Coenzyme A biosynthetic machinery in mammalian cells

David Lopez Martinez; Yugo Tsuchiya; Ivan Gout

doi:10.1042/bst20140124

Coenzyme A biosynthetic machinery in mammalian cells

Biochemical Society Transactions ◽

10.1042/bst20140124 ◽

2014 ◽

Vol 42 (4) ◽

pp. 1112-1117 ◽

Cited By ~ 27

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.

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Signalling functions of coenzyme A and its derivatives in mammalian cells

Biochemical Society Transactions ◽

10.1042/bst20140146 ◽

2014 ◽

Vol 42 (4) ◽

pp. 1056-1062 ◽

Cited By ~ 18

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.

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Protein CoAlation and antioxidant function of coenzyme A in prokaryotic cells

Biochemical Journal ◽

10.1042/bcj20180043 ◽

2018 ◽

Vol 475 (11) ◽

pp. 1909-1937 ◽

Cited By ~ 27

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.

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Coenzyme A: a protective thiol in bacterial antioxidant defence

Biochemical Society Transactions ◽

10.1042/bst20180415 ◽

2019 ◽

Vol 47 (1) ◽

pp. 469-476 ◽

Cited By ~ 10

Author(s):

Ivan Gout

Keyword(s):

Redox Regulation ◽

Coenzyme A ◽

Current Knowledge ◽

Thiol Group ◽

Covalent Modification ◽

Malonyl Coa ◽

Evolutionarily Conserved ◽

Coa Thioesters ◽

Living Organisms

Abstract Coenzyme A (CoA) is an indispensable cofactor in all living organisms. It is synthesized in an evolutionarily conserved pathway by enzymatic conjugation of cysteine, pantothenate (Vitamin B5), and ATP. This unique chemical structure allows CoA to employ its highly reactive thiol group for diverse biochemical reactions. The involvement of the CoA thiol group in the production of metabolically active CoA thioesters (e.g. acetyl CoA, malonyl CoA, and HMG CoA) and activation of carbonyl-containing compounds has been extensively studied since the discovery of this cofactor in the middle of the last century. We are, however, far behind in understanding the role of CoA as a low-molecular-weight thiol in redox regulation. This review summarizes our current knowledge of CoA function in redox regulation and thiol protection under oxidative stress in bacteria. In this context, I discuss recent findings on a novel mode of redox regulation involving covalent modification of cellular proteins by CoA, termed protein CoAlation.

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Coenzyme a Biochemistry: From Neurodevelopment to Neurodegeneration

Brain Sciences ◽

10.3390/brainsci11081031 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1031

Author(s):

Luca Mignani ◽

Barbara Gnutti ◽

Daniela Zizioli ◽

Dario Finazzi

Keyword(s):

Redox Regulation ◽

Coenzyme A ◽

Cell Metabolism ◽

Post Translational Modification ◽

Biochemical Processes ◽

Production And Distribution ◽

Extracellular Stimuli ◽

Cellular Stresses ◽

Living Organisms ◽

Cellular Compartments

Coenzyme A (CoA) is an essential cofactor in all living organisms. It is involved in a large number of biochemical processes functioning either as an activator of molecules with carbonyl groups or as a carrier of acyl moieties. Together with its thioester derivatives, it plays a central role in cell metabolism, post-translational modification, and gene expression. Furthermore, recent studies revealed a role for CoA in the redox regulation by the S-thiolation of cysteine residues in cellular proteins. The intracellular concentration and distribution in different cellular compartments of CoA and its derivatives are controlled by several extracellular stimuli such as nutrients, hormones, metabolites, and cellular stresses. Perturbations of the biosynthesis and homeostasis of CoA and/or acyl-CoA are connected with several pathological conditions, including cancer, myopathies, and cardiomyopathies. In the most recent years, defects in genes involved in CoA production and distribution have been found in patients affected by rare forms of neurodegenerative and neurodevelopmental disorders. In this review, we will summarize the most relevant aspects of CoA cellular metabolism, their role in the pathogenesis of selected neurodevelopmental and neurodegenerative disorders, and recent advancements in the search for therapeutic approaches for such diseases.

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

Biochemical Journal ◽

10.1042/bcj20170129 ◽

2017 ◽

Vol 474 (14) ◽

pp. 2489-2508 ◽

Cited By ~ 37

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.

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Coenzyme A, protein CoAlation and redox regulation in mammalian cells

Biochemical Society Transactions ◽

10.1042/bst20170506 ◽

2018 ◽

Vol 46 (3) ◽

pp. 721-728 ◽

Cited By ~ 27

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.

