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Articles 121 - 141 of 141
Full-Text Articles in Biochemistry, Biophysics, and Structural Biology
The Nudix Hydrolase 7 Is An Acyl-Coa Diphosphatase Involved In Regulating Peroxisomal Coenzyme A Homeostasis., Sarah-Jayne Reilly, Veronica Tillander, Rob Ofman, Stefan Alexson, Mary Hunt
The Nudix Hydrolase 7 Is An Acyl-Coa Diphosphatase Involved In Regulating Peroxisomal Coenzyme A Homeostasis., Sarah-Jayne Reilly, Veronica Tillander, Rob Ofman, Stefan Alexson, Mary Hunt
Articles
Coenzyme A (CoASH) is an obligate cofactor for lipids undergoing β-oxidation in peroxisomes. Although the peroxisomal membrane appears to be impermeable to CoASH, peroxisomes contain their own pool of CoASH. It is believed that CoASH enters peroxisomes as acyl-CoAs, but it is not known how this pool is regulated. The mouse nudix hydrolase 7 (NUDT7α) was previously identified in peroxisomes as a CoAdiphosphatase, and therefore suggested to be involved in regulation of peroxisomal CoASH levels. Here we show that mouse NUDT7α mainly acts as an acyl-CoA diphosphatase, with highest activity towards medium chain acyl-CoAs, and much lower activity with CoASH. …
Peroxisomes Contain A Specific Phytanoly-Coa/Pristanoyl-Coa Thioesterase Acting As A Novel Auxiliary Enzyme In Alpha-And Beta-Oxidation Of Methyl-Branched Fatty Acids In Mouse, Maria Westin, Mary Hunt, Stefan Alexson
Peroxisomes Contain A Specific Phytanoly-Coa/Pristanoyl-Coa Thioesterase Acting As A Novel Auxiliary Enzyme In Alpha-And Beta-Oxidation Of Methyl-Branched Fatty Acids In Mouse, Maria Westin, Mary Hunt, Stefan Alexson
Articles
Phytanic acid and pristanic acid are derived from phytol, which enter the body via the diet. Phytanic acid contains a methyl group in position three and therefore cannot undergo b-oxidation directly, but instead must first undergo a-oxidation to pristanic acid, which then enters b-oxidation. Both these pathways occur in peroxisomes, and in this study we have identified a novel peroxisomal acyl-CoA thioesterase, named ACOT6, which we show is specifically involved in phytanic acid and pristanic acid metabolism. Sequence analysis of ACOT6 revealed a putative peroxisomal targeting signal at the C-terminal end, and cellular localization experiments verified it as a peroxisomal …
A Peroxisomal Acyltransferase In Mouse Identifies A Novel Pathway For Taurine Conjugation Of Fatty Acids., Sarah-Jayne Reilly, Eithne O'Shea, O'Byrne James, Stefan Alexson, Mary Hunt
A Peroxisomal Acyltransferase In Mouse Identifies A Novel Pathway For Taurine Conjugation Of Fatty Acids., Sarah-Jayne Reilly, Eithne O'Shea, O'Byrne James, Stefan Alexson, Mary Hunt
Articles
A wide variety of endogenous carboxylic acids and xenobiotics are conjugated with amino acids, before excretion in urine or bile. The conjugation of carboxylic acids and bile acids with taurine and glycine has been widely characterized and de-novo synthesized bile acids are conjugated to either glycine or taurine in peroxisomes. Peroxisomes are also involved in the oxidation of several other lipid molecules, such as very long chain acyl-CoAs, branched chain acyl-CoAs and prostaglandins. In this study we have now identified a novel peroxisomal enzyme called acyl-CoA:amino acid N-acyltransferase (ACNAT1). Recombinantly expressed ACNAT1 acts as an acyltransferase that efficiently conjugates very …
In Vivo Mature Immunological Synapses Forming Smacs Mediate Clearance Of Virally Infected Astrocytes From The Brain, Carlos Barcia, Clare Thomas, James Curtin, Gwendalyn King, Kolja Wawrowsky, Marianela Candolfi, Weidong Xiong, Chunyan Liu, Kurt Kroeger, Olivier Boyer, Jerzy Kupiec-Weglinski, David Klatzmann, Maria Castro, Pedro Lowenstein
