Activity and structure of human acetyl‐CoA carboxylase targeted by a specific inhibitor

Jang, SoRi; Górnicki, Piotr; Marjanovic, Jasmina; Bass, Ethan; Iurcotta, Toni P.; Rodrı́guez, P.; Austin, Jotham R.; Haselkorn, Robert

doi:10.1002/1873-3468.13097

Cited by 6 publications

(8 citation statements)

References 59 publications

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“…The main mechanism of action (MOA) of the BC domain targeting inhibitors is allosterically inhibiting the dimerization of the BC domain, maintaining ACC1 molecules as inactive monomers that are unable to perform the catalytic activity (21). Soraphen A, AMPK activators, and ND-series inhibitors (ND-630, ND-646, ND-654) inhibit ACC1 belong to this category (73,91,(95)(96)(97)(98). These inhibitors can effectively inhibit ACCs activity and affect the process of lipid metabolism and the development of disease (10,26,28,29,90,99,100).…”

Section: Acetyl-coa Carboxylases-targeting Small Molecules For Therap...mentioning

confidence: 99%

Acetyl-CoA Carboxylases and Diseases

Wang

et al. 2022

Front. Oncol.

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Acetyl-CoA carboxylases (ACCs) are enzymes that catalyze the carboxylation of acetyl-CoA to produce malonyl-CoA. In mammals, ACC1 and ACC2 are two members of ACCs. ACC1 localizes in the cytosol and acts as the first and rate-limiting enzyme in the de novo fatty acid synthesis pathway. ACC2 localizes on the outer membrane of mitochondria and produces malonyl-CoA to regulate the activity of carnitine palmitoyltransferase 1 (CPT1) that involves in the β-oxidation of fatty acid. Fatty acid synthesis is central in a myriad of physiological and pathological conditions. ACC1 is the major member of ACCs in mammalian, mountains of documents record the roles of ACC1 in various diseases, such as cancer, diabetes, obesity. Besides, acetyl-CoA and malonyl-CoA are cofactors in protein acetylation and malonylation, respectively, so that the manipulation of acetyl-CoA and malonyl-CoA by ACC1 can also markedly influence the profile of protein post-translational modifications, resulting in alternated biological processes in mammalian cells. In the review, we summarize our understandings of ACCs, including their structural features, regulatory mechanisms, and roles in diseases. ACC1 has emerged as a promising target for diseases treatment, so that the specific inhibitors of ACC1 for diseases treatment are also discussed.

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Section: Acetyl-coa Carboxylases-targeting Small Molecules For Therap...mentioning

confidence: 99%

Acetyl-CoA Carboxylases and Diseases

Wang

et al. 2022

Front. Oncol.

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“…In periods of ischaemia, adenosine monophosphate (AMP) levels rise, which stimulates the activity of AMP-activated protein kinase (AMPK). 45,47 AMPK relieves the inhibition of malonyl-CoA on carnitine palmitoyltransferase I (CPT-1) via acetyl-CoA carboxylase inhibition 45,48 (Fig 2). CPT-1 is a ratelimiting step in free fatty acid (FFA) oxidation (β-Oxidation), therefore, AMPK acts to increase rates of β-Oxidation.…”

Section: A C C E P T E Dmentioning

confidence: 99%

Peritransplant Cardiometabolic and Mitochondrial Function: The Missing Piece in Donor Heart Dysfunction and Graft Failure

et al. 2021

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Primary graft dysfunction (PGD) is an important cause of morbidity and mortality after cardiac transplantation. Donor brain stem death (BSD) is a significant contributor to donor heart dysfunction (DHD) and PGD. There remain substantial gaps in the mechanistic understanding of peritransplant cardiac dysfunction. One of these gaps is cardiac metabolism and metabolic function. The healthy heart is an 'omnivore', capable of utilising multiple sources of nutrients to fuel its enormous energetic demand. When this fails, metabolic inflexibility leads to myocardial dysfunction. Data have hinted at metabolic disturbance in the BSD donor and subsequent HTx, however, there is limited evidence demonstrating specific metabolic or mitochondrial dysfunction. This review will examine the literature surrounding cardiometabolic and mitochondrial function in the BSD donor, organ preservation, and subsequent cardiac transplantation. A more comprehensive understanding of this subject may then help to identify important cardioprotective strategies to improve the number and quality of donor hearts.

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“…In human cancer cells, expression of ACLY and ACC is also markedly increased [ 6 ]. When the cellular energy state is low, AMP-activated protein kinase (AMPK) phosphorylates and directly inhibits ACC1 and ACC2 (S80 for ACC1 and S222 for ACC2 in humans, S79 for ACC1 and S212 for ACC2 in mice [ 8 ]). In mice with targeted knock-in mutations in which the AMPK phosphorylation sites on ACC1/2 are converted to alanine, there is a loss of AMPK-mediated ACC inhibition, elevated hepatic lipogenesis, insulin resistance, and early signs of NAFLD and fibrosis [ 9 ].…”

Section: Fatty Acid Synthesis and Targeting Strategies For Liver Dmentioning

confidence: 99%

NASH, Fibrosis and Hepatocellular Carcinoma: Lipid Synthesis and Glutamine/Acetate Signaling

Sunami

2020

IJMS

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Primary liver cancer is predicted to be the sixth most common cancer and the fourth leading cause of cancer mortality worldwide. Recent studies identified nonalcoholic fatty liver disease (NAFLD) as the underlying cause in 13–38.2% of patients with hepatocellular carcinoma unrelated to viral hepatitis and alcohol abuse. NAFLD progresses to nonalcoholic steatohepatitis (NASH), which increases the risk for the development of liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD is characterized by dysregulation of lipid metabolism. In addition, lipid metabolism is effected not only in NAFLD, but also in a broad range of chronic liver diseases and tumor development. Cancer cells manipulate a variety of metabolic pathways, including lipid metabolism, in order to build up their own cellular components. Identifying tumor dependencies on lipid metabolism would provide options for novel targeting strategies. This review article summarizes the research evidence on metabolic reprogramming and focuses on lipid metabolism in NAFLD, NASH, fibrosis, and cancer. As alternative routes of acetyl-CoA production for fatty acid synthesis, topics on glutamine and acetate metabolism are included. Further, studies on small compound inhibitors targeting lipid metabolism are discussed. Understanding reprogramming strategies in liver diseases, as well as the visualization of the metabolism reprogramming networks, could uncover novel therapeutic options.

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Activity and structure of human acetyl‐CoA carboxylase targeted by a specific inhibitor

Cited by 6 publications

References 59 publications

Acetyl-CoA Carboxylases and Diseases

Acetyl-CoA Carboxylases and Diseases

Peritransplant Cardiometabolic and Mitochondrial Function: The Missing Piece in Donor Heart Dysfunction and Graft Failure

NASH, Fibrosis and Hepatocellular Carcinoma: Lipid Synthesis and Glutamine/Acetate Signaling

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