Belapure, Jaydeep

Fratini, Marta

Hamdi, Farzad

Hause, Gerd

Heilmann, Ingo

Kastritis, Panagiotis L.

Kyrilis, Fotis L.

O’Reilly, Francis J.

Rappsilber, Juri

Skalidis, Ioannis

Träger, Toni K.

Tüting, Christian

English

The oxoglutarate dehydrogenase complex (OGDHc) participates in the tricarboxylic acid cycle and, in a multi-step reaction, decarboxylates α-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 Å 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.</p

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Structural analysis of an endogenous 4-megadalton succinyl-CoA-generating metabolon

https://www.research.ed.ac.uk/files/353430906/s42003_023_04885_0.pdf

Structural analysis of an endogenous 4-megadalton succinyl-CoA-generating metabolon

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