Clinical and Translational Medicine, Journal Year: 2025, Volume and Issue: 15(1)
Published: Jan. 1, 2025
Language: Английский
Science Advances, Journal Year: 2023, Volume and Issue: 9(18)
Published: May 3, 2023
The metabolite acetyl-CoA is necessary for both lipid synthesis in the cytosol and histone acetylation nucleus. two canonical precursors to nuclear-cytoplasmic compartment are citrate acetate, which processed by ATP-citrate lyase (ACLY) acyl-CoA synthetase short-chain 2 (ACSS2), respectively. It unclear whether other substantial routes nuclear-cytosolic exist. To investigate this, we generated cancer cell lines lacking ACLY ACSS2 [double knockout (DKO) cells]. Using stable isotope tracing, show that glucose fatty acids contribute pools DKO cells acetylcarnitine shuttling can transfer two-carbon units from mitochondria cytosol. Further, absence of ACLY, feed acid a carnitine responsive acetyltransferase (CrAT)-dependent manner. data define as an ACLY- ACSS2-independent precursor support acetylation, synthesis, growth.
Language: Английский
Citations
61
MedComm, Journal Year: 2024, Volume and Issue: 5(2)
Published: Feb. 1, 2024
Abstract Epigenetic modifications are defined as heritable changes in gene activity that do not involve the underlying DNA sequence. The oncogenic process is driven by accumulation of alterations impact genome's structure and function. Genetic mutations, which directly disrupt sequence, complemented epigenetic modulate expression, thereby facilitating acquisition malignant characteristics. Principals among these shifts methylation histone mark patterns, promote tumor development metastasis. Notably, reversible nature alterations, opposed to permanence genetic changes, positions machinery a prime target discovery novel therapeutics. Our review delves into complexities regulation, exploring its profound effects on initiation, metastatic behavior, metabolic pathways, microenvironment. We place particular emphasis dysregulation at each level modulation, including but limited to, aberrations enzymes responsible for modification, subunit loss or fusions chromatin remodeling complexes, disturbances higher‐order structure. Finally, we also evaluate therapeutic approaches leverage growing understanding dysregulation, offering new avenues cancer treatment.
Language: Английский
Citations
22
Nature Metabolism, Journal Year: 2024, Volume and Issue: 6(6), P. 1008 - 1023
Published: June 13, 2024
Language: Английский
Citations
22
Journal of Hepatology, Journal Year: 2025, Volume and Issue: unknown
Published: March 1, 2025
The liver acts as a central metabolic hub, integrating signals from the gastrointestinal tract and adipose tissue to regulate carbohydrate, lipid, amino acid metabolism. Gut-derived metabolites, such acetate ethanol non-esterified fatty acids white (WAT), influence hepatic processes, which rely on mitochondrial function maintain systemic energy balance. Metabolic dysregulation obesity, insulin resistance, type 2 diabetes disrupt these pathways, leading dysfunction-associated steatotic disease (MASLD) steatohepatitis (MASH). This review explores fluxes within gut-adipose tissue-liver axis, focusing pivotal role of de novo lipogenesis (DNL), dietary substrates like glucose fructose, changes in during MASLD progression. It highlights contributions resistance impaired dynamics lipid accumulation. Further understanding how interplay between substrate flux gastro-intestinal integrates with intersects structural functional alterations mitochondria will be important identify novel therapeutic targets advance treatment MASH.
Language: Английский
Citations
4
ACS Catalysis, Journal Year: 2025, Volume and Issue: 15(3), P. 1841 - 1853
Published: Jan. 17, 2025
Acetaldehyde is a toxic pollutant that can be detoxified by acetaldehyde dehydrogenases (ADAs) through its conversion to acetyl-CoA. This study developed an integrated approach combining virtual screening, rational design, and dual scoring mechanism identify engineer hyperactive ADA variants. A library of 5000 Dickeya parazeae (DpADA) homologues was created protein BLAST, deep learning tools predicted their Kcat values. The top 100 candidates were selected based on binding affinity, evaluated molecular docking phylogenetic analysis. Among these, ADA6 from Buttiauxella sp. S04-F03 exhibited the highest activity, converting 57.6% acetyl-CoA, which 14.1 times higher than DpADA. To improve ADA6's thermostability, folding engineering applied, resulting in P443C variant with 80.7% increase residual activity after heat treatment. Molecular dynamics simulation pinpointed I440 as bottleneck substrate tunnel, guiding design dual-scoring system integrates structural adjustments electronic optimization evaluate mutations for improved exposure activity. final optimized variant, P443C-I440T, achieved efficiency 93.2%. demonstrates effectiveness computational mutagenesis enhance enzyme stability engineering.
Language: Английский
Citations
3
Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(13)
Published: March 21, 2024
Polyamines are a class of small polycationic alkylamines that play essential roles in both normal and cancer cell growth. Polyamine metabolism is frequently dysregulated considered therapeutic target cancer. However, targeting polyamine as monotherapy often exhibits limited efficacy, the underlying mechanisms incompletely understood. Here we report activation catabolism promotes glutamine metabolism, leading to targetable vulnerability lung Genetic pharmacological spermidine/spermine N1-acetyltransferase 1 (SAT1), rate-limiting enzyme catabolism, enhances conversion glutamate subsequent glutathione (GSH) synthesis. This metabolic rewiring ameliorates oxidative stress support proliferation survival. Simultaneous limitation SAT1 result ROS accumulation, growth inhibition, death. Importantly, inhibition either one transport, glutaminase, or GSH biosynthesis combination with synergistically suppresses xenograft tumor formation. Together, this study unveils previously unappreciated functional interconnection between establishes cotargeting strategies potential therapeutics
Language: Английский
Citations
18
Drug Resistance Updates, Journal Year: 2024, Volume and Issue: 76, P. 101114 - 101114
Published: June 22, 2024
Language: Английский
Citations
17
Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(9), P. 1945 - 1962
Published: Sept. 1, 2024
Language: Английский
Citations
16
Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(8)
Published: Aug. 1, 2024
Abstract Pancreatic cancer is an aggressive with a poor prognosis. Metabolic abnormalities are one of the hallmarks pancreatic cancer, and cells can adapt to biosynthesis, energy intake, redox needs through metabolic reprogramming tolerate nutrient deficiency hypoxic microenvironments. use glucose, amino acids, lipids as maintain malignant growth. Moreover, they also metabolically interact in tumour microenvironment change cell fate, promote progression, even affect immune responses. Importantly, changes at body level deserve more attention. Basic research clinical trials based on targeted therapy or combination other treatments full swing. A comprehensive in-depth understanding regulation will not only enrich mechanisms disease progression but provide inspiration for new diagnostic therapeutic approaches.
Language: Английский
Citations
15
Cell Reports, Journal Year: 2024, Volume and Issue: 43(12), P. 115064 - 115064
Published: Dec. 1, 2024
The metabolic reprogramming of tumor cells is a crucial strategy for their survival and proliferation, involving tissue- condition-dependent remodeling certain pathways. While it has become increasingly clear that integrate extracellular intracellular signals to adapt proliferate, nutrient metabolite sensing also exert direct or indirect influences, although the underlying mechanisms remain incompletely understood. Furthermore, changes not only support rapid growth dissemination but promote immune evasion by metabolically "educating" in microenvironment (TME). Recent studies have highlighted profound impact on TME potential targeting pathways as therapeutic strategy, with several enzyme inhibitors showing promising results clinical trials. Thus, understanding how alter remodel proliferation may offer new strategies therapy immunotherapy.
Language: Английский
Citations
15