trans

218 PURINES AND PYRIMIDINES
FIGURE 9.9 De novo pathway for pyrimidine biosynthesis. Enzyme identities are shown in Table 9.1.
catabolic pathway far more intricate and complex
than that in humans. Much work on helminthic
purine pathways remains to be done.
PYRIMIDINES
Most parasites, with the noted exceptions of T.
foetus, T. vaginalis, and G. lamblia, are capable
of synthesizing pyrimidine nucleotides de novo.
This biosynthetic pathway requires six reactions
to generate UMP from CO 2 , glutamine,
aspartate, and PRPP (Figure 9.9). UMP then
serves as the precursor for all other pyrimidine
nucleotides.
In mammalian cells, UMP synthesis is catalyzed
by two cytosolic multifunctional proteins
and a single mitochondrial enzyme. The
first three enzymes, CPSII, ATC, and DHO, are
part of a trifunctional protein encoded by a
single transcript. The CPSII is the major site of
regulation in mammalian cells and is inhibited
by UTP and CTP. The fourth enzyme, DHODH,
is a mitochondrial flavoprotein that generates
orotate from dihydroorotate in an NAD -
dependent reaction. The synthesis of UMP
from orotate is then accomplished by a
bifunctional protein that accommodates both
OPRT and ODC activities. The former adds the
ribose phosphate moiety to the base in a PRPPdependent
reaction, while the latter decarboxylates
OMP to form UMP.
UMP synthesis is much less energetically
expensive than purine nucleotide synthesis.
Two ATP molecules are consumed in the first
reaction and an additional two ATP molecules
are required for the synthesis of PRPP. However,
the NADH product of the mitochondrial
reaction can be used by the electron transport
chain to produce three additional ATP molecules.
Thus, there is a net requirement for only
a single high-energy phosphate in the pyrimidine
biosynthetic pathway. It has been conjectured
that the large energy expenditure for
the purine biosynthetic pathway precipitated
its loss in parasites residing in energetically
BIOCHEMISTRY AND CELL BIOLOGY: PROTOZOA