scholarly journals Protein CoAlation and antioxidant function of coenzyme A in prokaryotic cells

2018 ◽  
Vol 475 (11) ◽  
pp. 1909-1937 ◽  
Author(s):  
Yugo Tsuchiya ◽  
Alexander Zhyvoloup ◽  
Jovana Baković ◽  
Naam Thomas ◽  
Bess Yi Kun Yu ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Redox Regulation ◽  
Coenzyme A ◽  
Regulation Of Gene Expression ◽  
Pantothenic Acid ◽  
Metabolic Stress ◽  
Background Level ◽  
Catalytic Cysteine ◽  
Living Organisms

In all living organisms, coenzyme A (CoA) is an essential cofactor with a unique design allowing it to function as an acyl group carrier and a carbonyl-activating group in diverse biochemical reactions. It is synthesized in a highly conserved process in prokaryotes and eukaryotes that requires pantothenic acid (vitamin B5), cysteine and ATP. CoA and its thioester derivatives are involved in major metabolic pathways, allosteric interactions and the regulation of gene expression. A novel unconventional function of CoA in redox regulation has been recently discovered in mammalian cells and termed protein CoAlation. Here, we report for the first time that protein CoAlation occurs at a background level in exponentially growing bacteria and is strongly induced in response to oxidizing agents and metabolic stress. Over 12% of Staphylococcus aureus gene products were shown to be CoAlated in response to diamide-induced stress. In vitro CoAlation of S. aureus glyceraldehyde-3-phosphate dehydrogenase was found to inhibit its enzymatic activity and to protect the catalytic cysteine 151 from overoxidation by hydrogen peroxide. These findings suggest that in exponentially growing bacteria, CoA functions to generate metabolically active thioesters, while it also has the potential to act as a low-molecular-weight antioxidant in response to oxidative and metabolic stress.

Coenzyme A biosynthetic machinery in mammalian cells

2014 ◽  
Vol 42 (4) ◽  
pp. 1112-1117 ◽  
Author(s):  
David Lopez Martinez ◽  
Yugo Tsuchiya ◽  
Ivan Gout
Keyword(s):  
Mammalian Cells ◽  
Coenzyme A ◽  
Regulation Of Gene Expression ◽  
Pantothenic Acid ◽  
Regulatory Interactions ◽  
Malonyl Coa ◽  
Extracellular Stimuli ◽  
Living Organisms ◽  
Enzyme Complexes ◽  
Biosynthetic Machinery

CoA (coenzyme A) is an essential cofactor in all living organisms. CoA and its thioester derivatives [acetyl-CoA, malonyl-CoA, HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) etc.] participate in diverse anabolic and catabolic pathways, allosteric regulatory interactions and the regulation of gene expression. The biosynthesis of CoA requires pantothenic acid, cysteine and ATP, and involves five enzymatic steps that are highly conserved from prokaryotes to eukaryotes. The intracellular levels of CoA and its derivatives change in response to extracellular stimuli, stresses and metabolites, and in human pathologies, such as cancer, metabolic disorders and neurodegeneration. In the present mini-review, we describe the current understanding of the CoA biosynthetic pathway, provide a detailed overview on expression and subcellular localization of enzymes implicated in CoA biosynthesis, their regulation and the potential to form multi-enzyme complexes for efficient and highly co-ordinated biosynthetic process.

scholarly journals Protein CoAlation: a redox-regulated protein modification by coenzyme A in mammalian cells

2017 ◽  
Vol 474 (14) ◽  
pp. 2489-2508 ◽  
Author(s):  
Yugo Tsuchiya ◽  
Sew Yeu Peak-Chew ◽  
Clare Newell ◽  
Sheritta Miller-Aidoo ◽  
Sriyash Mangal ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Protein Modification ◽  
Redox Regulation ◽  
Coenzyme A ◽  
Regulation Of Gene Expression ◽  
Covalent Attachment ◽  
Post Translational Modification ◽  
Wide Range

Coenzyme A (CoA) is an obligatory cofactor in all branches of life. CoA and its derivatives are involved in major metabolic pathways, allosteric interactions and the regulation of gene expression. Abnormal biosynthesis and homeostasis of CoA and its derivatives have been associated with various human pathologies, including cancer, diabetes and neurodegeneration. Using an anti-CoA monoclonal antibody and mass spectrometry, we identified a wide range of cellular proteins which are modified by covalent attachment of CoA to cysteine thiols (CoAlation). We show that protein CoAlation is a reversible post-translational modification that is induced in mammalian cells and tissues by oxidising agents and metabolic stress. Many key cellular enzymes were found to be CoAlated in vitro and in vivo in ways that modified their activities. Our study reveals that protein CoAlation is a widespread post-translational modification which may play an important role in redox regulation under physiological and pathophysiological conditions.

