Mitochondrial STAT5A Promotes Metabolic Remodeling and the Warburg Effect by Inactivating the Pyruvate Dehydrogenase Complex
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Supplement 1 Overview of Dystonia Genes
Supplement 1 Overview of genes that may cause dystonia in children and adolescents Gene (OMIM) Disease name/phenotype Mode of inheritance 1: (Formerly called) Primary dystonias (DYTs): TOR1A (605204) DYT1: Early-onset generalized AD primary torsion dystonia (PTD) TUBB4A (602662) DYT4: Whispering dystonia AD GCH1 (600225) DYT5: GTP-cyclohydrolase 1 AD deficiency THAP1 (609520) DYT6: Adolescent onset torsion AD dystonia, mixed type PNKD/MR1 (609023) DYT8: Paroxysmal non- AD kinesigenic dyskinesia SLC2A1 (138140) DYT9/18: Paroxysmal choreoathetosis with episodic AD ataxia and spasticity/GLUT1 deficiency syndrome-1 PRRT2 (614386) DYT10: Paroxysmal kinesigenic AD dyskinesia SGCE (604149) DYT11: Myoclonus-dystonia AD ATP1A3 (182350) DYT12: Rapid-onset dystonia AD parkinsonism PRKRA (603424) DYT16: Young-onset dystonia AR parkinsonism ANO3 (610110) DYT24: Primary focal dystonia AD GNAL (139312) DYT25: Primary torsion dystonia AD 2: Inborn errors of metabolism: GCDH (608801) Glutaric aciduria type 1 AR PCCA (232000) Propionic aciduria AR PCCB (232050) Propionic aciduria AR MUT (609058) Methylmalonic aciduria AR MMAA (607481) Cobalamin A deficiency AR MMAB (607568) Cobalamin B deficiency AR MMACHC (609831) Cobalamin C deficiency AR C2orf25 (611935) Cobalamin D deficiency AR MTRR (602568) Cobalamin E deficiency AR LMBRD1 (612625) Cobalamin F deficiency AR MTR (156570) Cobalamin G deficiency AR CBS (613381) Homocysteinuria AR PCBD (126090) Hyperphelaninemia variant D AR TH (191290) Tyrosine hydroxylase deficiency AR SPR (182125) Sepiaterine reductase -
1 Silencing Branched-Chain Ketoacid Dehydrogenase Or
bioRxiv preprint doi: https://doi.org/10.1101/2020.02.21.960153; this version posted February 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Silencing branched-chain ketoacid dehydrogenase or treatment with branched-chain ketoacids ex vivo inhibits muscle insulin signaling Running title: BCKAs impair insulin signaling Dipsikha Biswas1, PhD, Khoi T. Dao1, BSc, Angella Mercer1, BSc, Andrew Cowie1 , BSc, Luke Duffley1, BSc, Yassine El Hiani2, PhD, Petra C. Kienesberger1, PhD, Thomas Pulinilkunnil1†, PhD 1Department of Biochemistry and Molecular Biology, Dalhousie Medicine New Brunswick, Saint John, New Brunswick, Canada, 2Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada. †Correspondence to Thomas Pulinilkunnil, PhD Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University Dalhousie Medicine New Brunswick, 100 Tucker Park Road, Saint John E2L4L5, New Brunswick, Canada. Telephone: (506) 636-6973; Fax: (506) 636-6001; email: [email protected]. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.02.21.960153; this version posted February 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International -
Transglutaminase-Catalyzed Inactivation Of
Proc. Natl. Acad. Sci. USA Vol. 94, pp. 12604–12609, November 1997 Medical Sciences Transglutaminase-catalyzed inactivation of glyceraldehyde 3-phosphate dehydrogenase and a-ketoglutarate dehydrogenase complex by polyglutamine domains of pathological length ARTHUR J. L. COOPER*†‡§, K.-F. REX SHEU†‡,JAMES R. BURKE¶i,OSAMU ONODERA¶i, WARREN J. STRITTMATTER¶i,**, ALLEN D. ROSES¶i,**, AND JOHN P. BLASS†‡,†† Departments of *Biochemistry, †Neurology and Neuroscience, and ††Medicine, Cornell University Medical College, New York, NY 10021; ‡Burke Medical Research Institute, Cornell University Medical College, White Plains, NY 10605; and Departments of ¶Medicine, **Neurobiology, and iDeane Laboratory, Duke University Medical Center, Durham, NC 27710 Edited by Louis Sokoloff, National Institutes of Health, Bethesda, MD, and approved August 28, 1997 (received for review April 24, 1997) ABSTRACT Several adult-onset neurodegenerative dis- Q12-containing peptide (16). In the work of Kahlem et al. (16) the eases are caused by genes with expanded CAG triplet repeats