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Molecular Genetics and Metabolism Nov 2022Studies aimed at supporting different treatment approaches for pantothenate kinase-associated neurodegeneration (PKAN) have revealed the complexity of coenzyme A (CoA)... (Review)
Review
Studies aimed at supporting different treatment approaches for pantothenate kinase-associated neurodegeneration (PKAN) have revealed the complexity of coenzyme A (CoA) metabolism and the limits of our current knowledge about disease pathogenesis. Here we offer a foundation for critically evaluating the myriad approaches, argue for the importance of unbiased disease models, and highlight some of the outstanding questions that are central to our understanding and treating PKAN.
Topics: Humans; Pantothenate Kinase-Associated Neurodegeneration; Coenzyme A; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 36240582
DOI: 10.1016/j.ymgme.2022.09.011 -
Nature Aug 2022In response to hormones and growth factors, the class I phosphoinositide-3-kinase (PI3K) signalling network functions as a major regulator of metabolism and growth,...
In response to hormones and growth factors, the class I phosphoinositide-3-kinase (PI3K) signalling network functions as a major regulator of metabolism and growth, governing cellular nutrient uptake, energy generation, reducing cofactor production and macromolecule biosynthesis. Many of the driver mutations in cancer with the highest recurrence, including in receptor tyrosine kinases, Ras, PTEN and PI3K, pathologically activate PI3K signalling. However, our understanding of the core metabolic program controlled by PI3K is almost certainly incomplete. Here, using mass-spectrometry-based metabolomics and isotope tracing, we show that PI3K signalling stimulates the de novo synthesis of one of the most pivotal metabolic cofactors: coenzyme A (CoA). CoA is the major carrier of activated acyl groups in cells and is synthesized from cysteine, ATP and the essential nutrient vitamin B5 (also known as pantothenate). We identify pantothenate kinase 2 (PANK2) and PANK4 as substrates of the PI3K effector kinase AKT. Although PANK2 is known to catalyse the rate-determining first step of CoA synthesis, we find that the minimally characterized but highly conserved PANK4 is a rate-limiting suppressor of CoA synthesis through its metabolite phosphatase activity. Phosphorylation of PANK4 by AKT relieves this suppression. Ultimately, the PI3K-PANK4 axis regulates the abundance of acetyl-CoA and other acyl-CoAs, CoA-dependent processes such as lipid metabolism and proliferation. We propose that these regulatory mechanisms coordinate cellular CoA supplies with the demands of hormone/growth-factor-driven or oncogene-driven metabolism and growth.
Topics: Acetyl Coenzyme A; Adenosine Triphosphate; Cell Proliferation; Coenzyme A; Cysteine; Lipid Metabolism; Mass Spectrometry; Metabolomics; Pantothenic Acid; Phosphatidylinositol 3-Kinase; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 35896750
DOI: 10.1038/s41586-022-04984-8 -
International Journal of Molecular... Apr 2022Coenzyme A (CoA) and its thioester derivatives are crucial components of numerous biosynthetic and degradative pathways of the cellular metabolism (including fatty acid...
Coenzyme A (CoA) and its thioester derivatives are crucial components of numerous biosynthetic and degradative pathways of the cellular metabolism (including fatty acid synthesis and oxidation, the Krebs cycle, ketogenesis, cholesterol and acetylcholine biosynthesis, amino acid degradation, and neurotransmitter biosynthesis), post-translational modifications of proteins, and the regulation of gene expression [...].
Topics: Coenzyme A; Ketone Bodies; Oxidation-Reduction; Protein Processing, Post-Translational; Proteins
PubMed: 35457189
DOI: 10.3390/ijms23084371 -
Cell Metabolism Dec 2021Metabolic programming is intricately linked to the anti-tumor properties of T cells. To study the metabolic pathways associated with increased anti-tumor T cell...
Metabolic programming is intricately linked to the anti-tumor properties of T cells. To study the metabolic pathways associated with increased anti-tumor T cell function, we utilized a metabolomics approach to characterize three different CD8 T cell subsets with varying degrees of anti-tumor activity in murine models, of which IL-22-producing Tc22 cells displayed the most robust anti-tumor activity. Tc22s demonstrated upregulation of the pantothenate/coenzyme A (CoA) pathway and a requirement for oxidative phosphorylation (OXPHOS) for differentiation. Exogenous administration of CoA reprogrammed T cells to increase OXPHOS and adopt the CD8 Tc22 phenotype independent of polarizing conditions via the transcription factors HIF-1α and the aryl hydrocarbon receptor (AhR). In murine tumor models, treatment of mice with the CoA precursor pantothenate enhanced the efficacy of anti-PDL1 antibody therapy. In patients with melanoma, pre-treatment plasma pantothenic acid levels were positively correlated with the response to anti-PD1 therapy. Collectively, our data demonstrate that pantothenate and its metabolite CoA drive T cell polarization, bioenergetics, and anti-tumor immunity.
