trans

PYRIMIDINES 219
Thymidine
Uridine
Deoxycytodine
38 41
dTMP
UMP
40
dUMP
15
14
dCMP
dTDP
UDP
37
dUDP
CDP
37
dCDP
dTTP
UTP
12
dUTP
CTP
dCTP
FIGURE 9.10 Mammalian pyrimidine salvage and interconversion pathways. Enzyme identities are listed in Table 9.1.
unfavorable environments. Consistent with this
supposition is the example of the amitochondriates
that cannot regenerate the three ATP
molecules via oxidative phosphorylation and
also are unable to synthesize pyrimidine
nucleotides de novo.
Cytidylate, deoxycytidylate, and thymidylate
nucleotides are generated from uridylate
nucleotides via three specific reactions
(Figure 9.10). The first is CTPS, which converts
UTP to CTP. The second is RR, which synthesizes
dCDP and dUDP (as well as dGDP and
dADP) from CDP and UDP, respectively. The
third enzyme, TS, catalyzes the reductive
methylation of dUMP using 5,10-methylenetetrahydrofolate
to produce TMP. TS is a well
characterized enzyme in many organisms and
has been targeted in anti-neoplastic chemotherapies.
The enzyme is covalently linked to
DHFR in many protozoan parasites, existing
as a DHFR–TS complex. Pyrimethamine, an
inhibitor of microbial DHFRs, is used in the
treatment of Plasmodium and Toxoplasma
infections (Chapter 17).
With three exceptions, all the parasites discussed
here possess pyrimidine biosynthetic,
CTPS, RR, and TS enzymes. G. lamblia and
T. vaginalis lack both RR and TS and must salvage
pyrimidines and their deoxynucleosides.
T. foetus possesses RR but not TS and must salvage
pyrimidines and thymidine but not other
deoxynucleotides.
Mammalian cells also can salvage pyrimidines,
but they do so mostly at the nucleoside
level. Salvage of pyrimidine bases is minimal,
and UPRT is missing. Mammalian cells have
cytosolic UK, TK1, and dCK enzymes, as well
as a mitochondrial TK2. UK recognizes uridine
and cytidine, TK1 is specific for thymidine,
dCK, although it prefers deoxycytidine, can
also phosphorylate deoxyadenosine and deoxyguanosine,
and TK2 is less selective than TK1.
There are also pyrimidine interconversion
enzymes including dCD and dCMPD.
Apicomplexa
Plasmodium spp.
Uninfected red blood cells have virtually
undetectable pyrimidine nucleotide pools
and are deficient in pyrimidine nucleotide
biosynthesis. The enzymes for UMP, TMP,
and CTP synthesis, however, all can be found
BIOCHEMISTRY AND CELL BIOLOGY: PROTOZOA