trans

PURINE METABOLISM 207
nucleobases and nucleosides. Recently, however,
with the completion of the Caenorhabditis
elegans genome and the emergence of partial
mRNA sequences for several parasitic nematodes,
multiple homologs have been identified
from both the ENT and CNT families.
PURINE METABOLISM
Purine ribonucleotides are synthesized by animal
cells from glutamine, glycine, aspartate,
ribose-5-phosphate, CO 2 , and tetrahydrofolate
cofactors. They can also be generated by
salvage of preformed purine bases, hypoxanthine,
guanine, and adenine (but not xanthine),
and adenosine (but not inosine or guanosine).
The biosynthetic pathway is highly conserved
among phylogenetically diverse organisms,
including most prokaryotes, yeast, plants, and
birds.
However, all parasitic protozoa and worms
studied to date are incapable of synthesizing
purines de novo, and thus are completely
dependent on salvage of host purines. This
conclusion was based upon the nutritional
dependence of parasites on an exogenous
purine supply and the inability of these organisms
to incorporate radiolabeled precursors
(i.e. [ 14 C]formate or [ 14 C]glycine) into purine
nucleotides. It should be noted that mammalian
cells might also not incorporate [ 14 C]formate
or [ 14 C]glycine into nucleotides under
conditions in which purines are present in the
environment, primarily because of feedback
mechanisms on the early steps of purine
biosynthesis. The lack of an intact purine pathway
in parasites is strongly supported by the
failure to detect a complete set of homologs of
purine biosynthesis enzymes within parasite
genomes.
In addition to the biosynthetic pathway,
mammalian cells also express a variety of
purine salvage and interconversion enzymes
(Figure 9.3). The salvage pathway functions to
take up purines obtained from nucleic acid
and nucleotide turnover, as well as from the
diet. The process of purine salvage is advantageous
to the cell since it is less energetically
expensive than the de novo pathway, which
requires hydrolysis of seven high-energy
phosphate bonds just to synthesize AMP
or GMP. Purine salvage also traps diffusible
purine bases and nucleosides as anionic,
phosphorylated metabolites, thereby ensuring
FIGURE 9.3 Mammalian purine salvage and interconversion pathways. Enzymes are designated numerically
and can be identified from Table 9.1.
BIOCHEMISTRY AND CELL BIOLOGY: PROTOZOA