In Vivo Mature Immunological Synapses Forming Smacs Mediate Clearance Of Virally Infected Astrocytes From The Brain, Carlos Barcia, Clare Thomas, James Curtin, Gwendalyn King, Kolja Wawrowsky, Marianela Candolfi, Weidong Xiong, Chunyan Liu, Kurt Kroeger, Olivier Boyer, Jerzy Kupiec-Weglinski, David Klatzmann, Maria Castro, Pedro Lowenstein
Articles
The microanatomy of immune clearance of infected brain cells remains poorly understood. Immunological synapses are essential anatomical structures that channel information exchanges between T cell–antigen-presenting cells (APC) during the priming and effector phases of T cells' function, and during natural killer–target cell interactions. The hallmark of immunological synapses established by T cells is the formation of the supramolecular activation clusters (SMACs), in which adhesion molecules such as leukocyte function-associated antigen 1 segregate to the peripheral domain of the immunological synapse (p-SMAC), which surrounds the T cell receptor–rich or central SMAC (c-SMAC). The inability so far to detect SMAC formation in …
Analysis Of The Mouse And Human Acyl-Coa Thioesterase (Acot) Gene Clusters Shows That Convergent, Functional Evolution Results In A Reduced Number Of Human Peroxisomal Acots., Mary Hunt, Anna Rautanen, Maria Westin, Thomas Svensson, Stefan Alexson
Analysis Of The Mouse And Human Acyl-Coa Thioesterase (Acot) Gene Clusters Shows That Convergent, Functional Evolution Results In A Reduced Number Of Human Peroxisomal Acots., Mary Hunt, Anna Rautanen, Maria Westin, Thomas Svensson, Stefan Alexson
Articles
The maintenance of cellular levels of free fatty acids and acyl-CoAs, the activated form of free fatty acids, is extremely important as imbalances in lipid metabolism have serious consequences for human health. Acyl-CoA thioesterases (ACOTs) hydrolyze acyl-CoAs to the free fatty acid and CoASH, and thereby have the potential to regulate intracellular levels of these compounds. We have previously identified and characterized a mouse ACOT gene cluster, comprised of six genes that apparently arose by gene duplications, encoding acyl- CoA thioesterases with localizations in cytosol (ACOT1), mitochondria (ACOT2) and peroxisomes (ACOT3-6). However, the corresponding human gene cluster contains only three …
Regulatable Gene Expression Systems For Gene Therapy Applications: Progress And Future Challenges, Shyam Goverdhana, Mariana Puntel, Weidong Xiong, Jeffrey Zirger, Carlos Barcia, James Curtin, Eric Soffer, Sonali Mondkar, Gwendalyn King, Jinwei Hu, Marianela Candolfi, Diane Greengold, Pedro Lowenstein, Maria Castro
Regulatable Gene Expression Systems For Gene Therapy Applications: Progress And Future Challenges, Shyam Goverdhana, Mariana Puntel, Weidong Xiong, Jeffrey Zirger, Carlos Barcia, James Curtin, Eric Soffer, Sonali Mondkar, Gwendalyn King, Jinwei Hu, Marianela Candolfi, Diane Greengold, Pedro Lowenstein, Maria Castro
Articles
Gene therapy aims to revert diseased phenotypes by the use of both viral and nonviral gene delivery systems. Substantial progress has been made in making gene transfer vehicles more efficient, less toxic, and nonimmunogenic and in allowing long-term transgene expression. One of the key issues in successfully implementing gene therapies in the clinical setting is to be able to regulate gene expression very tightly and consistently as and when it is needed. The regulation ought to be achievable using a compound that should be nontoxic, be able to penetrate into the desired target tissue or organ, and have a half-life …
