scholarly journals Extensive lysine acetylation occurs in evolutionarily conserved metabolic pathways and parasite-specific functions duringPlasmodium falciparumintraerythrocytic development

2013 ◽  
Vol 89 (4) ◽  
pp. 660-675 ◽  
Author(s):  
Jun Miao ◽  
Matthew Lawrence ◽  
Victoria Jeffers ◽  
Fangqing Zhao ◽  
Daniel Parker ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Lysine Acetylation ◽  
Evolutionarily Conserved

scholarly journals Metabolic Control of m6A RNA Modification

Metabolites ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 80
Author(s):  
Joohwan Kim ◽  
Gina Lee
Keyword(s):  
Cell Fate ◽  
Metabolic Pathways ◽  
Epigenetic Modification ◽  
Genetic Material ◽  
Rna Modification ◽  
Cell Fate Decisions ◽  
Disease States ◽  
Evolutionarily Conserved ◽  
Regulate Cell Growth ◽  
Epigenetic Processes

Nutrients and metabolic pathways regulate cell growth and cell fate decisions via epigenetic modification of DNA and histones. Another key genetic material, RNA, also contains diverse chemical modifications. Among these, N6-methyladenosine (m6A) is the most prevalent and evolutionarily conserved RNA modification. It functions in various aspects of developmental and disease states, by controlling RNA metabolism, such as stability and translation. Similar to other epigenetic processes, m6A modification is regulated by specific enzymes, including writers (methyltransferases), erasers (demethylases), and readers (m6A-binding proteins). As this is a reversible enzymatic process, metabolites can directly influence the flux of this reaction by serving as substrates and/or allosteric regulators. In this review, we will discuss recent understanding of the regulation of m6A RNA modification by metabolites, nutrients, and cellular metabolic pathways.

scholarly journals Ketogenesis Impact on Liver Metabolism Revealed by Proteomics of Lysine β-hydroxybutyrylation

2021 ◽  
Author(s):  
Kevin B. Koronowski ◽  
Carolina M. Greco ◽  
He Huang ◽  
Jin-Kwang Kim ◽  
Jennifer L. Fribourgh ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Ketone Bodies ◽  
Hepatic Metabolism ◽  
Mass Spectrometry Analysis ◽  
Metabolic Enzyme ◽  
Spectrometry Analysis ◽  
Evolutionarily Conserved ◽  
Specific Manner ◽  
Rate Limiting

SUMMARYKetone bodies are evolutionarily conserved metabolites that function as energy substrates, signaling molecules and epigenetic regulators. β-hydroxybutyrate (β-OHB) is utilized in lysine β-hydroxybutyrylation (Kbhb) of histones, which associates with starvation-responsive genes, effectively coupling ketogenic metabolism with gene expression. The emerging diversity of the lysine acylation landscape prompted us to investigate the full proteomic impact of Kbhb. Global protein Kbhb is induced in a tissue-specific manner by a variety of interventions that evoke β-OHB. Mass spectrometry analysis of the β-hydroxybutyrylome in mouse liver revealed 891 sites of Kbhb within 267 proteins enriched for fatty acid, amino acid, detoxification and 1-carbon metabolic pathways. Kbhb of S-adenosyl-L-homocysteine hydrolase (AHCY), a rate-limiting enzyme of the methionine cycle, results in inhibition of enzymatic activity. Our results illuminate the role of Kbhb on hepatic metabolism under ketogenic conditions and demonstrate the functional consequence of this modification on a central metabolic enzyme.

scholarly journals α-Lipoic acid promotes α-tubulin hyperacetylation and blocks the turnover of mitochondria through mitophagy

2016 ◽  
Vol 473 (12) ◽  
pp. 1821-1830 ◽  
Author(s):  
Michael W. Stoner ◽  
Dharendra Thapa ◽  
Manling Zhang ◽  
Gregory A. Gibson ◽  
Michael J. Calderon ◽  
...  
Keyword(s):  
Lipoic Acid ◽  
Pyruvate Dehydrogenase ◽  
Metabolic Pathways ◽  
Pyruvate Dehydrogenase Complex ◽  
Lysine Acetylation ◽  
Acetyl Coa ◽  
Chemical Inducers ◽  
Tightly Coupled ◽  
Metabolic Conditions ◽  
Dehydrogenase Complex

