trans

PYRIMIDINES 221
activities have been detected in a multiplicity
of strains. None of the enzymes has been well
studied at the biochemical level.
Trypanosoma cruzi
Pyrimidine metabolism in T. cruzi is similar
to that in Leishmania. All the biosynthetic
enzymes have been found in extracts, and
Aoki and coworkers have isolated all of the
T. cruzi pyrimidine biosynthetic genes. The
six enzymes are encoded by five genes, all of
which are encompassed within a 25 kb DNA
fragment, indicating that they are co-localized
in the T. cruzi genome. The last two enzymes,
OPRT and ODC, are encoded by a single gene
and are covalently linked as a bifunctional
protein in the order opposite to the mammalian
OPRT–ODC bifunctional protein. The
T. cruzi OPRT–ODC also possesses an archetypal
glycosomal targeting signal. Thymidylate
nucleotides are, as for all protozoan parasites,
generated by a bifunctional DHFR–TS. Pyrimidine
interconversion and salvage pathways
in epimastigotes are like those of Leishmania.
Pyrimidine metabolism appears similar in all
stages of the T. cruzi life cycle, except that a
UPRT activity has not been detected in
amastigotes.
the last two UMP biosynthetic enzymes, the
apparent cytosolic milieu of the DHODH, and
the existence and absence of UPRT and UK
enzymes, respectively.
Amitochondriates
Tritrichomonas foetus
T. foetus cannot synthesize pyrimidine
nucleotides de novo and are obligatory scavengers
of host pyrimidines. Uracil is the pyrimidine
that is most efficiently salvaged. Uridine,
cytidine, and thymidine are taken up at rates
10%, 10%, and 1% that of uracil, respectively,
and cytosine and thymine are not metabolized.
Uracil and uridine are only incorporated
into RNA, and thymidine only into DNA. The
lack of UMP synthesis and DHFR–TS enzymes
is consistent with the metabolic data. Uracil is
incorporated through UPRT. Other pyrimidine
salvage enzymes detected include TP, CP,
UP, and dCD. The lack of TS activity and the
inability to incorporate uracil into DNA indicates
that T. foetus is dependent upon thymidine
salvage. Yet the parasite apparently
possesses a hydroxyurea-refractory RR activity
that is capable of synthesizing deoxycytidylate
nucleotides.
Trypanosoma brucei
African trypanosomes metabolize pyrimidines
in a fashion akin to T. cruzi and
Leishmania. All six biosynthetic enzymes have
been detected in lysates of the bloodstream
form of T.b. brucei, and UPRT, dCD, pyrimidine
nucleoside cleavage activities, but not UK, have
been detected in parasite homogenates.
In summary, pyrimidine metabolism in
Kinetoplastida is like that of the mammalian
host. The only discrepancies uncovered to date
are the bifunctional and glycosomal nature of
Trichomonas vaginalis
T. vaginalis cannot synthesize pyrimidines
de novo, a conclusion based on experiments in
which the parasite failed to incorporate radiolabeled
precursors into pyrimidine nucleotides.
Pyrimidine salvage in T. vaginalis differs quantitatively
but not qualitatively from that in
T. foetus. Unlike T. foetus, which salvages uracil
most efficiently, cytidine is the preferred pyrimidine,
although uracil, uridine, and thymidine
are also taken up. Cytidine is incorporated
into both cytidylate and uridylate nucleotides,
BIOCHEMISTRY AND CELL BIOLOGY: PROTOZOA