A Revised Nomenclature For Mammalian Acyl-Coa Thioesterases/Hydrolases, Mary Hunt, Junji Yamada, Lois Maltais, Mathew Wright, Ernesto Podesta, Stefan Alexson
A Revised Nomenclature For Mammalian Acyl-Coa Thioesterases/Hydrolases, Mary Hunt, Junji Yamada, Lois Maltais, Mathew Wright, Ernesto Podesta, Stefan Alexson
Articles
Acyl-CoA thioesterases, also known as acyl-CoA hydrolases, are a group of enzymes that hydrolyze CoA esters such as acyl-CoAs (saturated, unsaturated, branched chain), bile acid-CoAs, CoA esters of prostaglandins etc, to the corresponding free acid and coenzyme A. There is however significant confusion regarding the nomenclature of these genes. In agreement with the HUGO Gene Nomenclature Committee (HGNC) and the Mouse Genomic Nomenclature Committee (MGNC), a revised nomenclature for mammalian acyl-CoA thioesterases/hydrolases has been suggested for the 12 member family. The family root symbol is ACOT, with human genes named ACOT1-12, and rat and mouse named Acot1-12. Several of the …
New Insights Into Bile Acid Amidation, Mary Hunt, Eithne O'Shea, Karianne Solaas, Bengt Kase, Stefan Alexson
New Insights Into Bile Acid Amidation, Mary Hunt, Eithne O'Shea, Karianne Solaas, Bengt Kase, Stefan Alexson
Articles
No abstract provided.
Identification Of Fatty Acid Oxidation Disorder Patients With Lowered Acyl-Coa Thioesterase Activity In Human Skin Fibroblasts, Mary Hunt, Jos Ruiter, Petra Mooyer, Carlo W T Van Roermond, Rob Ofman, Lodewig Ijlst, Ronald J A Wanders
Identification Of Fatty Acid Oxidation Disorder Patients With Lowered Acyl-Coa Thioesterase Activity In Human Skin Fibroblasts, Mary Hunt, Jos Ruiter, Petra Mooyer, Carlo W T Van Roermond, Rob Ofman, Lodewig Ijlst, Ronald J A Wanders
Articles
Background: Acyl-CoA thioesterases are enzymes that hydrolyze acyl-CoAs to the free fatty acid and coenzyme A (CoASH). These enzymes have been identified in several cellular compartments and are thought to regulate intracellular levels of acyl-CoAs, free fatty acids and CoASH. However, to date no patients deficient in acyl-CoA thioesterases have been identified. Design: Acyl-CoA thioesterase activity was measured in human skin fibroblasts. Western blot analysis was used to determine Type-II acyl-CoA thioesterase protein levels in patients. Results: Activity was found in human fibroblasts with all saturated acyl-CoAs from C4:0- to C18:0-CoA, with highest activity detected with lauroyl-CoA and myristoyl-CoA (C12:0 …
Isolation Of Cancer Stem Cells From Adult Glioblastoma Multiforme, Xianpeng Yuan, James Curtin, Yizhi Xiong, Gentao Liu, Sebastian Waschsmann-Hogiu, Daniel Farkas, Keith Black, John Yu
Isolation Of Cancer Stem Cells From Adult Glioblastoma Multiforme, Xianpeng Yuan, James Curtin, Yizhi Xiong, Gentao Liu, Sebastian Waschsmann-Hogiu, Daniel Farkas, Keith Black, John Yu
Articles
Glioblastoma multiforme (GBM) is the most common adult primary brain tumor and is comprised of a heterogeneous population of cells. It is unclear which cells within the tumor mass are responsible for tumor initiation and maintenance. In this study, we report that brain tumor stem cells can be identified from adult GBMs. These tumor stem cells form neurospheres, possess the capacity for self-renewal, express genes associated with neural stem cells (NSCs), generate daughter cells of different phenotypes from one mother cell, and differentiate into the phenotypically diverse populations of cells similar to those present in the initial GBM. Having a …
Jnk Regulates Hipk3 Expression And Promotes Resistance To Fas-Mediated Apoptosis In Du 145 Prostate Carcinoma Cells, James Curtin, Thomas Cotter
