Acetate Revisited: A Key Biomolecule at the Nexus of Metabolism, Epigenetics and Oncogenesis—Part 1: Acetyl-CoA, Acetogenesis and Acyl-CoA Short-Chain Synthetases

Moffett, John R.; Puthillathu, Narayanan; Vengilote, Ranjini; Jaworski, Diane M.; Namboodiri, Aryan M.A.

doi:10.3389/fphys.2020.580167

Cited by 81 publications

(69 citation statements)

References 198 publications

(229 reference statements)

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“…There are times when ACSS2-mediated acetyl-CoA synthesis becomes very important. This was somewhat surprising given the relatively low plasma acetate levels in rodents and humans [ 52 ]. Serum acetate levels are normally 80–200 µM in non-fasted humans [ 52 ].…”

Section: Acly Synthesizes the Majority Of Nucleocytoplasmic Acetyl-coa While Acetyl-coa Synthetase 2 (Acss2) Plays A Smaller But Importanmentioning

confidence: 99%

“…This was somewhat surprising given the relatively low plasma acetate levels in rodents and humans [ 52 ]. Serum acetate levels are normally 80–200 µM in non-fasted humans [ 52 ]. In rats serum acetate levels were shown to drop by 10% after one day of fasting and drop by 30% after three days of fasting [ 53 ], likely due to decreased acetate production by the intestinal microbiota [ 54 ], which in the fed state are the major source of serum acetate.…”

Section: Acly Synthesizes the Majority Of Nucleocytoplasmic Acetyl-coa While Acetyl-coa Synthetase 2 (Acss2) Plays A Smaller But Importanmentioning

confidence: 99%

“…In rats serum acetate levels were shown to drop by 10% after one day of fasting and drop by 30% after three days of fasting [ 53 ], likely due to decreased acetate production by the intestinal microbiota [ 54 ], which in the fed state are the major source of serum acetate. Fasting increases the hepatic hydrolysis of acetyl-CoA to acetate by the enzyme acyl-CoA thioesterase 12 (ACOT12), formerly called acetyl-CoA hydrolase 1, leading to a two to three fold increase in the release of hepatic acetate into the bloodstream [ 52 ]. Therefore, acetate is released from liver in a similar way as ketone bodies during fasting.…”

Section: Acly Synthesizes the Majority Of Nucleocytoplasmic Acetyl-coa While Acetyl-coa Synthetase 2 (Acss2) Plays A Smaller But Importanmentioning

confidence: 99%

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Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan

Bradshaw

2021

Antioxidants

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Acetyl-CoA is a metabolite at the crossroads of central metabolism and the substrate of histone acetyltransferases regulating gene expression. In many tissues fasting or lifespan extending calorie restriction (CR) decreases glucose-derived metabolic flux through ATP-citrate lyase (ACLY) to reduce cytoplasmic acetyl-CoA levels to decrease activity of the p300 histone acetyltransferase (HAT) stimulating pro-longevity autophagy. Because of this, compounds that decrease cytoplasmic acetyl-CoA have been described as CR mimetics. But few authors have highlighted the potential longevity promoting roles of nuclear acetyl-CoA. For example, increasing nuclear acetyl-CoA levels increases histone acetylation and administration of class I histone deacetylase (HDAC) inhibitors increases longevity through increased histone acetylation. Therefore, increased nuclear acetyl-CoA likely plays an important role in promoting longevity. Although cytoplasmic acetyl-CoA synthetase 2 (ACSS2) promotes aging by decreasing autophagy in some peripheral tissues, increased glial AMPK activity or neuronal differentiation can stimulate ACSS2 nuclear translocation and chromatin association. ACSS2 nuclear translocation can result in increased activity of CREB binding protein (CBP), p300/CBP-associated factor (PCAF), and other HATs to increase histone acetylation on the promoter of neuroprotective genes including transcription factor EB (TFEB) target genes resulting in increased lysosomal biogenesis and autophagy. Much of what is known regarding acetyl-CoA metabolism and aging has come from pioneering studies with yeast, fruit flies, and nematodes. These studies have identified evolutionary conserved roles for histone acetylation in promoting longevity. Future studies should focus on the role of nuclear acetyl-CoA and histone acetylation in the control of hypothalamic inflammation, an important driver of organismal aging.

