trans

GLYCOLYSIS 343
ethanol; it is in redox balance and yields two
mol of ATP per mol of glucose degraded.
However, malate is not excreted like lactate
or ethanol, but instead is transported into
the mitochondria for further anaerobic
metabolism, as discussed in greater detail
below. This pathway is common in many
parasitic helminths, especially the lumendwelling
helminths like A. suum.
Several glycolytic enzymes have been
purified from parasitic helminths and studied
in great detail. These studies were stimulated by
the early observation that the chemotherapeutic
action of antimonials on schistosomes was
associated with an inhibition of its phosphofructokinase
(PFK), a rate-limiting glycolytic
enzyme. Helminth PFKs appear to be much
more sensitive to these anti-schistosomal drugs
than the PFK of the host. Chemotherapeutic
attack on the energy-generating systems of parasites
is one of the more rational and promising
approaches to combat parasitic diseases, since
energy (ATP) is one of the few commodities that
parasites cannot directly obtain from the host.
Special attention has been, of course, directed
towards enzymes that are absent in the host,
or where differences are observed between
enzymes of host and parasite.
The initial enzyme in the glycolytic
sequence, hexokinase, controls the entry of
glucose into the pathway, and is critical in the
regulation of carbohydrate utilization. In
mammals four hexokinase isoforms have been
identified. Isoenzymes I–III are monomers with
molecular weights of about 100 000, have a high
affinity for glucose and are strongly inhibited
by glucose 6-phosphate. Type IV, also called
glucokinase, is a monomer of about 50 000
molecular weight, has a low affinity for glucose
and is weakly inhibited by glucose 6-phosphate.
Only a few hexokinases from parasitic
helminths have been studied in detail. In adult
A. suum only a single hexokinase isoform
appears to be present, and its properties differ
from the corresponding mammalian isoforms.
The ascarid hexokinase is a monomer with a
molecular weight of about 100 000, has a low
affinity for glucose (K m 4.7 mM) and is only
weakly inhibited by glucose 6-phosphate. The
high K m for glucose and the weak affinity for
glucose 6-phosphate may facilitate glycogen
synthesis in adult ascarid muscle. Hexokinase
activity appears to be ‘rate-limiting’ in S. mansoni
glucose metabolism. Cercariae and adults
contain only a single form, which has a relatively
high affinity for glucose and is moderately
sensitive to inhibition by glucose 6-phosphate.
The schistosomal enzyme is structurally related
to other members of the hexokinase family. It is
recognized by antisera against rat type I hexokinase,
and the amino acid sequence shows a
significant identity to the mammalian hexokinases.
The relationship of this schistosomal
enzyme with other hexokinases is interesting,
as the schistosomal hexokinase, with its relatively
high affinity for glucose and sensitivity for
inhibition by glucose 6-phosphate, kinetically
resembles the 100 kDa mammalian isoforms,
although it is only about 50 kDa. The extensive
sequence similarity of the schistosomal hexokinase
with the mammalian isoforms is consistent
with the view that the 100 kDa isoforms
were formed via duplication of a gene encoding
an ancestral hexokinase whose descendant is
still present as a 50 kDa, glucose 6-phosphatesensitive
hexokinase in S. mansoni. Hexokinase
appears to play a distinctive role in the rapid
transition in energy metabolism that occurs in
schistosomes when free-living cercariae enter
the host (see section on the Aerobic/Anaerobic
Transition).
Phosphofructokinase, another key glycolytic
regulatory enzyme, catalyzes the ATPdependent
conversion of fructose 6-phosphate
to fructose 1,6,-bisphosphate and is regulated
BIOCHEMISTRY AND CELL BIOLOGY: HELMINTHS