Topics: Animals; CD8-Positive T-Lymphocytes; Cell Differentiation; Coenzyme A; Humans; Lymphocyte Activation; Mice; T-Lymphocyte Subsets
PubMed: 34879240
DOI: 10.1016/j.cmet.2021.11.010 -
International Journal of Molecular... Nov 2020The importance of coenzyme A (CoA) as a carrier of acyl residues in cell metabolism is well understood. Coenzyme A participates in more than 100 different catabolic and... (Review)
Review
The importance of coenzyme A (CoA) as a carrier of acyl residues in cell metabolism is well understood. Coenzyme A participates in more than 100 different catabolic and anabolic reactions, including those involved in the metabolism of lipids, carbohydrates, proteins, ethanol, bile acids, and xenobiotics. However, much less is known about the importance of the concentration of this cofactor in various cell compartments and the role of altered CoA concentration in various pathologies. Despite continuous research on these issues, the molecular mechanisms in the regulation of the intracellular level of CoA under pathological conditions are still not well understood. This review summarizes the current knowledge of (a) CoA subcellular concentrations; (b) the roles of CoA synthesis and degradation processes; and (c) protein modification by reversible CoA binding to proteins (CoAlation). Particular attention is paid to (a) the roles of changes in the level of CoA under pathological conditions, such as in neurodegenerative diseases, cancer, myopathies, and infectious diseases; and (b) the beneficial effect of CoA and pantethine (which like CoA is finally converted to Pan and cysteamine), used at pharmacological doses for the treatment of hyperlipidemia.
Topics: Animals; Biosynthetic Pathways; Coenzyme A; Humans; Mammals; Polymorphism, Single Nucleotide; Protein Processing, Post-Translational; Substrate Specificity
PubMed: 33260564
DOI: 10.3390/ijms21239057 -
The Journal of Biological Chemistry Mar 2022Pantothenate kinase-associated neurodegeneration (PKAN) is an incurable rare genetic disorder of children and young adults caused by mutations in the PANK2 gene, which... (Review)
Review
Pantothenate kinase-associated neurodegeneration (PKAN) is an incurable rare genetic disorder of children and young adults caused by mutations in the PANK2 gene, which encodes an enzyme critical for the biosynthesis of coenzyme A. Although PKAN affects only a small number of patients, it shares several hallmarks of more common neurodegenerative diseases of older adults such as Alzheimer's disease and Parkinson's disease. Advances in etiological understanding and treatment of PKAN could therefore have implications for our understanding of more common diseases and may shed new lights on the physiological importance of coenzyme A, a cofactor critical for the operation of various cellular metabolic processes. The large body of knowledge that accumulated over the years around PKAN pathology, including but not limited to studies of various PKAN models and therapies, has contributed not only to progress in our understanding of the disease but also, importantly, to the crystallization of key questions that guide future investigations of the disease. In this review, we will summarize this knowledge and demonstrate how it forms the backdrop to new avenues of research.
Topics: Animals; Coenzyme A; Humans; Mutation; Neurodegenerative Diseases; Pantothenate Kinase-Associated Neurodegeneration; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 35041826
DOI: 10.1016/j.jbc.2022.101577 -
Progress in Lipid Research Apr 2020Coenzyme A (CoA) is the predominant acyl carrier in mammalian cells and a cofactor that plays a key role in energy and lipid metabolism. CoA and its thioesters... (Review)
Review
Coenzyme A (CoA) is the predominant acyl carrier in mammalian cells and a cofactor that plays a key role in energy and lipid metabolism. CoA and its thioesters (acyl-CoAs) regulate a multitude of metabolic processes at different levels: as substrates, allosteric modulators, and via post-translational modification of histones and other non-histone proteins. Evidence is emerging that synthesis and degradation of CoA are regulated in a manner that enables metabolic flexibility in different subcellular compartments. Degradation of CoA occurs through distinct intra- and extracellular pathways that rely on the activity of specific hydrolases. The pantetheinase enzymes specifically hydrolyze pantetheine to cysteamine and pantothenate, the last step in the extracellular degradation pathway for CoA. This reaction releases pantothenate in the bloodstream, making this CoA precursor available for cellular uptake and de novo CoA synthesis. Intracellular degradation of CoA depends on specific mitochondrial and peroxisomal Nudix hydrolases. These enzymes are also active against a subset of acyl-CoAs and play a key role in the regulation of subcellular (acyl-)CoA pools and CoA-dependent metabolic reactions. The evidence currently available indicates that the extracellular and intracellular (acyl-)CoA degradation pathways are regulated in a coordinated and opposite manner by the nutritional state and maximize the changes in the total intracellular CoA levels that support the metabolic switch between fed and fasted states in organs like the liver. The objective of this review is to update the contribution of these pathways to the regulation of metabolism, physiology and pathology and to highlight the many questions that remain open.
