trans

344 ENERGY METABOLISM IN HELMINTHS
by a variety of effectors. Both the mammalian
and parasitic helminth PFKs are activated by
fructose 2,6-bisphosphate and AMP and inhibited
by ATP. In contrast to the mammalian PFK,
phosphorylation of the helminth PFKs (at least
in Fasciola hepatica and A. suum) results in activation
of the enzyme. However, activation by
phosphorylation is not unique to the helminth
PFKs, as it also occurs in other invertebrates,
such as earthworms and molluscs. Structurally,
helminth and mammalian PFKs appear to be
quite similar, although the sequence around
the phosphorylation sites of the PFKs differs
among helminth enzymes and is distinct from
that of the mammalian-type PFK.
As described above, the final reactions
in the cytosolic degradation of glucose can differ
widely in various parasitic helminths
(Figure 14.1). Pyruvate kinase (PK) may convert
PEP to pyruvate, which can be then reduced
in the cytosol to lactate or ethanol, or translocated
into the mitochondrion for further
oxidation by the tricarboxylic acid cycle. In
contrast, PEPCK may carboxylate PEP to oxaloacetate
which can then be reduced to malate
by malate dehydrogenase. Not surpringly, the
regulation of the PK/PEPCK branch point is
potentially important in many parasitic
helminths (Figure 14.1).
The PK-catalyzed conversion of PEP to pyruvate
is coupled to ATP production. PKs from
F. hepatica and S. mansoni closely resemble
the L-type pyruvate kinase from mammalian
liver. Both helminth enzymes show cooperative
kinetics with PEP, but Michaelis–Menten
kinetics in the presence of fructose 1,6-
bisphosphate. Both helminth enzymes are
inhibited by ATP, and this inhibition can be
relieved by fructose 1,6-bisphosphate. Regulation
of helminth PK via phosphorylation/
dephosphorylation or by other effectors like
fructose 2,6-bisphosphate, which stimulates
trypanosomatid PKs, has not yet been reported.
In parasitic helminths, PEPCK physiologically
fixes CO 2 , and converts PEP to oxaloacetate
(OAA) and, in common with PKs, is
coupled to a substrate-level phosphorylation.
This contrasts dramatically with the role of
PEPCK in mammals, where PEPCK decarboxylates
OAA as a prelude to gluconeogenesis.
Therefore, not surprisingly, PEPCKs from parasitic
helminths have been studied extensively
in a search for molecular differences between
host and parasites. However, the size and the
kinetic properties of PEPCKs from parasitic
helminths are similar to those of host enzymes
with one exception: the K m for HCO 3 is significantly
lower for the helminth PEPCK. This
observation, coupled with the high pCO 2 in
the habitat of many parasitic helminths, might
explain why PEPCK acts in the carboxylating
direction in helminth tissues. In contrast to PK
activity, which is under tight allosteric control,
PEPCK activity appears to be controlled primarily
by the concentrations of enzyme, substrates
and products.
MITOCHONDRIAL
METABOLISM AND ENERGY
GENERATION
One of the first observed metabolic differences
between parasitic helminths and their
hosts was the identification of novel anaerobic
mitochondrial energy-generating pathways in
the helminths by Saz and Bueding. However,
the role played by oxygen in helminth metabolism
has remained enigmatic. It is clear that
almost all adult parasitic helminths generate a
significant portion of their energy anaerobically,
and that they also exhibit a wide variation
in their ability to use oxygen as a terminal
electron acceptor. In general, two basic metabolic
schemes have emerged. Blood- and tissuedwelling
helminths, such as schistosomes and
BIOCHEMISTRY AND CELL BIOLOGY: HELMINTHS