largest Qn domain studied was Q18. We found that both a within their coding regions and extended polyglutamine (Qn) nonpathological-length Qn domain (n 5 10) and a longer, patho- domains within the expressed proteins. Generally, in clinically logical-length Qn domain (n 5 62) are excellent substrates of affected individuals n > 40. Glyceraldehyde 3-phosphate dehy- tTGase (17, 18). drogenase binds tightly to four Qn disease proteins, but the Burke et al. (1) showed that huntingtin, huntingtin-derived significance of this interaction is unknown. We now report that fragments, and the dentatorubralpallidoluysian atrophy protein purified glyceraldehyde 3-phosphate dehydrogenase is inacti- bind selectively to glyceraldehyde 3-phosphate dehydrogenase vated by tissue transglutaminase in the presence of glutathione (GAPDH) in human brain homogenates and to immobilized S-transferase constructs containing a Qn domain of pathological rabbit muscle GAPDH. -
1 Silencing Branched-Chain Ketoacid Dehydrogenase Or
bioRxiv preprint doi: https://doi.org/10.1101/2020.02.21.960153; this version posted February 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Silencing branched-chain ketoacid dehydrogenase or treatment with branched-chain ketoacids ex vivo inhibits muscle insulin signaling Running title: BCKAs impair insulin signaling Dipsikha Biswas1, PhD, Khoi T. Dao1, BSc, Angella Mercer1, BSc, Andrew Cowie1 , BSc, Luke Duffley1, BSc, Yassine El Hiani2, PhD, Petra C. Kienesberger1, PhD, Thomas Pulinilkunnil1†, PhD 1Department of Biochemistry and Molecular Biology, Dalhousie Medicine New Brunswick, Saint John, New Brunswick, Canada, 2Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada. †Correspondence to Thomas Pulinilkunnil, PhD Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University Dalhousie Medicine New Brunswick, 100 Tucker Park Road, Saint John E2L4L5, New Brunswick, Canada. Telephone: (506) 636-6973; Fax: (506) 636-6001; email: [email protected]. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.02.21.960153; this version posted February 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International -
Aerobic Glycolysis Fuels Platelet Activation: Small-Molecule Modulators of Platelet Metabolism As Anti-Thrombotic Agents
ARTICLE Platelet Biology & its Disorders Aerobic glycolysis fuels platelet activation: Ferrata Storti Foundation small-molecule modulators of platelet metabolism as anti-thrombotic agents Paresh P. Kulkarni,1† Arundhati Tiwari,1† Nitesh Singh,1 Deepa Gautam,1 Vijay K. Sonkar,1 Vikas Agarwal2 and Debabrata Dash1 1Department of Biochemistry, Institute of Medical Sciences and 2Department of Cardiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Haematologica 2019 Pradesh, India Volume 104(4):806-818 † PPK and AT contributed equally to this work. ABSTRACT latelets are critical to arterial thrombosis, which underlies myocardial infarction and stroke. Activated platelets, regardless of the nature of Ptheir stimulus, initiate energy-intensive processesthat sustain throm- bus, while adapting to potential adversities of hypoxia and nutrient depri- vation within the densely packed thrombotic milieu. We report here that stimulated platelets switch their energy metabolism to robicae glycolysis by modulating enzymes at key checkpoints in glucose metabolism. We found that aerobic glycolysis, in turn, accelerates flux through the pentose phos- phate pathway and supports platelet activation. Hence, reversing metabolic adaptations of platelets could be an effective alternative to conventional anti-platelet approaches, which are crippled by remarkable redundancy in platelet agonists and ensuing signaling pathways. In support of this hypoth- esis, small-molecule modulators of pyruvate dehydrogenase, pyruvate kinase M2 and glucose-6-phosphate dehydrogenase, all of which impede aerobic glycolysis and/or the pentose phosphate pathway, restrained the Correspondence: agonist-induced platelet responsesex vivo. These drugs, which include the DEBABRATA DASH anti-neoplastic candidate, dichloroacetate, and the Food and Drug [email protected] Administration-approved dehydroepiandrosterone, profoundly impaired thrombosis in mice, thereby exhibiting potential as anti-thrombotic agents. -
