Abstract
The pyruvate dehydrogenase complex (PDHc) links glycolysis to the citric acid cycle by converting pyruvate into acetyl-coenzyme A. PDHc encompasses three enzymatically active subunits, namely pyruvate dehydrogenase, dihydrolipoyl transacetylase, and dihydrolipoyl dehydrogenase. Dihydrolipoyl transacetylase is a multidomain protein comprising a varying number of lipoyl domains, a peripheral subunit-binding domain, and a catalytic domain. It forms the structural core of the complex, provides binding sites for the other enzymes, and shuffles reaction intermediates between the active sites through covalently bound lipoyl domains. The molecular mechanism by which this shuttling occurs has remained elusive. Here, we report a cryo-EM reconstruction of the native E. coli dihydrolipoyl transacetylase core in a resting state. This structure provides molecular details of the assembly of the core and reveals how the lipoyl domains interact with the core at the active site.
Highlights
The pyruvate dehydrogenase complex (PDHc) links glycolysis to the citric acid cycle by converting pyruvate into acetyl-coenzyme A
The pyruvate dehydrogenase complex (PDHc) is a multienzyme complex of megadalton size that converts pyruvate into acetyl-coenzyme A (Fig. 1a, b), thereby linking glycolysis to the citric acid cycle and to the biosynthesis of fatty acids and steroids[1]
We report here the cryo-EM reconstruction of the cubic E2p core of E. coli PDHc in a native resting state, in which a lipoyl domain is bound to the catalytic domain of each E2p and the dihydrolipoyllysine residue is immerged deep in the E2p active site channel
Summary
The pyruvate dehydrogenase complex (PDHc) links glycolysis to the citric acid cycle by converting pyruvate into acetyl-coenzyme A. Each lipoyl domain can carry one lipoic acid covalently attached to a lysine residue[20] (Fig. 1d), and they function as swinging arms channeling the substrate between the individual enzymes’ active sites in the PDHc8,21,22 (Fig. 1f).
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