scholarly journals Coenzyme A, protein CoAlation and redox regulation in mammalian cells

2018 ◽  
Vol 46 (3) ◽  
pp. 721-728 ◽  
Author(s):  
Ivan Gout
Keyword(s):  
Mammalian Cells ◽  
Redox Regulation ◽  
Coenzyme A ◽  
Regulation Of Gene Expression ◽  
Metabolic Stress ◽  
Thiol Group ◽  
Covalent Attachment ◽  
Current Status ◽  
Experimental Conditions ◽  
Diverse Range

In a diverse family of cellular cofactors, coenzyme A (CoA) has a unique design to function in various biochemical processes. The presence of a highly reactive thiol group and a nucleotide moiety offers a diversity of chemical reactions and regulatory interactions. CoA employs them to activate carbonyl-containing molecules and to produce various thioester derivatives (e.g. acetyl CoA, malonyl CoA and 3-hydroxy-3-methylglutaryl CoA), which have well-established roles in cellular metabolism, production of neurotransmitters and the regulation of gene expression. A novel unconventional function of CoA in redox regulation, involving covalent attachment of this coenzyme to cellular proteins in response to oxidative and metabolic stress, has been recently discovered and termed protein CoAlation (S-thiolation by CoA or CoAthiolation). A diverse range of proteins was found to be CoAlated in mammalian cells and tissues under various experimental conditions. Protein CoAlation alters the molecular mass, charge and activity of modified proteins, and prevents them from irreversible sulfhydryl overoxidation. This review highlights the role of a key metabolic integrator CoA in redox regulation in mammalian cells and provides a perspective of the current status and future directions of the emerging field of protein CoAlation.

Signalling functions of coenzyme A and its derivatives in mammalian cells

2014 ◽  
Vol 42 (4) ◽  
pp. 1056-1062 ◽  
Author(s):  
Hongorzul Davaapil ◽  
Yugo Tsuchiya ◽  
Ivan Gout
Keyword(s):  
Mammalian Cells ◽  
Coenzyme A ◽  
Current Knowledge ◽  
Pantothenic Acid ◽  
Future Developments ◽  
Malonyl Coa ◽  
Vitamin B5 ◽  
Coa Thioesters ◽  
Living Organisms

In all living organisms, CoA (coenzyme A) is synthesized in a highly conserved process that requires pantothenic acid (vitamin B5), cysteine and ATP. CoA is uniquely designed to function as an acyl group carrier and a carbonyl-activating group in diverse biochemical reactions. The role of CoA and its thioester derivatives, including acetyl-CoA, malonyl-CoA and HMG-CoA (3-hydroxy-3-methylglutaryl-CoA), in the regulation of cellular metabolism has been extensively studied and documented. The main purpose of the present review is to summarize current knowledge on extracellular and intracellular signalling functions of CoA/CoA thioesters and to speculate on future developments in this area of research.

scholarly journals Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jie Yu ◽  
Peiwei Chai ◽  
Minyue Xie ◽  
Shengfang Ge ◽  
Jing Ruan ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Regulation Of Gene Expression ◽  
Metabolic Stress ◽  
Ocular Melanoma ◽  
Rna Modifications ◽  
M1 Macrophage ◽  
Melanoma Therapy

Abstract Background Histone lactylation, a metabolic stress-related histone modification, plays an important role in the regulation of gene expression during M1 macrophage polarization. However, the role of histone lactylation in tumorigenesis remains unclear. Results Here, we show histone lactylation is elevated in tumors and is associated with poor prognosis of ocular melanoma. Target correction of aberrant histone lactylation triggers therapeutic efficacy both in vitro and in vivo. Mechanistically, histone lactylation contributes to tumorigenesis by facilitating YTHDF2 expression. Moreover, YTHDF2 recognizes the m6A modified PER1 and TP53 mRNAs and promotes their degradation, which accelerates tumorigenesis of ocular melanoma. Conclusion We reveal the oncogenic role of histone lactylation, thereby providing novel therapeutic targets for ocular melanoma therapy. We also bridge histone modifications with RNA modifications, which provides novel understanding of epigenetic regulation in tumorigenesis.