Lysine acetylation is tightly coupled to the nutritional status of the cell, as the availability of its cofactor, acetyl-CoA, fluctuates with changing metabolic conditions. Recent studies have demonstrated that acetyl-CoA levels act as an indicator of cellular nourishment, and increased abundance of this metabolite can block the induction of cellular recycling programmes. In the present study we investigated the cross-talk between mitochondrial metabolic pathways, acetylation and autophagy, using chemical inducers of mitochondrial acetyl-CoA production. Treatment of cells with α-lipoic acid (αLA), a cofactor of the pyruvate dehydrogenase complex, led to the unexpected hyperacetylation of α-tubulin in the cytosol. This acetylation was blocked by pharmacological inhibition of mitochondrial citrate export (a source for mitochondria-derived acetyl-CoA in the cytosol), was dependent on the α-tubulin acetyltransferase (αTAT) and was coupled to a loss in function of the cytosolic histone deacetylase, HDAC6. We further demonstrate that αLA slows the flux of substrates through autophagy-related pathways, and severely limits the ability of cells to remove depolarized mitochondria through PTEN-associated kinase 1 (PINK1)-mediated mitophagy.

scholarly journals Interconversion between Anticipatory and Active GID E3 Ubiquitin Ligase Conformations via Metabolically Driven Substrate Receptor Assembly

2019 ◽  
Author(s):  
Shuai Qiao ◽  
Christine R. Langlois ◽  
Jakub Chrustowicz ◽  
Dawafuti Sherpa ◽  
Ozge Karayel ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Metabolic Pathways ◽  
Environmental Changes ◽  
E3 Ligase ◽  
Environmental Perturbations ◽  
Cryo Electron Microscopy ◽  
Evolutionarily Conserved ◽  
Extracellular Stimuli ◽  
Receptor Assembly ◽  
Carbon Stress

SUMMARYCells respond to environmental changes by toggling metabolic pathways, preparing for homeostasis, and anticipating future stresses. For example, in Saccharomyces cerevisiae, carbon stress-induced gluconeogenesis is terminated upon glucose availability, a process that involves the multiprotein E3 ligase, GIDSR4, recruiting N-termini and catalyzing ubiquitylation of gluconeogenic enzymes. Here, genetics, biochemistry, and cryo electron microscopy define molecular underpinnings of glucose-induced degradation. Unexpectedly, carbon stress induces an inactive anticipatory complex (GIDAnt), which awaits a glucose-induced substrate receptor to form the active GIDSR4. Meanwhile, other environmental perturbations elicit production of an alternative substrate receptor assembling into a related E3 ligase complex. The intricate structure of GIDAnt enables anticipating and ultimately binding various N-degron targeting (i.e. “N-end rule”) substrate receptors, while the GIDSR4 E3 forms a clamp-like structure juxtaposing substrate lysines with the ubiquitylation active site. The data reveal evolutionarily conserved GID complexes as a family of multisubunit E3 ubiquitin ligases responsive to extracellular stimuli.

scholarly journals Acetylproteomics analyses reveal critical features of lysine-ε-acetylation in Arabidopsis and a role of 14-3-3 protein acetylation in alkaline response

2022 ◽  
Vol 2 (1) ◽  
Author(s):  
Jianfei Guo ◽  
Xiaoqiang Chai ◽  
Yuchao Mei ◽  
Jiamu Du ◽  
Haining Du ◽  
...  
Keyword(s):  
Metabolic Regulation ◽  
Alkaline Stress ◽  
Lysine Acetylation ◽  
Protein Acetylation ◽  
Post Translational Modification ◽  
Evolutionarily Conserved ◽  
Lysine Residues ◽  
Protein Lysine Acetylation ◽  
Subsequent Activation