Topics: Animals; Coenzyme A; Humans; Proteolysis
PubMed: 32234503
DOI: 10.1016/j.plipres.2020.101028 -
Biochemical Society Transactions Jun 2018In 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... (Review)
Review
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.
Topics: Animals; Coenzyme A; Gene Expression Regulation; Oxidation-Reduction; Oxidative Stress; Protein Processing, Post-Translational; Proteins
PubMed: 29802218
DOI: 10.1042/BST20170506 -
PloS One 2021Coenzyme A (CoA) is a fundamental cofactor involved in a number of important biochemical reactions in the cell. Altered CoA metabolism results in severe conditions such...
Coenzyme A (CoA) is a fundamental cofactor involved in a number of important biochemical reactions in the cell. Altered CoA metabolism results in severe conditions such as pantothenate kinase-associated neurodegeneration (PKAN) in which a reduction of the activity of pantothenate kinase isoform 2 (PANK2) present in CoA biosynthesis in the brain consequently lowers the level of CoA in this organ. In order to develop a new drug aimed at restoring the sufficient amount of CoA in the brain of PKAN patients, we looked at its turnover. We report here the results of two experiments that enabled us to measure the half-life of pantothenic acid, free CoA (CoASH) and acetylCoA in the brains and livers of male and female C57BL/6N mice, and total CoA in the brains of male mice. We administered (intrastriatally or orally) a single dose of a [13C3-15N-18O]-labelled coenzyme A precursor (fosmetpantotenate or [13C3-15N]-pantothenic acid) to the mice and measured, by liquid chromatography-mass spectrometry, unlabelled- and labelled-coenzyme A species appearance and disappearance over time. We found that the turnover of all metabolites was faster in the liver than in the brain in both genders with no evident gender difference observed. In the oral study, the CoASH half-life was: 69 ± 5 h (male) and 82 ± 6 h (female) in the liver; 136 ± 14 h (male) and 144 ± 12 h (female) in the brain. AcetylCoA half-life was 74 ± 9 h (male) and 71 ± 7 h (female) in the liver; 117 ± 13 h (male) and 158 ± 23 (female) in the brain. These results were in accordance with the corresponding values obtained after intrastriatal infusion of labelled-fosmetpantotenate (CoASH 124 ± 13 h, acetylCoA 117 ± 11 and total CoA 144 ± 17 in male brain).
Topics: Acetyl Coenzyme A; Administration, Oral; Animals; Biotransformation; Brain; Coenzyme A; Female; Half-Life; Humans; Injections, Intraventricular; Liver; Male; Mice; Mice, Inbred C57BL; Organ Specificity; Pantothenic Acid
PubMed: 34019583
DOI: 10.1371/journal.pone.0251981 -
Annual Review of Biochemistry Jun 2023Thiolases are CoA-dependent enzymes that catalyze the thiolytic cleavage of 3-ketoacyl-CoA, as well as its reverse reaction, which is the thioester-dependent Claisen... (Review)
Review
Thiolases are CoA-dependent enzymes that catalyze the thiolytic cleavage of 3-ketoacyl-CoA, as well as its reverse reaction, which is the thioester-dependent Claisen condensation reaction. Thiolases are dimers or tetramers (dimers of dimers). All thiolases have two reactive cysteines: () a nucleophilic cysteine, which forms a covalent intermediate, and () an acid/base cysteine. The best characterized thiolase is the thiolase, which is a bacterial biosynthetic thiolase belonging to the CT-thiolase subfamily. The thiolase active site is also characterized by two oxyanion holes, two active site waters, and four catalytic loops with characteristic amino acid sequence fingerprints. Three thiolase subfamilies can be identified, each characterized by a unique sequence fingerprint for one of their catalytic loops, which causes unique active site properties. Recent insights concerning the thiolase reaction mechanism, as obtained from recent structural studies, as well as from classical and recent enzymological studies, are addressed, and open questions are discussed.
Topics: Coenzyme A; Cysteine; Models, Molecular; Acetyl-CoA C-Acetyltransferase; Catalytic Domain
PubMed: 37068769
DOI: 10.1146/annurev-biochem-052521-033746