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Itaconate Alters Succinate and Coenzyme A Metabolism via Inhibition of Mitochondrial Complex II and Methylmalonyl-CoA Mutase

Metabolites ◽

10.3390/metabo11020117 ◽

2021 ◽

Vol 11 (2) ◽

pp. 117

Author(s):

Thekla Cordes ◽

Christian M. Metallo

Keyword(s):

Amino Acid ◽

Metabolic Pathways ◽

Mammalian Cells ◽

Coenzyme A ◽

Cultured Cells ◽

Tca Cycle ◽

Regulatory Function ◽

Reversible Inhibitor ◽

Complex Ii ◽

Branched Chain

Itaconate is a small molecule metabolite that is endogenously produced by cis-aconitate decarboxylase-1 (ACOD1) in mammalian cells and influences numerous cellular processes. The metabolic consequences of itaconate in cells are diverse and contribute to its regulatory function. Here, we have applied isotope tracing and mass spectrometry approaches to explore how itaconate impacts various metabolic pathways in cultured cells. Itaconate is a competitive and reversible inhibitor of Complex II/succinate dehydrogenase (SDH) that alters tricarboxylic acid (TCA) cycle metabolism leading to succinate accumulation. Upon activation with coenzyme A (CoA), itaconyl-CoA inhibits adenosylcobalamin-mediated methylmalonyl-CoA (MUT) activity and, thus, indirectly impacts branched-chain amino acid (BCAA) metabolism and fatty acid diversity. Itaconate, therefore, alters the balance of CoA species in mitochondria through its impacts on TCA, amino acid, vitamin B12, and CoA metabolism. Our results highlight the diverse metabolic pathways regulated by itaconate and provide a roadmap to link these metabolites to potential downstream biological functions.

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Peptides encoded by noncoding genes: challenges and perspectives

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-019-0092-3 ◽

2019 ◽

Vol 4 (1) ◽

Cited By ~ 3

Author(s):

Shuo Wang ◽

Chuanbin Mao ◽

Shanrong Liu

Keyword(s):

Critical Review ◽

Life Sciences ◽

Future Trends ◽

Biological Functions ◽

Entry Points ◽

Extracellular Stimuli ◽

Living Organisms ◽

Action Modes ◽

Adjustment Mechanisms

AbstractIn recent years, noncoding gene (NCG) translation events have been frequently discovered. The resultant peptides, as novel findings in the life sciences, perform unexpected functions of increasingly recognized importance in many fundamental biological and pathological processes. The emergence of these novel peptides, in turn, has advanced the field of genomics while indispensably aiding living organisms. The peptides from NCGs serve as important links between extracellular stimuli and intracellular adjustment mechanisms. These peptides are also important entry points for further exploration of the mysteries of life that may trigger a new round of revolutionary biotechnological discoveries. Insights into NCG-derived peptides will assist in understanding the secrets of life and the causes of diseases, and will also open up new paths to the treatment of diseases such as cancer. Here, a critical review is presented on the action modes and biological functions of the peptides encoded by NCGs. The challenges and future trends in searching for and studying NCG peptides are also critically discussed.

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Microplastics - an emerging silent menace to public health

Life Sciences, Medicine and Biomedicine ◽

10.28916/lsmb.5.10.2021.72 ◽

2021 ◽

Vol 5 (10) ◽

Author(s):

Li-Yin Pang ◽

Shola Sonagara ◽

Oreoluwatomide Oduwole ◽

Christopher Gibbins ◽

Ting Kang Nee

Keyword(s):

Public Health ◽

Health Effects ◽

Mammalian Cells ◽

Circulatory System ◽

Epidemiological Studies ◽

Specific Effects ◽

Important Pathway ◽

Living Organisms ◽

Respiratory Conditions

Over the past few decades, microplastics have become increasingly ubiquitous in the environment and now contaminate the bodies of many living organisms, including humans. Microplastics, as defined here, are plastics within the size range 0.1 μm and 5 mm and are a worrying form of pollution due to public health concerns. This mini-review aims to summarise the route of entry of microplastics into humans and explore the potential detrimental health effects of microplastics. Trophic transfer is an important pathway for microplastic to be transferred across different groups of organisms, with ingestion is regarded as one of the major routes of exposure for humans. Other pathways include inhalation and dermal contact. The health consequences of microplastics manifest because these materials can translocate into the circulatory system and accumulate in the lungs, liver, kidney, and even brain, regardless of the route of entry. Health effects include gastrointestinal disturbances such as inflammation and gut microbiota disruption, respiratory conditions, neurotoxicity and potential cancers. Overall, while it is apparent that microplastics are causing adverse effects on different biological groups and ecosystems, current research is largely focused on marine organisms and aquaculture. Therefore, more studies are needed to investigate specific effects in mammalian cells and tissues, with more long-term epidemiological studies needed on human population considered to be at high-risk due to socioeconomic or other circumstance. Knowledge of the toxicity and long-term health impacts of microplastics is currently limited and requires urgent attention.

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