6QFB
Structure of the human ATP citrate lyase holoenzyme in complex with citrate, coenzyme A and Mg.ADP
Summary for 6QFB
| Entry DOI | 10.2210/pdb6qfb/pdb |
| Related | 6hxh |
| Descriptor | ATP-citrate synthase, DIHYDROGENPHOSPHATE ION, COENZYME A, ... (6 entities in total) |
| Functional Keywords | atp citrate lyase, central metabolism, acetyl-coa, citrate shuttle, rtca cycle, citryl-coa, lipogenesis, lyase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 468902.56 |
| Authors | Verstraete, K.,Verschueren, K. (deposition date: 2019-01-09, release date: 2019-04-10, Last modification date: 2024-01-24) |
| 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 Cited by 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: 30944476DOI: 10.1038/s41586-019-1095-5 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.25 Å) |
Structure validation
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