trans

152 ENERGY METABOLISM – TRYPANOSOMATIDAE
differ much more from their respective homologs
found in other eukaryotes than can be
explained by a normal line of descent. Moreover,
some of these enzymes are clearly more related
to their prokaryotic than to their eukaryotic
counterparts (e.g. G3PDH, PGK, 6PGL, 6PGDH).
Other enzymes, such as aldolase, PGAM, TAO
and G6PDH, more closely resemble their
homologs from plants and algae. Thus, most
likely these enzymes entered the trypanosome
ancestor by mechanisms of horizontal transfer.
Trypanosomatids and the euglenids together
belong to the group of the Euglenozoa. Within
this group many euglenids are photosynthetic
and contain chloroplasts, while others have
lost these photosynthetic organelles. Trypanosomatids
are non-photosynthetic, and
there is no evidence for the presence of chloroplasts
in these organisms. The present day
chloroplasts of the euglenids are supposed to
have been derived from an algal endosymbiont,
which once was phagocytosed by the euglenid
ancestor and then lost again, except for its
chloroplasts which were retained by the host.
The presence in the trypanosomatid genome of
genes of either prokaryotic or of typical plant
or algal origin, which code for key enzymes of
carbohydrate metabolism, may suggest that it
was a common ancestor of both Euglenids and
Trypanosomatids that once harbored such an
endosymbiont. While in Euglena the chloroplasts
were retained, the trypanosomatids lost
them completely, but only after some of the
algal and chloroplast genes had been transferred
to the nucleus of the trypanosomatid.
Apart from the cytosolic PGAM and the mitochondrial
TAO, most of these enzymes have
acquired a peroxisome-targeting signal and are
now found inside glycosomes. These glycosomal
enzymes, which in the trypanosomatid
are now involved in carbohydrate catabolism,
may have fulfilled an essential role in the photosynthetic
Calvin cycle or in carbohydrate
synthesis in the algal endosymbiont. Apparently
enzymes of chloroplast/cyanobacterial
origin originally involved in the synthesis of
carbohydrates in a common ancestor of kinetoplastids
and euglenids were all relocated to
the kinetoplastid peroxisome when the chloroplast
was lost. This relocation of a large number
of algal enzymes could then have triggered
the formation of the glycosome, which then
adopted carbohydrate catabolism as its major
new function.
SUMMARY AND
CONCLUSIONS
Through the combined efforts of many
researchers in various disciplines over many
years, we have now obtained a good understanding
of the glycolytic pathway of the African
trypanosome. These efforts have led to the
cloning, sequencing and overexpression of all
the enzymes of the pathway and the resolution
of the crystal structure of many. Theoretical
calculations and gene knockout experiments
have demonstrated that glycolysis constitutes a
valid drug target. Most of the enzymes involved
have been fully characterized and in some
cases, such as GAPDH, this already has led to
the design of very potent inhibitors that exert
their effect not only in vitro, but also in vivo, and
not only on T. brucei, but also on T. cruzi and
Leishmania. Recently a start has been made
with a similar approach to the enzymes of the
HMP. The possibility that chloroplast- or algalderived
enzymes and, perhaps, complete
plant-derived pathways are still present in trypanosomatids
opens new possibilities for the
identification of drug targets. Since such
enzymes should not be present in mammals,
drugs directed against those targets could provide
high selectivity. Moreover, there is a wide
range of herbicides that has been developed
BIOCHEMISTRY AND CELL BIOLOGY: PROTOZOA