Nature. 2019 Apr;568(7753):571-575. doi: 10.1038/s41586-019-1095-5. Epub 2019 Apr 3.
Structure of ATP citrate lyase (ACLY) and the origin of citrate synthase(CS) in the Krebs cycle.
Verschueren KHG1,2, Blanchet C3, Felix J4, Dansercoer A1,2, De Vos D5, Bloch Y1,2, Van Beeumen J6, Svergun D3, Gutsche I4, Savvides SN1,2, Verstraete K7,8.
- 1Unit for Structural Biology, VIB Center for Inflammation Research, Ghent, Belgium.
- 2Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium.3European Molecular Biology Laboratory (EMBL), Hamburg Outstation c/o DESY, Hamburg, Germany.4University of Grenoble Alpes, CNRS, CEA, CNRS, IBS, Grenoble, France.5Integrated Molecular Plant Physiology Research, Department of Biology, University of Antwerp, Antwerp, Belgium.6Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium.7Unit for Structural Biology, VIB Center for Inflammation Research, Ghent, Belgium. kenneth.verstraete@ugent.be.8Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium. kenneth.verstraete@ugent.be.
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 cancer8,9,10,11 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.
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 cancer8,9,10,11 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.
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