Emerging Roles of P53 Family Members in Glucose Metabolism
International Journal of Molecular Sciences Review Emerging Roles of p53 Family Members in Glucose Metabolism Yoko Itahana and Koji Itahana * Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore; [email protected] * Correspondence: [email protected]; Tel.: +65-6516-2554; Fax: +65-6221-2402 Received: 19 January 2018; Accepted: 22 February 2018; Published: 8 March 2018 Abstract: Glucose is the key source for most organisms to provide energy, as well as the key source for metabolites to generate building blocks in cells. The deregulation of glucose homeostasis occurs in various diseases, including the enhanced aerobic glycolysis that is observed in cancers, and insulin resistance in diabetes. Although p53 is thought to suppress tumorigenesis primarily by inducing cell cycle arrest, apoptosis, and senescence in response to stress, the non-canonical functions of p53 in cellular energy homeostasis and metabolism are also emerging as critical factors for tumor suppression. Increasing evidence suggests that p53 plays a significant role in regulating glucose homeostasis. Furthermore, the p53 family members p63 and p73, as well as gain-of-function p53 mutants, are also involved in glucose metabolism. Indeed, how this protein family regulates cellular energy levels is complicated and difficult to disentangle. This review discusses the roles of the p53 family in multiple metabolic processes, such as glycolysis, gluconeogenesis, aerobic respiration, and autophagy. We also discuss how the dysregulation of the p53 family in these processes leads to diseases such as cancer and diabetes. Elucidating the complexities of the p53 family members in glucose homeostasis will improve our understanding of these diseases. -
The Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’S Disease
life Article The Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’s Disease Dora Csaban 1, Klara Pentelenyi 1, Renata Toth-Bencsik 1, Anett Illes 2, Zoltan Grosz 1, Andras Gezsi 3 and Maria Judit Molnar 1,* 1 Institute of Genomic Medicine and Rare Disorders, Semmelweis University, H-1082 Budapest, Hungary; [email protected] (D.C.); pentelenyi.klara@ med.semmelweis-univ.hu (K.P.); [email protected] (R.T.-B.); [email protected] (Z.G.) 2 PentaCore Laboratory Budapest, H-1094 Budapest, Hungary; [email protected] 3 Department of Measurement and Information Systems, Budapest University of Technology and Economics, H-1117 Budapest, Hungary; [email protected] * Correspondence: [email protected] Abstract: There is increasing evidence that several mitochondrial abnormalities are present in the brains of patients with Alzheimer’s disease (AD). Decreased alpha-ketoglutarate dehydrogenase complex (αKGDHc) activity was identified in some patients with AD. The αKGDHc is a key enzyme in the Krebs cycle. This enzyme is very sensitive to the harmful effect of reactive oxygen species, which gives them a critical role in the Alzheimer and mitochondrial disease research area. Previously, several genetic risk factors were described in association with AD. Our aim was to analyze the associations of rare damaging variants in the genes encoding αKGDHc subunits and AD. The three genes (OGDH, DLST, DLD) encoding αKGDHc subunits were sequenced from different brain regions Citation: Csaban, D.; Pentelenyi, K.; of 11 patients with histologically confirmed AD and the blood of further 35 AD patients. -
Glycolysis Citric Acid Cycle Oxidative Phosphorylation Calvin Cycle Light