Jnk Regulates Hipk3 Expression And Promotes Resistance To Fas-Mediated Apoptosis In Du 145 Prostate Carcinoma Cells, James Curtin, Thomas Cotter
Articles
Elevated endogenous JNK activity and resistance to Fas receptor-mediated apoptosis have recently been implicated in progression of prostate cancer and can promote resistance to apoptosis in response to chemotherapeutic drugs. In addition, JNK has been demonstrated to promote transformation of epithelial cells by increasing both proliferation and survival. Although numerous studies have reported a role for JNK in promoting Fas receptor-mediated apoptosis, there is a paucity in the literature studying the antiapoptotic function of JNK during Fas receptor-mediated apoptosis. Consequently, we have used the recently described specific JNK inhibitor SP600125 and RNA interference to inhibit endogenous JNK activity in the …
Molecular Cloning And Characterization Of Two Mouse Peroxisome Proliferator-Activated Receptor Alpha (Ppara) Regulated Peroxisomal Acyl-Coa Thioesterases., Maria Westin, Mary Hunt, Stefan Alexson
Molecular Cloning And Characterization Of Two Mouse Peroxisome Proliferator-Activated Receptor Alpha (Ppara) Regulated Peroxisomal Acyl-Coa Thioesterases., Maria Westin, Mary Hunt, Stefan Alexson
Articles
Peroxisomes are organelles that function in the b-oxidation of very-long and long-chain acyl-CoAs, bile acid-CoA intermediates, prostaglandins, leukotrienes, thromboxanes, dicarboxylic fatty acids, pristanic acid and xenobiotic carboxylic acids. The very long- and long-chain acyl-CoAs are mainly chain-shortened and then transported to mitochondria for further metabolism. We have now identified and characterized two peroxisomal acyl- CoA thioesterases, named PTE-Ia and PTE-Ic, which hydrolyze acyl-CoAs to the free fatty acid and coenzyme A. PTE-Ia and PTE-Ic show 82% sequence identity at amino acid level and a putative peroxisomal type 1 targeting signal of –AKL was identified at the carboxy-terminal end of both …
Live And Let Die: Regulatory Mechanisms In Fas-Mediated Apoptosis, James Curtin, Thomas Cotter
Live And Let Die: Regulatory Mechanisms In Fas-Mediated Apoptosis, James Curtin, Thomas Cotter
Articles
Activation of Fas receptor by Fas ligand causes caspase 8 activation and apoptosis in cells and is an important mechanism by which normal tissue homeostasis and function are maintained. Activation of caspase 8 is preceded by the formation of a death-inducing signalling complex (DISC), and a number of redundant mechanisms regulate DISC formation in vivo. Fas receptor is widely expressed in tissues, and dysfunction of the regulatory mechanisms in Fas receptor signalling has been reported in several diseases including autoimmune disease and cancer. This review aims to identify and discuss the various mechanisms employed by cells to alter their sensitivity …
Defects In Death-Inducing Signalling Complex Formation Prevent Jnk Activation And Fas-Mediated Apoptosis In Du 145 Prostate Carcinoma Cells, James Curtin, Thomas Cotter
Defects In Death-Inducing Signalling Complex Formation Prevent Jnk Activation And Fas-Mediated Apoptosis In Du 145 Prostate Carcinoma Cells, James Curtin, Thomas Cotter
Articles
Androgen-independent prostate carcinomas are resistant to chemotherapy and cell lines derived from androgen-independent prostate carcinomas such as DU 145 cells are highly resistant to Fas-mediated apoptosis. The incubation of DU 145 cells with anti-Fas IgM agonistic antibody of Fas receptor fails to activate JNK, a stress kinase involved in regulating apoptosis. We have previously shown that JNK activation is sufficient and necessary to promote Fas-mediated apoptosis in DU 145 cells. We investigate the mechanisms by which JNK activation and apoptosis are abrogated. HSP27 is overexpressed in DU 145 cells and has previously been reported to sequester DAXX and prevent JNK …
