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Propionyl-CoA and Adenosylcobalamin Metabolism in C. elegans : Evidence for a Role of Methylmalonyl-CoA Epimerase in Intermediary Metabolism
Ist Teil von
Molecular genetics and metabolism, 2006-01, Vol.89 (1-2), p.64-73
Erscheinungsjahr
2006
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
We have utilized
Caenorhabditis elegans
to study human methylmalonic acidemia. Using bioinformatics, a full complement of mammalian homologues for the conversion of propionyl-CoA to succinyl-CoA in the genome of
C. elegans
, including propionyl-CoA carboxylase subunits A and B (
pcca-1, pccb-1
), methylmalonic acidemia cobalamin A complementation group (
mmaa-1
), co(I)balamin adenosyltransferase (
mmab-1
), MMACHC (
cblc-1
), methylmalonyl-CoA epimerase (
mce-1
) and methylmalonyl-CoA mutase (
mmcm-1
) were identified. To verify predictions that the entire intracellular adenosylcobalamin metabolic pathway existed and was functional, the kinetic properties of the
C. elegans mmcm-1
were examined. RNA interference against
mmcm-1, mmab-1, mmaa-1
in the presence of propionic acid revealed a chemical phenotype of increased methylmalonic acid; deletion mutants of
mmcm-1, mmab-1
and
mce-1
displayed reduced 1-[
14
C]-propionate incorporation into macromolecules. The mutants produced increased amounts of methylmalonic acid in the culture medium, proving that a functional block in the pathway caused metabolite accumulation. Lentiviral delivery of the
C. elegans mmcm-1
into fibroblasts derived from a patient with
mut
o
class methylmalonic acidemia could partially restore propionate flux. The
C. elegans mce-1
deletion mutant demonstrates for the first time that a lesion at the racemase step of methylmalonyl-CoA metabolism can functionally impair flux through the methylmalonyl-CoA mutase pathway and suggests that malfunction of MCEE may cause methylmalonic acidemia in humans. The
C. elegans
system we describe represents the first lower metazoan model organism of mammalian propionate spectrum disorders and demonstrates that mass spectrometry can be employed to study a small molecule chemical phenotype in
C. elegans
RNAi and deletion mutants.