Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle

Koen H. G. Verschueren, Clement Blanchet, Jan Felix, Ann Dansercoer, Dirk De Vos, Yehudi Bloch, Jozef Van Beeumen, Dmitri Svergun, Irina Gutsche, Savvas N. Savvides and Kenneth Verstraete ()
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Koen H. G. Verschueren: Unit for Structural Biology, VIB Center for Inflammation Research
Clement Blanchet: European Molecular Biology Laboratory (EMBL), Hamburg Outstation c/o DESY
Jan Felix: University of Grenoble Alpes, CNRS, CEA, CNRS, IBS
Ann Dansercoer: Unit for Structural Biology, VIB Center for Inflammation Research
Dirk De Vos: University of Antwerp
Yehudi Bloch: Unit for Structural Biology, VIB Center for Inflammation Research
Jozef Van Beeumen: Ghent University
Dmitri Svergun: European Molecular Biology Laboratory (EMBL), Hamburg Outstation c/o DESY
Irina Gutsche: University of Grenoble Alpes, CNRS, CEA, CNRS, IBS
Savvas N. Savvides: Unit for Structural Biology, VIB Center for Inflammation Research
Kenneth Verstraete: Unit for Structural Biology, VIB Center for Inflammation Research

Nature, 2019, vol. 568, issue 7753, 571-575

Abstract: Abstract Across different kingdoms of life, ATP citrate lyase (ACLY, also known as ACL) catalyses the ATP-dependent and coenzyme A (CoA)-dependent conversion of citrate, a metabolic product of the Krebs cycle, to oxaloacetate and the high-energy biosynthetic precursor acetyl-CoA1. The latter fuels pivotal biochemical reactions such as the synthesis of fatty acids, cholesterol and acetylcholine2, and the acetylation of histones and proteins3,4. In autotrophic prokaryotes, ACLY is a hallmark enzyme of the reverse Krebs cycle (also known as the reductive tricarboxylic acid cycle), which fixates two molecules of carbon dioxide in acetyl-CoA5,6. In humans, ACLY links carbohydrate and lipid metabolism and is strongly expressed in liver and adipose tissue1 and in cholinergic neurons2,7. The structural basis of the function of ACLY remains unknown. Here we report high-resolution crystal structures of bacterial, archaeal and human ACLY, and use distinct substrate-bound states to link the conformational plasticity of ACLY to its multistep catalytic itinerary. Such detailed insights will provide the framework for targeting human ACLY in cancer8–11 and hyperlipidaemia12,13. Our structural studies also unmask a fundamental evolutionary relationship that links citrate synthase, the first enzyme of the oxidative Krebs cycle, to an ancestral tetrameric citryl-CoA lyase module that operates in the reverse Krebs cycle. This molecular transition marked a key step in the evolution of metabolism on Earth.

Date: 2019
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DOI: 10.1038/s41586-019-1095-5

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