Historical Perspectives (Apoptosis), James Curtin, Thomas Cotter
Historical Perspectives (Apoptosis), James Curtin, Thomas Cotter
Articles
Apoptosis is one of the most widely studied fields in biology and accounts for over 2% of all life science publications annually. It plays a fundamental role in development, and defects in the regulation of apoptosis are directly implicated in numerous well-known diseases including cancer, neurodegenerative disorders, tissue atrophy and auto-immune diseases. However, the field of apoptosis has humble beginnings and was neglected by biologists for much of its history. This chapter reviews the history of research in apoptosis and highlights key experiments that have contributed significantly to our current understanding of apoptosis. In addition, the topics covered in later …
Anisomycin Activates Jnk And Sensitises Du 145 Prostate Carcinoma Cells To Fas Mediated Apoptosis, James Curtin, Thomas Cotter
Anisomycin Activates Jnk And Sensitises Du 145 Prostate Carcinoma Cells To Fas Mediated Apoptosis, James Curtin, Thomas Cotter
Articles
Treatment of the hormone refractory prostate cancer cell line DU 145 with sublethal concentrations of chemotherapeutic drugs has been reported to sensitise these cells to Fas mediated apoptosis. However, the mechanism by which this occurs has not been determined. Our group has shown that inhibition of JNK activity completely abrogates the effects of chemotherapeutic drugs. Using anisomycin, a potent JNK agonist, we have demonstrated a role for JNK in Fas mediated apoptosis in DU 145 cells. Inhibition of Caspase 8 and Caspase 9 completely inhibits this process which suggests that DU 145 cells require mitochondrial amplification of the Fas apoptotic …
Regulation And Measurement Of Oxidative Stress In Apoptosis, James Curtin, Maryanne Donovan, Thomas Cotter
Regulation And Measurement Of Oxidative Stress In Apoptosis, James Curtin, Maryanne Donovan, Thomas Cotter
Articles
Cells are constantly generating reactive oxygen species (ROS) during aerobic metabolism. As a consequence, each cell is equipped with an extensive antioxidant defence system to combat excessive production of ROS. Oxidative stress occurs in cells when the generation of ROS overwhelms the cell's natural antioxidant defences. There is a growing consensus that oxidative stress and the redox state of a cell plays a pivotal role in regulating apoptosis, a tightly controlled form of cell death in which a cell partakes in its own demise. More recently, a role for reactive nitrogen species (RNI) as both positive and negative regulators of …
Characterization Of An Acyl-Coa Thioesterase That Functions As A Major Regulator Of Peroxisomal Lipid Metabolism, Mary Hunt, Karianne Solaas, Bengt F. Kase, Stefan E H Alexson
Characterization Of An Acyl-Coa Thioesterase That Functions As A Major Regulator Of Peroxisomal Lipid Metabolism, Mary Hunt, Karianne Solaas, Bengt F. Kase, Stefan E H Alexson
Articles
Peroxisomes function in b-oxidation of very long- and long-chain fatty acids, dicarboxylic fatty acids, bile acid intermediates, prostaglandins, leukotrienes, thromboxanes, pristanic acid and xenobiotic carboxylic acids. These lipids are mainly chain-shortened for excretion as the carboxylic acids or transported to mitochondria for further metabolism. Several of these carboxylic acids are slowly oxidized and may therefore sequester coenzyme A (CoASH). To prevent CoASH sequestration and to facilitate excretion of chain-shortened carboxylic acids, acyl-CoA thioesterases, which catalyze the hydrolysis of acyl-CoAs to the free acid and CoASH, may play important roles. We have here cloned and characterized a peroxisomal acyl-CoA thioesterase from …
