6HXO

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

(2019) Nature 568: 571-575

• PubMed: 30944476 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1038/s41586-019-1095-5
• Primary Citation of Related Structures:  
  6HXH, 6HXI, 6HXJ, 6HXK, 6HXL, 6HXM, 6HXN, 6HXO, 6HXP, 6HXQ, 6QCL, 6QFB


• 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 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.

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Organizational Affiliation: 

Unit for Structural Biology, VIB Center for Inflammation Research, Ghent, Belgium.