Stage 3: RuBP regeneration Glycolysis Ribulose 5- Light-Dependent Reaction (Cytosol) phosphate 3 ATP + C6H12O6 + 2 NAD + 2 ADP + 2 Pi 3 ADP + 3 Pi + + 1 GA3P 6 NADP + H Pi NADPH + ADP + Pi ATP 2 C3H4O3 + 2 NADH + 2 H + 2 ATP + 2 H2O 3 CO2 Stage 1: ATP investment ½ glucose + + Glucose 2 H2O 4H + O2 2H Ferredoxin ATP Glyceraldehyde 3- Ribulose 1,5- Light Light Fx iron-sulfur Sakai-Kawada, F Hexokinase phosphate bisphosphate - 4e + center 2016 ADP Calvin Cycle 2H Stroma Mn-Ca cluster + 6 NADP + Light-Independent Reaction Phylloquinone Glucose 6-phosphate + 6 H + 6 Pi Thylakoid Tyr (Stroma) z Fe-S Cyt f Stage 1: carbon membrane Phosphoglucose 6 NADPH P680 P680* PQH fixation 2 Plastocyanin P700 P700* D-(+)-Glucose isomerase Cyt b6 1,3- Pheophytin PQA PQB Fructose 6-phosphate Bisphosphoglycerate ATP Lumen Phosphofructokinase-1 3-Phosphoglycerate ADP Photosystem II P680 2H+ Photosystem I P700 Stage 2: 3-PGA Photosynthesis Fructose 1,6-bisphosphate reduction 2H+ 6 ADP 6 ATP 6 CO2 + 6 H2O C6H12O6 + 6 O2 H+ + 6 Pi Cytochrome b6f Aldolase Plastoquinol-plastocyanin ATP synthase NADH reductase Triose phosphate + + + CO2 + H NAD + CoA-SH isomerase α-Ketoglutarate + Stage 2: 6-carbonTwo 3- NAD+ NADH + H + CO2 Glyceraldehyde 3-phosphate Dihydroxyacetone phosphate carbons Isocitrate α-Ketoglutarate dehydogenase dehydrogenase Glyceraldehyde + Pi + NAD Isocitrate complex 3-phosphate Succinyl CoA Oxidative Phosphorylation dehydrogenase NADH + H+ Electron Transport Chain GDP + Pi 1,3-Bisphosphoglycerate H+ Succinyl CoA GTP + CoA-SH Aconitase synthetase -
Prehatch Intestinal Maturation of Turkey Embryos Demonstrated Through Gene Expression Patterns
MOLECULAR, CELLULAR, AND DEVELOPMENTAL BIOLOGY Prehatch intestinal maturation of turkey embryos demonstrated through gene expression patterns J. E. de Oliveira ,*1 S. Druyan ,*2 Z. Uni ,† C. M. Ashwell ,* and P. R. Ferket *3 * North Carolina State University, Department of Poultry Science, Raleigh 27695; and † Hebrew University, Faculty of Agriculture, Department of Animal Science, Rehovot, Israel 76100 ABSTRACT Some of the challenges faced by neonatal by gene expression pattern similarity into 4 groups. turkeys include weakness, reduced feed intake, impaired The expression pattern of hormone receptors revealed growth, susceptibility to disease, and mortality. These that intestinal tissues may be less responsive to growth symptoms may be due to depleted energy reserves after hormone, insulin, glucagon, and triiodothyronine dur- hatch and an immature digestive system unable to re- ing the last 48 h before hatch, when developmental plenish energy reserves from consumed feed. To better emphasis switches from cell proliferation to functional understand enteric development in turkeys just before maturation. Based on gene expression patterns, we con- hatch, a new method was used to identify the patterns cluded that at hatch, poults should have the capacity of intestinal gene expression by utilizing a focused mi- to 1) digest disaccharides but not oligopeptides, due croarray. The duodenums of 24 turkey embryos were to increased expression of sucrase-isomaltase but de- sampled on embryonic day (E)20, E24, E26, and hatch creased expression of aminopeptidases and 2) absorb (E28). The RNA populations of 96 chosen genes were monosaccharides and small peptides due to high ex- measured at each time point, from which 81 signifi- pression of sodium-glucose cotransporter-4 and peptide cantly changed (P < 0.01). -
Lipoyl Moieties in the Pyruvate and A-Ketoglutarate Dehydrogenase
Vol. 74, No. 10, pp 42&S-4227, October 1977 Biochemistry Acyl group and electron pair relay system: A network of interacting lipoyl moieties in the pyruvate and a-ketoglutarate dehydrogenase complexes from Escherichia coli (multienzyme complexes/thiol-disulfide interchange/crosslinking of subunits) JIMMY H. COLLINS AND LESTER J. REED Clayton Foundation Biochemical Institute and Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712 Contributed by Lester J. Reed, August 18, 1977 ABSTRACT The dihydrolipoyl transacetylase component complex by [2-'4C]pyruvate (6) and of the pyruvate-dependent of the Escherichia coli pyruvate dehydrogenase complex [pyr- reaction of N-ethyl[2,3-14C]maleimide with the complex (7) uvate:lipoate oxidoreductase (decarboxylating and acceptor- indicate the presence of two functionally active lipoyl acetylating), EC 1.2.4.11 bears two sites on each of its 24poly- moieties peptide chains that undergo reductive acetylation by on each transacetylase chain. 