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Publication Abstract from PubMed

The oxoglutarate dehydrogenase complex (OGDHc) participates in the tricarboxylic acid cycle and, in a multi-step reaction, decarboxylates alpha-ketoglutarate, transfers succinyl to CoA, and reduces NAD+. Due to its pivotal role in metabolism, OGDHc enzymatic components have been studied in isolation; however, their interactions within the endogenous OGDHc remain elusive. Here, we discern the organization of a thermophilic, eukaryotic, native OGDHc in its active state. By combining biochemical, biophysical, and bioinformatic methods, we resolve its composition, 3D architecture, and molecular function at 3.35 A resolution. We further report the high-resolution cryo-EM structure of the OGDHc core (E2o), which displays various structural adaptations. These include hydrogen bonding patterns confining interactions of OGDHc participating enzymes (E1o-E2o-E3), electrostatic tunneling that drives inter-subunit communication, and the presence of a flexible subunit (E3BPo), connecting E2o and E3. This multi-scale analysis of a succinyl-CoA-producing native cell extract provides a blueprint for structure-function studies of complex mixtures of medical and biotechnological value.

Structural analysis of an endogenous 4-megadalton succinyl-CoA-generating metabolon.,Skalidis I, Kyrilis FL, Tuting C, Hamdi F, Trager TK, Belapure J, Hause G, Fratini M, O'Reilly FJ, Heilmann I, Rappsilber J, Kastritis PL Commun Biol. 2023 May 22;6(1):552. doi: 10.1038/s42003-023-04885-0. PMID:37217784^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.