Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
Ergebnis 25 von 37

Details

Autor(en) / Beteiligte
Titel
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.
Sprache
Englisch
Identifikatoren
ISSN: 1096-7192
eISSN: 1096-7206
DOI: 10.1016/j.ymgme.2006.06.001
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2761207
Format

Weiterführende Literatur

Empfehlungen zum selben Thema automatisch vorgeschlagen von bX