Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle
- Author
- Koen Verschueren (UGent) , Clement Blanchet, Jan Felix, Ann Dansercoer (UGent) , Dirk De Vos, Yehudi Bloch (UGent) , Jozef Van Beeumen (UGent) , Dmitri Svergun, Irina Gutsche, Savvas Savvides (UGent) and Kenneth Verstraete (UGent)
- Organization
- 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-CoA(1). The latter fuels pivotal biochemical reactions such as the synthesis of fatty acids, cholesterol and acetylcholine(2), and the acetylation of histones and proteins(3,4). 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-CoA(5,6). In humans, ACLY links carbohydrate and lipid metabolism and is strongly expressed in liver and adipose tissue(1) and in cholinergic neurons(2,7). 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 cancer(8-11) and hyperlipidaemia(12,13). 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.
- Keywords
- CLEAVAGE REACTION, COA SYNTHETASE, ENZYME, ACID, IDENTIFICATION, INHIBITION, ACTIVATION, MECHANISM, FIXATION, COENZYME
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-8616368
- MLA
- Verschueren, Koen, et al. “Structure of ATP Citrate Lyase and the Origin of Citrate Synthase in the Krebs Cycle.” NATURE, vol. 568, no. 7753, 2019, pp. 571–75, doi:10.1038/s41586-019-1095-5.
- APA
- Verschueren, K., Blanchet, C., Felix, J., Dansercoer, A., De Vos, D., Bloch, Y., … Verstraete, K. (2019). Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle. NATURE, 568(7753), 571–575. https://doi.org/10.1038/s41586-019-1095-5
- Chicago author-date
- Verschueren, Koen, Clement Blanchet, Jan Felix, Ann Dansercoer, Dirk De Vos, Yehudi Bloch, Jozef Van Beeumen, et al. 2019. “Structure of ATP Citrate Lyase and the Origin of Citrate Synthase in the Krebs Cycle.” NATURE 568 (7753): 571–75. https://doi.org/10.1038/s41586-019-1095-5.
- Chicago author-date (all authors)
- Verschueren, Koen, Clement Blanchet, Jan Felix, Ann Dansercoer, Dirk De Vos, Yehudi Bloch, Jozef Van Beeumen, Dmitri Svergun, Irina Gutsche, Savvas Savvides, and Kenneth Verstraete. 2019. “Structure of ATP Citrate Lyase and the Origin of Citrate Synthase in the Krebs Cycle.” NATURE 568 (7753): 571–575. doi:10.1038/s41586-019-1095-5.
- Vancouver
- 1.Verschueren K, Blanchet C, Felix J, Dansercoer A, De Vos D, Bloch Y, et al. Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle. NATURE. 2019;568(7753):571–5.
- IEEE
- [1]K. Verschueren et al., “Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle,” NATURE, vol. 568, no. 7753, pp. 571–575, 2019.
@article{8616368,
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-CoA(1). The latter fuels pivotal biochemical reactions such as the synthesis of fatty acids, cholesterol and acetylcholine(2), and the acetylation of histones and proteins(3,4). 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-CoA(5,6). In humans, ACLY links carbohydrate and lipid metabolism and is strongly expressed in liver and adipose tissue(1) and in cholinergic neurons(2,7). 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 cancer(8-11) and hyperlipidaemia(12,13). 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.}},
author = {{Verschueren, Koen and Blanchet, Clement and Felix, Jan and Dansercoer, Ann and De Vos, Dirk and Bloch, Yehudi and Van Beeumen, Jozef and Svergun, Dmitri and Gutsche, Irina and Savvides, Savvas and Verstraete, Kenneth}},
issn = {{0028-0836}},
journal = {{NATURE}},
keywords = {{CLEAVAGE REACTION,COA SYNTHETASE,ENZYME,ACID,IDENTIFICATION,INHIBITION,ACTIVATION,MECHANISM,FIXATION,COENZYME}},
language = {{eng}},
number = {{7753}},
pages = {{571--575}},
title = {{Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle}},
url = {{http://doi.org/10.1038/s41586-019-1095-5}},
volume = {{568}},
year = {{2019}},
}
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