific hexose transporter
that can be inhibited by cytochalasin B.
PfHT1 also has the capacity to transport fructose,
prompting experiments which have now
FIGURE 7.6 Hexose uptake and metabolism in Plasmodium falciparum-infected erythrocytes. Both glucose and
fructose are transported into the host cell via high-capacity hexose transporters (GLUT1 and GLUT5, respectively).
After diffusion through the parasitophorous vacuole, a single transporter (PfHT1) is responsible for hexose import
into the parasite cytoplasm. Most apicomplexans express a pyrophosphate-dependent phosphofructose kinase,
which leads to a net production of three ATP/hexose rather than the usual two. A potent lactate dehydrogenase
activity produces lactic acid and regenerates NAD . Branching pathways include the pentose phosphate shunt,
which generates NADPH critical for oxidative stress protection, and carbon dioxide fixation into oxaloacetate,
a TCA-cycle intermediate.
BIOCHEMISTRY AND CELL BIOLOGY: PROTOZOA