6HXO

Structure of the citryl-CoA lyase core module of Chlorobium limicola ATP citrate lyase (space group P21)

Summary for 6HXO

• Entry DOI: 10.2210/pdb6hxo/pdb
• Descriptor: ATP-citrate lyase alpha-subunit, CITRATE ANION, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (4 entities in total)
• Functional Keywords: atp citrate lyase, central metabolism, acetyl-coa, citrate shuttle, rtca cycle, citryl-coa, lipogenesis, lyase
• Biological source: Chlorobium limicola
• Total number of polymer chains: 8
• Total formula weight: 247763.14

Authors

Verstraete, K.,Verschueren, K. (deposition date: 2018-10-17, release date: 2019-04-10, Last modification date: 2024-05-01)

Primary citation

Verschueren, K.H.G.,Blanchet, C.,Felix, J.,Dansercoer, A.,De Vos, D.,Bloch, Y.,Van Beeumen, J.,Svergun, D.,Gutsche, I.,Savvides, S.N.,Verstraete, K.
Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle.
Nature, 568:571-575, 2019

PubMed 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. The latter fuels pivotal biochemical reactions such as the synthesis of fatty acids, cholesterol and acetylcholine, and the acetylation of histones and proteins. 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. In humans, ACLY links carbohydrate and lipid metabolism and is strongly expressed in liver and adipose tissue and in cholinergic neurons. 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 and hyperlipidaemia. 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.

PubMed: 30944476
DOI: 10.1038/s41586-019-1095-5

Experimental method

X-RAY DIFFRACTION (1.5 Å)