An allosteric mechanism for potent inhibition of human ATP-citrate lyase

Jia, Wei; Leit, Silvana; Kuai, Jun; Therrien, Éric; Rafi, Salma B.; Harwood, H. James; DeLaBarre, Byron; Tong, Liang

doi:10.1038/s41586-019-1094-6

Cited by 114 publications

(109 citation statements)

References 45 publications

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“…Once citryl‐CoA has bound, the active site closes to catalyze cleavage to oxaloacetate and acetyl‐CoA at site III. This proposal is consistent with the recently published structures of hACLY and Methanothrix soehngenii ACLY . The location of the N‐terminal portion with respect to the C‐terminal portion shows that the citryl end of citryl‐CoA swings 35 å from site I to site III.…”

Section: Discussionsupporting

confidence: 91%

“…Recent publications also showed ACLY in an open conformation with CoA bound, and two structures in a closed conformation one with malate and acetyl‐CoA bound and one with citrate bound . No structure had been determined with only the addition of acetyl‐CoA in the absence of an organic acid.…”

Section: Discussionmentioning

confidence: 99%

“…Recent publications also showed ACLY in an open conformation with CoA bound, and two structures in a closed conformation one with malate and acetyl-CoA bound and one with citrate bound. 17,18 No structure had been determined with only the addition of acetyl-CoA in the absence of an organic acid. The open conformation in the presence of acetyl-CoA proves that binding of an appropriate organic acid is what induces a closed conformation, regardless of whether acetyl-CoA is bound.…”

Section: Comparison Of Clacly With Css Of the Tca Cyclementioning

confidence: 99%

“…This proposal is consistent with the recently published structures of hACLY and Methanothrix soehngenii ACLY. 17,18 The location of the N-terminal portion with respect to the C-terminal portion shows that the citryl end of citryl-CoA swings 35 Å from site I to site III.…”

Section: Delivery Of Citryl-coa From the N-terminal Portion Of Aclymentioning

confidence: 99%

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Identification of the active site residues in ATP‐citrate lyase's carboxy‐terminal portion

et al. 2019

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ATP‐citrate lyase (ACLY) catalyzes production of acetyl‐CoA and oxaloacetate from CoA and citrate using ATP. In humans, this cytoplasmic enzyme connects energy metabolism from carbohydrates to the production of lipids. In certain bacteria, ACLY is used to fix carbon in the reductive tricarboxylic acid cycle. The carboxy(C)‐terminal portion of ACLY shows sequence similarity to citrate synthase of the tricarboxylic acid cycle. To investigate the roles of residues of ACLY equivalent to active site residues of citrate synthase, these residues in ACLY from Chlorobium limicola were mutated, and the proteins were investigated using kinetics assays and biophysical techniques. To obtain the crystal structure of the C‐terminal portion of ACLY, full‐length C. limicola ACLY was cleaved, first non‐specifically with chymotrypsin and subsequently with Tobacco Etch Virus protease. Crystals of the C‐terminal portion diffracted to high resolution, providing structures that show the positions of active site residues and how ACLY tetramerizes.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Comparison Of Clacly With Css Of the Tca Cyclementioning

confidence: 99%

Section: Delivery Of Citryl-coa From the N-terminal Portion Of Aclymentioning

confidence: 99%

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Identification of the active site residues in ATP‐citrate lyase's carboxy‐terminal portion

et al. 2019

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“…The correct pose is particularly important for methods such as free energy perturbation calculations, where a compound is alchemically mutated to an analogue over the course of a molecular simulation and the relative free energy of binding is calculated, as was recently successfully shown on a cryoEM derived structure for human ATP-citrate lyase 7 . Furthermore, a sufficiently high-resolution (usually <2.5 Å) structure will allow for the identification of bound water molecules, which can play crucial roles in drug design 8 .…”

Section: Introductionmentioning

confidence: 99%

GemSpot: A Pipeline for Robust Modeling of Ligands into CryoEM Maps

Robertson¹,

Zundert

Borrelli

et al. 2019

Preprint

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AbstractProducing an accurate atomic model of biomolecule-ligand interactions from maps generated by cryo-electron microscopy often presents challenges inherent to the methodology and the dynamic nature of ligand binding. Here we have developed GemSpot, a pipeline of computational chemistry methods that take into account EM map potentials, quantum mechanics energy calculations, and water molecule site prediction to generate candidate poses and provide a measure of the degree of confidence. The pipeline is validated through several published cryoEM structures of complexes in different resolution ranges and various types of ligands. In all cases, at least one identified pose produced both excellent interactions with the target and agreement with the map. GemSpot will be valuable for the robust identification of ligand poses and drug discovery efforts through cryoEM.

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Adenosine Triphosphate Citrate Lyase and Fatty Acid Synthesis Inhibition

Lau

Giugliano

2023

JAMA Cardiol

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ImportanceAdenosine triphosphate citrate lyase (ACLY) is a key regulatory enzyme of glucose metabolism, cholesterol and fatty acid synthesis, and the inflammatory cascade. Bempedoic acid, an ACLY inhibitor, significantly reduces atherogenic lipid markers, including low-density lipoprotein cholesterol (LDL-C), non–high-density lipoprotein cholesterol, and apolipoprotein B. Additional effects of ACLY inhibition include antitumor growth; reduction of triglycerides and proinflammatory molecules such as high-sensitivity C-reactive protein; less insulin resistance; reduction of hepatic lipogenesis; and weight loss.ObservationsWhile numerous ACLY inhibitors have been identified, most of the clinical data have focused on bempedoic acid. The Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) program was a series of phase 3 clinical trials that evaluated its effects on lipid parameters and safety, leading to US Food and Drug Administration approval in 2020. CLEAR Outcomes was a phase 3, double-blind, randomized, placebo-controlled trial in individuals with a history of statin intolerance, serum LDL-C level of 100 mg/dL or higher, and a history of, or at high risk for, cardiovascular disease. Bempedoic acid modestly reduced the primary 4-way cardiovascular composite end point as well as the individual components of myocardial infarction and coronary revascularization but did not reduce stroke, cardiovascular death, or all-cause mortality. Rates of gout and cholelithiasis were higher with bempedoic acid, and small increases in serum creatinine, uric acid, and hepatic-enzyme levels were also observed.Conclusions and relevanceACLY inhibition with bempedoic acid has been established as a safe and effective therapy in high-risk patients who require further LDL-C lowering, particularly for those with a history of statin intolerance. The recently published CLEAR Outcomes trial revealed modest reductions in cardiovascular events with bempedoic acid, proportional to its LDL-C lowering, in high-risk individuals with statin intolerance and LDL-C levels of 100 mg/dL or higher. The additional effects of ACLY inhibition have prompted a more thorough search for novel ACLY inhibitors for conditions such as cancer, hypertriglyceridemia, chronic inflammation, type 2 diabetes, fatty liver disease, obesity, and metabolic syndrome. Similarly, therapies that reduce fatty acid synthesis are being explored for their use in cardiometabolic conditions.

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An allosteric mechanism for potent inhibition of human ATP-citrate lyase

Cited by 114 publications

References 45 publications

Identification of the active site residues in ATP‐citrate lyase's carboxy‐terminal portion

Identification of the active site residues in ATP‐citrate lyase's carboxy‐terminal portion

GemSpot: A Pipeline for Robust Modeling of Ligands into CryoEM Maps

Adenosine Triphosphate Citrate Lyase and Fatty Acid Synthesis Inhibition

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