Polyprenols in hairy roots of Coluria geoides

2000 ◽  
Vol 28 (6) ◽  
pp. 790-791 ◽  
Author(s):  
K. Skorupińska-Tudek ◽  
V. S. Hung ◽  
O. Olszowska ◽  
M. Furmanowa ◽  
T. Chojnacki ◽  
...  
Keyword(s):  
Agrobacterium Rhizogenes ◽  
Hairy Root ◽  
Lipid Content ◽  
Mammalian Cells ◽  
Root Culture ◽  
Dry Weight ◽  
Hairy Root Culture ◽  
Living Organisms ◽  
Long Chain

Long-chain polyisoprenoid alcohols built from several up to more than 100 isoprenoid units are common constituents of all living organisms. They were found mostly in plants, bacteria, yeasts and mammalian cells. In vitro hairy root culture of Coluria geoides was obtained from plants transformed with Agrobacterium rhizogenes. Growth was optimal at 0.75% (w/v) glucose and at 22 °C. Dry samples of roots were extracted and lipid content was analysed by HPLC. According to our estimation, polyprenols are accumulated in roots of C. geoides cultivated in vitro as a mixture of several prenologues with the dominating prenol composed of 16 isoprenoid units. The content of polyprenols in tissue was approx. 300 μg/g of dry weight.

scholarly journals Extensive Anti-CoA Immunostaining in Alzheimer’s Disease and Covalent Modification of Tau by a Key Cellular Metabolite Coenzyme A

2021 ◽  
Vol 15 ◽  
Author(s):  
Tammaryn Lashley ◽  
Maria-Armineh Tossounian ◽  
Neve Costello Heaven ◽  
Samantha Wallworth ◽  
Sew Peak-Chew ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Cellular Response ◽  
Protein Modification ◽  
Coenzyme A ◽  
Neurodegenerative Disorder ◽  
Regulation Of Gene Expression ◽  
Covalent Modification

Alzheimer’s disease (AD) is a neurodegenerative disorder, accounting for at least two-thirds of dementia cases. A combination of genetic, epigenetic and environmental triggers is widely accepted to be responsible for the onset and development of AD. Accumulating evidence shows that oxidative stress and dysregulation of energy metabolism play an important role in AD pathogenesis, leading to neuronal dysfunction and death. Redox-induced protein modifications have been reported in the brain of AD patients, indicating excessive oxidative damage. Coenzyme A (CoA) is essential for diverse metabolic pathways, regulation of gene expression and biosynthesis of neurotransmitters. Dysregulation of CoA biosynthesis in animal models and inborn mutations in human genes involved in the CoA biosynthetic pathway have been associated with neurodegeneration. Recent studies have uncovered the antioxidant function of CoA, involving covalent protein modification by this cofactor (CoAlation) in cellular response to oxidative or metabolic stress. Protein CoAlation has been shown to both modulate the activity of modified proteins and protect cysteine residues from irreversible overoxidation. In this study, immunohistochemistry analysis with highly specific anti-CoA monoclonal antibody was used to reveal protein CoAlation across numerous neurodegenerative diseases, which appeared particularly frequent in AD. Furthermore, protein CoAlation consistently co-localized with tau-positive neurofibrillary tangles, underpinning one of the key pathological hallmarks of AD. Double immunihistochemical staining with tau and CoA antibodies in AD brain tissue revealed co-localization of the two immunoreactive signals. Further, recombinant 2N3R and 2N4R tau isoforms were found to be CoAlated in vitro and the site of CoAlation mapped by mass spectrometry to conserved cysteine 322, located in the microtubule binding region. We also report the reversible H2O2-induced dimerization of recombinant 2N3R, which is inhibited by CoAlation. Moreover, CoAlation of transiently expressed 2N4R tau was observed in diamide-treated HEK293/Pank1β cells. Taken together, this study demonstrates for the first time extensive anti-CoA immunoreactivity in AD brain samples, which occurs in structures resembling neurofibrillary tangles and neuropil threads. Covalent modification of recombinant tau at cysteine 322 suggests that CoAlation may play an important role in protecting redox-sensitive tau cysteine from irreversible overoxidation and may modulate its acetyltransferase activity and functional interactions.

