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CARBOHYDRATE METABOLISM 155
as a human pathogen, the extensive biochemical
information available for this species,
and the comprehensive catalog of genome
sequence data now entering the public
domain. P. falciparum provides an adequate
‘type specimen’ for considering many aspects
of apicomplexan biochemistry, including
energy metabolism, but this phylum includes
several thousand species, exhibiting considerable
diversity. In particular, apicomplexan
parasites infect a bewildering array of host
species and tissues, which places diverse constraints
on intracellular survival. The red
blood cell, for example, is a highly inhospitable
environment, with little endogenous
metabolic activity and high potential for
oxidative damage to the parasite. Most
Apicomplexa reside within the far more hospitable
environment provided by the cytoplasm
of nucleated cells. The gut pathogen
Cryptosporidium parvum most closely resembles
anaerobic protozoa during its energy production,
and appears to harbor only a relict
mitochondrion.
Most of the Apicomplexa also undergo distinct
morphological and physiological changes
in the course of their complex life cycle, and
differences in these developmental stages are
also noted. For example, coccidian parasites
such as Toxoplasma and Eimeria differ from
Plasmodium in their ability to metabolize carbohydrates
during certain stages of growth.
The two developmental phases of T. gondii
within mammalian hosts (tachyzoites and
bradyzoites) vary markedly not only in their
glycolytic pathways but also in their ability to
store energy in the form of polymerized sugars
(amylopectin). Energy metabolism during the
sporulation stage of Eimeria species is highlighted
by an accumulation of the carbohydrate
mannitol, revealing a branch of the
glycolytic pathway previously unknown in the
protozoa.
CARBOHYDRATE
METABOLISM
The earliest biochemical studies on P. falciparum
characterized a robust glycolytic pathway
during intra-erythrocytic replication. This
parasite harbors no energy reserves in the form
of polysaccharides or fatty acids, and therefore
relies upon an extracellular supply of glucose
as its primary energy source. Uninfected
human erythrocytes utilize 5 micromoles of
glucose during a 24-hour period. In contrast,
P. falciparum-infected erythrocytes consume
150 micromoles of glucose per day, with peak
levels approaching two orders of magnitude
above the uninfected red cell background.
Although it is conceivable that the host glycolytic
machinery could operate at an accelerated
rate during parasite infection, all evidence
indicates that parasite pathways are responsible
for this increased activity. P. falciparum
enzymes are less sensitive than the host cell
glycolytic machinery to the lower pH found in
parasitized erythrocytes, and surveys of gene
expression patterns using DNA microarrays
show strong transcriptional stimulation of key
parasite glycolytic enzymes during the early
stages of infection. Although seemingly at odds
with its parasitic lifestyle, recent studies indicate
that the malaria parasite even provides the
host cell with major products from its own
carbohydrate metabolism, including ATP and
reduced glutathione. A complete system for the
uptake and consumption of glucose, and for the
removal of the lactic acid end-product of anaerobic
metabolism, has been described biochemically
and confirmed by genomic analyses.
Nutrient uptake
As with other intracellular pathogens, P. falciparum
faces the challenge of importing
BIOCHEMISTRY AND CELL BIOLOGY: PROTOZOA