AbstractLysine-ε-acetylation (Kac) is a post-translational modification (PTM) that is critical for metabolic regulation and cell signaling in mammals. However, its prevalence and importance in plants remain to be determined. Employing high-resolution tandem mass spectrometry, we analyzed protein lysine acetylation in five representative Arabidopsis organs with 2 ~ 3 biological replicates per organ. A total of 2887 Kac proteins and 5929 Kac sites were identified. This comprehensive catalog allows us to analyze proteome-wide features of lysine acetylation. We found that Kac proteins tend to be more uniformly expressed in different organs, and the acetylation status exhibits little correlation with the gene expression level, indicating that acetylation is unlikely caused by stochastic processes. Kac preferentially targets evolutionarily conserved proteins and lysine residues, but only a small percentage of Kac proteins are orthologous between rat and Arabidopsis. A large portion of Kac proteins overlap with proteins modified by other PTMs including ubiquitination, SUMOylation and phosphorylation. Although acetylation, ubiquitination and SUMOylation all modify lysine residues, our analyses show that they rarely target the same sites. In addition, we found that “reader” proteins for acetylation and phosphorylation, i.e., bromodomain-containing proteins and GRF (General Regulatory Factor)/14-3-3 proteins, are intensively modified by the two PTMs, suggesting that they are main crosstalk nodes between acetylation and phosphorylation signaling. Analyses of GRF6/14-3-3λ reveal that the Kac level of GRF6 is decreased under alkaline stress, suggesting that acetylation represses plant alkaline response. Indeed, K56ac of GRF6 inhibits its binding to and subsequent activation of the plasma membrane H+-ATPase AHA2, leading to hypersensitivity to alkaline stress. These results provide valuable resources for protein acetylation studies in plants and reveal that protein acetylation suppresses phosphorylation output by acetylating GRF/14-3-3 proteins.

Hepatic FGF21 preserves thermoregulation and cardiovascular function during bacterial inflammation

2021 ◽  
Vol 218 (10) ◽  
Author(s):  
Sarah C. Huen ◽  
Andrew Wang ◽  
Kyle Feola ◽  
Reina Desrouleaux ◽  
Harding H. Luan ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Cold Adaptation ◽  
Fibroblast Growth Factor 21 ◽  
Target Tissue ◽  
Bacterial Sepsis ◽  
Acute Infections ◽  
Evolutionarily Conserved ◽  
Sickness Behaviors ◽  
Deficient Mice ◽  
Glucose Supplementation

Sickness behaviors, including anorexia, are evolutionarily conserved responses to acute infections. Inflammation-induced anorexia causes dramatic metabolic changes, of which components critical to survival are unique depending on the type of inflammation. Glucose supplementation during the anorectic period induced by bacterial inflammation suppresses adaptive fasting metabolic pathways, including fibroblast growth factor 21 (FGF21), and decreases survival. Consistent with this observation, FGF21-deficient mice are more susceptible to mortality from endotoxemia and polybacterial peritonitis. Here, we report that increased circulating FGF21 during bacterial inflammation is hepatic derived and required for survival through the maintenance of thermogenesis, energy expenditure, and cardiac function. FGF21 signaling downstream of its obligate coreceptor, β-Klotho (KLB), is required in bacterial sepsis. However, FGF21 modulates thermogenesis and chronotropy independent of the adipose, forebrain, and hypothalamus, which are operative in cold adaptation, suggesting that in bacterial inflammation, either FGF21 signals through a novel, undescribed target tissue or concurrent signaling of multiple KLB-expressing tissues is required.

scholarly journals Cross-species identification of cancer-resistance associated genes uncovers their relevance to human cancer risk

2021 ◽  
Author(s):  
Nishanth Ulhas Nair ◽  
Kuoyuan Cheng ◽  
Lamis Naddaf ◽  
Elad Sharon ◽  
Lipika R Pal ◽  
...  
Keyword(s):  
Cancer Risk ◽  
Metabolic Pathways ◽  
Human Cancer ◽  
Cancer Resistance ◽  
Loss Of Function ◽  
Driver Genes ◽  
Lifetime Cancer Risk ◽  
Cancer Driver ◽  
Evolutionarily Conserved ◽  
Resistance Score

Cancer is an evolutionarily conserved disease that occurs in a wide variety of species. We applied a comparative genomics approach to systematically characterize the genes whose conservation levels significantly correlates positively (PC) or negatively (NC) with a broad spectrum of cancer-resistance estimates, computed across almost 200 vertebrate species. PC genes are enriched in pathways relevant to tumor suppression including cell cycle, DNA repair, and immune response, while NC genes are enriched with a host of metabolic pathways. The conservation levels of the PC and NC genes in a species serve to build the first genomics-based predictor of its cancer resistance score. We find that PC genes are less tolerant to loss of function (LoF) mutations, are enriched in cancer driver genes and are associated with germline mutations that increase human cancer risk. Furthermore, their expression levels are associated with lifetime cancer risk across human tissues. Finally, their knockout in mice results in increased cancer incidence. In sum, we find that many genes associated with cancer resistance across species are implicated in human cancers, pointing to several additional candidate genes that may have a functional role in human cancer.