The Peroxisome Proliferator-Activated Receptor Alpha (Ppar ) Regulates Bile Acid Biosynthesis., Mary Hunt, Yi-Zeng Yang, Gosta Eggertsen, Claes Carneheim, Mats Gafvels, Curt Einarsson, Stefan Alexson
The Peroxisome Proliferator-Activated Receptor Alpha (Ppar ) Regulates Bile Acid Biosynthesis., Mary Hunt, Yi-Zeng Yang, Gosta Eggertsen, Claes Carneheim, Mats Gafvels, Curt Einarsson, Stefan Alexson
Articles
Fibrates are a group of hypolipidemic agents which efficiently lower serum triglyceride levels by affecting the expression of many genes involved in lipid metabolism. These effects are exerted via the peroxisome proliferator-activated receptor alpha (PPARa). In addition, fibrates also lower serum cholesterol levels, suggesting a possible link between the PPARa and cholesterol metabolism. Bile acid formation represents an important pathway for elimination of cholesterol, and the sterol 12a-hydroxylase is a branch-point enzyme in the bile acid biosynthetic pathway, which determines the ratio of cholic acid to chenodeoxycholic acid. Treatment of mice for one week with the peroxisome proliferator WY-14,643 or …
Typical Friedreich’S Ataxia Without Gaa Expansions And Gaa Epansions Wthout Typical Friedreich’S Ataxia, Dominick Mccabe, Fergus Ryan, D. Moore, Shirley Mcquaid, M. King, A. Kelly, K. Daly, David Barton, R. Murphy
Typical Friedreich’S Ataxia Without Gaa Expansions And Gaa Epansions Wthout Typical Friedreich’S Ataxia, Dominick Mccabe, Fergus Ryan, D. Moore, Shirley Mcquaid, M. King, A. Kelly, K. Daly, David Barton, R. Murphy
Articles
We clinically assessed and performed polymerase chain reaction analysis for the GAA trinucleotide repeat expansion in 103 patients from 73 families in Ireland, with a prior clinical diagnosis of Friedreich’s ataxia (FA) or an unclassified progressive ataxic syndrome. The patients were classified as “typical” or “atypical” FA according to Harding’s mandatory clinical diagnostic criteria. All patients underwent blood glucose analysis, and electrocardiography and echocardiography was performed in 99 and 101 patients, respectively. Mutation screening for expanded CAG trinucleotide repeats, associated with spinocerebellar ataxia (SCA) 1, 2, 3 and 6 was performed in 86 patients overall, including all GAA negative patients. …
Hyperinsulinism Caused By Paternal-Specific Inheritance Of A Recessive Mutation In The Sulfonylurea-Receptor Gene, Benjamin Glaser, Fergus Ryan, Marc Donath, Heddy Landau, Charles Stanley, Lester Baker, David Barton, Paul Thornton
Hyperinsulinism Caused By Paternal-Specific Inheritance Of A Recessive Mutation In The Sulfonylurea-Receptor Gene, Benjamin Glaser, Fergus Ryan, Marc Donath, Heddy Landau, Charles Stanley, Lester Baker, David Barton, Paul Thornton
Articles
Neonatal hyperinsulinism (HI) is a genetic disorder of pancreatic b-cells characterized by failure to suppress insulin secretion in the presence of hypoglycemia, resulting in brain damage or death if not adequately treated. Germline mutations in four genes have been associated with HI. Some patients have focal regions of b-cell proliferation (focal HI). Seventy HI probands in whom at least one S U R - 1 mutation was identified were studied. Clinical data from patients with two S U R - 1 mutant alleles were compared with those from patients with single paternally inherited mutations. Thirtyseven probands were homozygous or compound …