Regulation of coenzyme A synthesis in heart muscle: effects of diabetes and fasting

1981 ◽  
Vol 240 (4) ◽  
pp. H606-H611 ◽  
Author(s):  
D. K. Reibel ◽  
B. W. Wyse ◽  
D. A. Berkich ◽  
J. R. Neely
Keyword(s):  
Heart Muscle ◽  
Coenzyme A ◽  
Pantothenic Acid ◽  
Strong Inhibitor ◽  
Perfused Rat Heart ◽  
Uptake Data ◽  
Beta Hydroxybutyrate ◽  
Circulating Levels

Regulation of coenzyme A (CoA) synthesis was studied in the isolated perfused rat heart. Incorporation of [14C]pantothenic acid ([14C]PA) into CoA was determined to estimate rates of CoA synthesis. Although CoA levels were elevated in hearts removed from fasted and diabetic animals, in vitro rates of CoA synthesis were not elevated. The presence of 1.2 mM palmitate, 5 mM pyruvate, or 10 mM beta-hydroxybutyrate in the perfusate-reduced PA incorporation into CoA in control hearts by 40, 60, and 80%, respectively. Insulin (25 mU/ml) reduced incorporation by 90%. The alterations in CoA synthesis in hearts perfused with buffer containing palmitate, pyruvate, beta-hydroxybutyrate, and insulin were associated with no change in myocardial PA uptake. Data indicate that these substrates and insulin inhibit the first step in the pathway of CoA synthesis, pantothenate kinase. Because insulin is a strong inhibitor of CoA synthesis in vitro, decreased circulating levels of insulin in fasted and diabetic animals may account for the increased levels of CoA in vivo.

scholarly journals A genetically encoded biosensor roKate for monitoring the redox state of the glutathione pool

2019 ◽  
pp. 86-92 ◽  
Author(s):  
AG Shokhina ◽  
VV Belousov ◽  
DS Bilan
Keyword(s):  
Mammalian Cells ◽  
Redox State ◽  
Fluorescent Protein ◽  
Spectral Characteristics ◽  
Disulfide Bridge ◽  
Site Directed Mutagenesis ◽  
Amino Acid Residues ◽  
Living Organisms ◽  
Cysteine Amino Acid

Genetically encoded fluorescent sensors are exploited to study a variety of biological processes in living organisms in real time. In recent years, a whole family of biosensors has been developed, serving to visualize changes in the glutathione redox state. The aim of our experiment was to design a biosensor based on the red fluorescent protein mKate2 for measuring the 2GSH/GSSG ratio. A pair of cysteine amino acid residues were introduced into the structure of the fluorescent protein using site-directed mutagenesis. These residues form a disulfide bridge when the surrounding glutathione pool is oxidized, affecting the spectral characteristics of the protein. Our biosensor, which we called roKate, was tested in vitro on an isolated protein. Specifically, we examined the spectral characteristics, pH and the redox potential of the sensor. Additionally, the performance of roKate was evaluated using the culture of living mammalian cells. The fluorescent signal emitted by the sensor was very bright and remarkably stable under pH conditions varying in the physiological range. Irreversibly oxidized in mammalian cells, roKate stands out from other members of this biosensor family. This biosensor should be preferred in the experiments when the time between the manipulations with the biological object and the subsequent analysis of the induced effect is substantial, as is the case with long sample preparation.

scholarly journals Provitamin B5 (Pantothenol) Inhibits Growth of the Intraerythrocytic Malaria Parasite

2005 ◽  
Vol 49 (2) ◽  
pp. 632-637 ◽  
Author(s):  
Kevin J. Saliba ◽  
Isabelle Ferru ◽  
Kiaran Kirk
Keyword(s):  
Drug Target ◽  
Malaria Parasite ◽  
Coenzyme A ◽  
External Medium ◽  
Pantothenic Acid ◽  
Significant Inhibition ◽  
Pantothenate Kinase ◽  
Human Malaria Parasite ◽  
Plasmodium Vinckei

ABSTRACT Pantothenic acid, a precursor of the crucial enzyme cofactor coenzyme A, is one of a relatively few nutrients for which the intraerythrocytic parasite has an absolute and acute requirement from the external medium. In some organisms the provitamin pantothenol can serve as a source of pantothenic acid; however, this was not the case for the human malaria parasite Plasmodium falciparum. Instead, pantothenol inhibited the in vitro growth of P. falciparum via a mechanism that involves competition with pantothenate and which can be attributed to inhibition of the parasite's pantothenate kinase. Oral administration of pantothenol to mice infected with the murine parasite Plasmodium vinckei vinckei resulted in a significant inhibition of parasite proliferation. This study highlights the potential of the coenzyme A biosynthesis pathway in general, and pantothenate kinase in particular, as an antimalarial drug target.

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