trans

FURTHER READING 355
identified, from the deletion of non-essential
enzymes to the overexpression of key anaerobicspecific
isoforms. For example, complex II
functions as a succinate dehydrogenase in
aerobic stages, but as a fumarate reductase in
anaerobic stages, such as adult F. hepatica or
A. suum body wall muscle. Not surprisingly,
significant kinetic differences between complexes
isolated from aerobic larval and anaerobic
adult A. suum have been described. In
fact, stage-specific isoforms of key Complex II
subunits have been identified in both A. suum
and H. contortus, whose differential expression
parallels the aerobic/anaerobic transition.
Similarly, stage-specific isoforms of the
E1 subunit of the PDC (E1I and E1II) also
have been identified in A. suum. These isoforms
are over 90% identical at the amino acid
sequence level, but are expressed in different
stages and exhibit markedly different responses
to phosphorylation. E1II contains the three
phosphorylation sites present in mammalian
E1s, is most abundant in the aerobic L3 and
exhibits a stoichiometry of phosphorylation/
inactivation identical to that observed for E1s
isolated from the host. In contrast, E1I contains
only two phosphorylation sites and is
identical to the E1 isolated directly from adult
muscle. More importantly, substantially more
phosphate is incorporated into E1I than
E1II as inactivation proceeds, dramatically
decreasing the effectiveness of phosphorylation
in inactivating of the complex (see section
on Anaerobic Mitochondrial Metabolism). This
difference helps to maintain PDC activity in the
presence of the potentially inhibitory reducing
conditions encountered in the host gut.
PERSPECTIVE
Of all the metabolic pathways operating in
parasitic helminths, the reactions associated
with carbohydrate metabolism and energy
generation are, by far, the best understood.
However, many key questions remain unresolved.
For example, little is known about the
physiological factors regulating glycogen metabolism,
glycolytic flux, end-product formation
or muscle contraction, and complete carbon
balances have yet to be published for any
physiologically functional anaerobic helminth
mitochondria capable of volatile organic acid
formation. In addition, the role of oxygen in
helminth metabolism has remained enigmatic,
and a CN-insensitive terminal oxidase
has yet to be definitively identified. Little is
known about individual ionic fluxes associated
with electron transport or the pathway
of rhodoquinone biosynthesis, and we are
just beginning to understand tissue and stagespecific
differences in energy generation at the
molecular level. Clearly, energy generation in
parasitic helminths differs substantially from
that of the host, and remains an important target
for chemotherapy. In fact, a potentially new
anthelminthic, nafuredin, has recently been
identified, that appears to specifically inhibit
anaerobic helminth electron transport at the
level of Complex I. Future studies will certainly
continue to identify molecular differences
between the metabolisms of host and parasite
and hopefully will also identify additional new
targets for chemotherapy.
FURTHER READING
Aggarwal, S.R., Lindros, K.O. and Palmer, T.N. (1995).
Glucagon stimulates phosphorylation of different
peptides in isolated periportal and perivenous
hepatocytes. FEBS Lett. 377, 439–443.
Amino, H., Wang, H., Hirawake, H. et al. (2000).
Stage-specific isoforms of Ascaris suum complex
II. II. The fumarate reductase of the parasitic
adult and succinic dehydrogenase of free-living
larvae share a common iron–sulfur subunit.
Mol. Biochem. Parasitol. 106, 63–76.
BIOCHEMISTRY AND CELL BIOLOGY: HELMINTHS