scholarly journals A quantitative screen for metabolic enzyme structures reveals patterns of assembly across the yeast metabolic network

2019 ◽  
Vol 30 (21) ◽  
pp. 2721-2736 ◽  
Author(s):  
Chalongrat Noree ◽  
Kyle Begovich ◽  
Dane Samilo ◽  
Risa Broyer ◽  
Elena Monfort ◽  
...  
Keyword(s):  
Branch Point ◽  
Biological Networks ◽  
Metabolic Pathways ◽  
Metabolic Regulation ◽  
De Novo ◽  
Metabolic Enzyme ◽  
Control Points ◽  
Branch Points ◽  
De Novo Purine Biosynthesis ◽  
Evolutionarily Conserved

Despite the proliferation of proteins that can form filaments or phase-separated condensates, it remains unclear how this behavior is distributed over biological networks. We have found that 60 of the 440 yeast metabolic enzymes robustly form structures, including 10 that assemble within mitochondria. Additionally, the ability to assemble is enriched at branch points on several metabolic pathways. The assembly of enzymes at the first branch point in de novo purine biosynthesis is coordinated, hierarchical, and based on their position within the pathway, while the enzymes at the second branch point are recruited to RNA stress granules. Consistent with distinct classes of structures being deployed at different control points in a pathway, we find that the first enzyme in the pathway, PRPP synthetase, forms evolutionarily conserved filaments that are sequestered in the nucleus in higher eukaryotes. These findings provide a roadmap for identifying additional conserved features of metabolic regulation by condensates/filaments.

scholarly journals Ancient Regulatory Role of Lysine Acetylation in Central Metabolism

mBio ◽  
2017 ◽  
Vol 8 (6) ◽  
Author(s):  
Ernesto S. Nakayasu ◽  
Meagan C. Burnet ◽  
Hanna E. Walukiewicz ◽  
Christopher S. Wilkins ◽  
Anil K. Shukla ◽  
...  
Keyword(s):  
Protein Function ◽  
Active Sites ◽  
Metabolic Regulation ◽  
Lysine Acetylation ◽  
Post Translational Modification ◽  
Protein Activity ◽  
Direct Role ◽  
Data Set ◽  
Evolutionarily Conserved ◽  
Lysine Residues

ABSTRACT Lysine acetylation is a common protein post-translational modification in bacteria and eukaryotes. Unlike phosphorylation, whose functional role in signaling has been established, it is unclear what regulatory mechanism acetylation plays and whether it is conserved across evolution. By performing a proteomic analysis of 48 phylogenetically distant bacteria, we discovered conserved acetylation sites on catalytically essential lysine residues that are invariant throughout evolution. Lysine acetylation removes the residue’s charge and changes the shape of the pocket required for substrate or cofactor binding. Two-thirds of glycolytic and tricarboxylic acid (TCA) cycle enzymes are acetylated at these critical sites. Our data suggest that acetylation may play a direct role in metabolic regulation by switching off enzyme activity. We propose that protein acetylation is an ancient and widespread mechanism of protein activity regulation. IMPORTANCE Post-translational modifications can regulate the activity and localization of proteins inside the cell. Similar to phosphorylation, lysine acetylation is present in both eukaryotes and prokaryotes and modifies hundreds to thousands of proteins in cells. However, how lysine acetylation regulates protein function and whether such a mechanism is evolutionarily conserved is still poorly understood. Here, we investigated evolutionary and functional aspects of lysine acetylation by searching for acetylated lysines in a comprehensive proteomic data set from 48 phylogenetically distant bacteria. We found that lysine acetylation occurs in evolutionarily conserved lysine residues in catalytic sites of enzymes involved in central carbon metabolism. Moreover, this modification inhibits enzymatic activity. Our observations suggest that lysine acetylation is an evolutionarily conserved mechanism of controlling central metabolic activity by directly blocking enzyme active sites.

Sign in / Sign up

Export Citation Format

Share Document