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Section: Acly Synthesizes the Majority Of Nucleocytoplasmic Acetyl-coa While Acetyl-coa Synthetase 2 (Acss2) Plays A Smaller But Importanmentioning

confidence: 99%

Section: Acly Synthesizes the Majority Of Nucleocytoplasmic Acetyl-coa While Acetyl-coa Synthetase 2 (Acss2) Plays A Smaller But Importanmentioning

confidence: 99%

Section: Acly Synthesizes the Majority Of Nucleocytoplasmic Acetyl-coa While Acetyl-coa Synthetase 2 (Acss2) Plays A Smaller But Importanmentioning

confidence: 99%

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Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan

Bradshaw

2021

Antioxidants

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“…Despite its origination from sources other than pyruvate, mitochondrial acetyl-CoA supplies might remain low in the face of high proliferative demand, vascular insufficiency and nutrient scarcity and thus eventually become rate-limiting in tumors. Acetate, originating in the gut microbiome, or from intracellular deacetylation reactions, and converted to acetyl-CoA by the nucelo-cytoplasmic enzyme acetyl-CoA synthetase 2 (ACCS2) is necessary for the attainment of maximal tumor growth, particularly during hypoxia [ 11 , 266 ]. This could relieve the dependency on mitochondrial-derived acetyl- CoA and citrate that are the canonical starting substrates for de novo lipogenesis while conserving TCA cycle substrates for energy production [ 267 , 268 , 269 ].…”

Section: The Direct Generation Of Acetate From Pyruvatementioning

confidence: 99%

“…In addition to the above sources, acetate is also derived from the diet and the hydrolysis of acetyl-CoA, [ 11 , 12 , 266 , 270 , 271 ]. However, evidence for its direct synthesis by eukaryotic cells has been largely indirect [ 132 , 272 , 273 ].…”

Section: The Direct Generation Of Acetate From Pyruvatementioning

confidence: 99%

The Metabolic Fates of Pyruvate in Normal and Neoplastic Cells

Prochownik

Wang

2021

Cells

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Pyruvate occupies a central metabolic node by virtue of its position at the crossroads of glycolysis and the tricarboxylic acid (TCA) cycle and its production and fate being governed by numerous cell-intrinsic and extrinsic factors. The former includes the cell’s type, redox state, ATP content, metabolic requirements and the activities of other metabolic pathways. The latter include the extracellular oxygen concentration, pH and nutrient levels, which are in turn governed by the vascular supply. Within this context, we discuss the six pathways that influence pyruvate content and utilization: 1. The lactate dehydrogenase pathway that either converts excess pyruvate to lactate or that regenerates pyruvate from lactate for use as a fuel or biosynthetic substrate; 2. The alanine pathway that generates alanine and other amino acids; 3. The pyruvate dehydrogenase complex pathway that provides acetyl-CoA, the TCA cycle’s initial substrate; 4. The pyruvate carboxylase reaction that anaplerotically supplies oxaloacetate; 5. The malic enzyme pathway that also links glycolysis and the TCA cycle and generates NADPH to support lipid bio-synthesis; and 6. The acetate bio-synthetic pathway that converts pyruvate directly to acetate. The review discusses the mechanisms controlling these pathways, how they cross-talk and how they cooperate and are regulated to maximize growth and achieve metabolic and energetic harmony.

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Citric Acid: A Nexus Between Cellular Mechanisms and Biomaterial Innovations

Xu,

Yan,

Gerhard

et al. 2024

Advanced Materials

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Citrate‐based biodegradable polymers have emerged as a distinctive biomaterial platform with tremendous potential for diverse medical applications. By harnessing their versatile chemistry, these polymers exhibit a wide range of material and bioactive properties, enabling them to regulate cell metabolism and stem cell differentiation through energy metabolism, metabonegenesis, angiogenesis and immunomodulation. Moreover, the recent U.S. Food and Drug Administration (FDA) clearance of the biodegradable poly(octamethylene citrate) (POC)/hydroxyapatite‐based orthopedic fixation devices represent a translational research milestone for biomaterial science. POC joins a short list of biodegradable synthetic polymers that have ever been authorized by the FDA for use in humans. The clinical success of POC has sparked enthusiasm and accelerated the development of next‐generation citrate‐based biomaterials. This review presents a comprehensive, forward‐thinking discussion on the pivotal role of citrate chemistry and metabolism in various tissue regeneration and on the development of functional citrate‐based metabotissugenic biomaterials for regenerative engineering applications.This article is protected by copyright. All rights reserved

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Acetate Revisited: A Key Biomolecule at the Nexus of Metabolism, Epigenetics and Oncogenesis—Part 1: Acetyl-CoA, Acetogenesis and Acyl-CoA Short-Chain Synthetases

Cited by 81 publications

References 198 publications

Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan

Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan

The Metabolic Fates of Pyruvate in Normal and Neoplastic Cells

Citric Acid: A Nexus Between Cellular Mechanisms and Biomaterial Innovations

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