trans

AMINO ACID METABOLISM 185
Glutamine
Apart from the requirement of glutamine for
optimal intraerythrocytic growth of P. falciparum,
mentioned in the section on Amino
acid Transport, little is known about the relevance
of glutamine and its catabolism in parasitic
protozoa. Helminths, such as filarids
and schistosomes, oxidize glutamine to CO 2
through the TCA cycle and the respiratory
chain. This oxidation implies the formation of
-ketoglutarate, which can be obtained by
transamination of the glutamate produced in
the glutaminase reaction (Figure 8.2), or succinate,
if glutamine is first metabolized to
-aminobutyrate and succinic semialdehyde.
Although the latter pathway has been proposed,
evidence for a functional -aminobutyrate
bypass is incomplete, since succinic
semialdehyde dehydrogenase has not been
identified to date.
Methionine, cysteine and homocysteine.
Methionine recycling
The catabolism of methionine is intimately
connected with biosynthetic processes, participating
as S-adenosyl methionine; these
processes include methylation and polyamine
biosynthesis (see section on Arginine, Methionine
and Synthesis of Polyamines). Part of the
carbon chain of methionine can be used to
generate energy, but most organisms contain
systems for the recycling of the metabolites
arising from biosynthetic reactions back to
methionine (Figure 8.3).
Methionine can be degraded in mammals to
-ketobutyrate, methanethiol and NH 4 by the
concerted action of two enzymes, catalyzing
first a transamination reaction leading to 2-
keto-4-methylthiobutyrate, and then a dethiomethylation
reaction. In T. vaginalis, however,
this process is accomplished by a single
enzyme, methionine -lyase; methanethiol
is produced and excreted by the parasite.
This pyridoxal 5 phosphate-requiring enzyme
also has homocysteine desulphurase activity,
degrading homocysteine to -ketobutyrate,
SH 2 and NH 4 . -ketobutyrate and -hydroxybutyrate
are not excreted by T. vaginalis, and
-ketobutyrate may be used in the production
of propionyl-CoA in the pyruvate:ferredoxin
oxidoreductase reaction, leading to the excretion
of propionate and to energy conservation
in the form of ATP.
Recycling of methionine can occur starting
from S-adenosylhomocysteine, after transfer
of the methyl group in a transmethylation
reaction, or from 5-methylthioadenosine
(MTA), after transfer of the aminopropyl group
for polyamine biosynthesis (Figure 8.3). In the
former case, most of the methionine carbon is
recovered, whereas in the latter only the methyl
group in the recovered methionine originates
in the original molecule, the rest of the carbon
atoms coming from the ribose in the nucleoside.
In general, these pathways are similar
to those operative in the mammalian host.
For example, S-adenosylmethionine synthetase
and S-adenosylmethionine decarboxylase, as
well as S-adenosylhomocysteine hydrolase and
the cobalamin-dependent, tetrahydrofolateutilizing
methionine synthase, have been
characterized in P. falciparum. However, some
parasitic protozoa exhibit one important difference
at the level of conversion of MTA to
5-methylthioribose-5-phosphate. In mammals,
as well as in T. brucei and in P. falciparum, this
reaction is catalyzed by a single enzyme, MTA
phosphorylase. In G. lamblia and E. histolytica,
this reaction is performed by the concerted
action of two enzymes, MTA nucleosidase and
5-methylthioribose kinase. Since the latter
enzyme is found only in bacteria and these
primitive protozoa, it may be a suitable target
for chemotherapy.
BIOCHEMISTRY AND CELL BIOLOGY: PROTOZOA