2-4C pyruvate and thiamin pyrophosphate, acetylation by In this communication, we confirm and extend this latter [lMClacetyl-CoA in the presence of DPNH, and reaction with finding, and we present evidence indicating that the trans- N-ethyl[2,3-14Clmaleimide in the presence of pyruvate and succinylase component of the a-ketoglutarate dehydrogenase thiamin pyrophosphate. The data strongly ir tat these sites complex bears one functionally active lipoyl moiety per chain are covalent y bound lipoyl moieties. The results of similar ex- and that the 48 lipoyl moieties in periments with the E. coli a-ketoglutarate dehydrogenase the transacetylase and the 24 complex [2-oxoglutaratelipoate oxidoreductase (decarboxylating lipoyl moieties in the transsuccinylase comprise a network that and acceptor-succinylating), EC 1±2.4.2] indicate that its dihy- functions as an acyl group and electron pair relay system drolipoyl transsuccinylase component bears only one lipoyl through thiol-disulfide and acyl-transfer reactions among all moiety on each of its 24 chains. -
Unstructured Regions of Large Enzymatic Complexes Control The
Skalidis et al. Cell Communication and Signaling (2020) 18:136 https://doi.org/10.1186/s12964-020-00631-9 REVIEW Open Access Unstructured regions of large enzymatic complexes control the availability of metabolites with signaling functions Ioannis Skalidis1,2 , Christian Tüting1,2 and Panagiotis L. Kastritis1,2,3* Abstract Metabolites produced via traditional biochemical processes affect intracellular communication, inflammation, and malignancy. Unexpectedly, acetyl-CoA, α-ketoglutarate and palmitic acid, which are chemical species of reactions catalyzed by highly abundant, gigantic enzymatic complexes, dubbed as “metabolons”, have broad “nonmetabolic” signaling functions. Conserved unstructured regions within metabolons determine the yield of these metabolites. Unstructured regions tether functional protein domains, act as spatial constraints to confine constituent enzyme communication, and, in the case of acetyl-CoA production, tend to be regulated by intricate phosphorylation patterns. This review presents the multifaceted roles of these three significant metabolites and describes how their perturbation leads to altered or transformed cellular function. Their dedicated enzymatic systems are then introduced, namely, the pyruvate dehydrogenase (PDH) and oxoglutarate dehydrogenase (OGDH) complexes, and the fatty acid synthase (FAS), with a particular focus on their structural characterization and the localization of unstructured regions. Finally, upstream metabolite regulation, in which spatial occupancy of unstructured regions within -
Germline DLST Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma
Germline DLST Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma Alexandre Buffet, Juan Zhang, Heggert Rebel, Eleonora Corssmit, Jeroen Jansen, Erik Hensen, Judith Bovée, Aurélien Morini, Anne-Paule Gimenez-Roqueplo, Frederik Hes, et al. To cite this version: Alexandre Buffet, Juan Zhang, Heggert Rebel, Eleonora Corssmit, Jeroen Jansen, et al.. Germline DLST Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma. The Journal of Clinical Endocrinology & Metabolism, 2020, 10.1210/clinem/dgaa819. hal-03111589 HAL Id: hal-03111589 https://hal.archives-ouvertes.fr/hal-03111589 Submitted on 25 Jan 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. The Journal of Clinical Endocrinology & Metabolism, 2020, Vol. XX, No. XX, 1–13 doi:10.1210/clinem/dgaa819 Clinical Research Article Downloaded from https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgaa819/5979643 by Centre de Doc Medico Pharmaceutique user on 08 January 2021 Clinical Research Article Germline DLST Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma Alexandre Buffet,*1,2 Juan Zhang,*3 Heggert Rebel,3 Eleonora P. M. Corssmit,4 Jeroen C. Jansen,5 Erik F. Hensen,5 Judith V. M. G. Bovée,6 Aurélien Morini,7 Anne-Paule Gimenez-Roqueplo,1,2 Frederik J.