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    Anthony Carruthers PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentBiochemistry and Molecular Pharmacology
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North, S1-824
    Worcester MA 01655
    Phone508-856-6074
      Other Positions
      InstitutionUMMS - School of Medicine
      DepartmentMicrobiology and Physiological Systems

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentTranslational Science

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentBioinformatics and Integrative Biology

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentCenter for AIDS Research

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentDiabetes and Endocrinology Research Center

        Overview 
        Narrative

        Academic Background

        Dean of the Graduate School of Biomedical Sciences

        Tony Carruthers received his B.Sc. degree from the University of Manchester (U.K.) in 1977 and his Ph.D.in cellular physiology from King's College, London, in 1980. In 1982 he received a Wellcome Trust Travel Award and a NATO Overseas Postdoctoral Fellowship to perform postdoctoral work at the University of Massachusetts Medical Center.

        Following his postdoctoral work, he remained at UMass Medical School as a faculty member in the Department of Biochemistry and Molecular Pharmacology.

        Carrier-mediated transport

        Research in my laboratory is aimed at understanding protein-mediated transport of nutrients and other small molecules across cell membranes.

        The Major Facilitator Superfamily (MFS) of transport proteins comprises more than 1,000 unique proteins that mediate passive and secondary active transmembrane transport of nutrients, drugs, ions, neurotransmitters, and other molecules in all organisms. The facilitative glucose transporter family (GLUT1-14) mediates the uniport of monosaccharides and other small molecules in vertebrates. GLUT proteins are expressed in an organ-system specific manner allowing them to meet the metabolic needs of the organism. For example, GLUT2 is found in the liver and glucose sensing cells of the CNS, GLUT3 is expressed in neuronal cells, and insulin-sensitive GLUT4 is found in muscle and adipose tissue. GLUT1 is found in many tissues throughout the body but is expressed most highly in CNS astrocytes, in β-cells of the human pancreas, in the circulatory system and at blood-tissue barriers such as the blood-brain barrier where it mediates glucose transfer from blood to brain. The focus of our laboratory is to understand the molecular basis of GLUT function and regulation.

        Our methods include molecular biology, genetics, protein chemistry, mass spectrometry, biochemistry, biophysics and cellular physiology. More details about the laboratory may be found at our lab web page http://glutxi.umassmed.edu/index.html

         

        Figures

        Ultrastructure of Human Erythrocyte GLUT1

        Ultrastructure of Human Erythrocyte GLUT1

        Analysis of GLUT1 aggregation state by freeze-fracture electron microscopy. High magnification of unidirectionally shadowed freeze-fractured electron micrographs of GLUT1 proteoliposomes. Composite of nonreduced (left) and reduced (middle), purified GLUT1 Integral Membrane Particles. The bar represents 10 nm. The images represent the average of 60 particles. The rightmost image shows the dimensions of monomeric GLUT1 threaded through GlpT structure.

        Structural basis of GLUT1 regulation by ATP

        Structural basis of GLUT1 regulation by ATP

        ATP regulation of GLUT1. GLUT1 membrane spanning topography is illustrated. GLUT1 behavior is illustrated in the presence of AMP (left) or ATP (right). Trypsin cleavage sites (yellow and brown circles), sites of antibody recognition (green and red sequence), and sites where IgG binding is not detected (blue sequence) are indicated. In the presence of ATP (right), ATP-sensitive (red sequence) and insensitive (green sequence) IgG binding domains are also indicated. The circles show ATP-insensitive tryptic cleavage sites (yellow circles), ATP-protected tryptic cleavage sites (brown circles), and ATP-protected sites of lysine covalent modification by Sulfo-NHS-LC-Biotin (red circles). We propose that the GLUT1 C-terminus and the C-terminal half of the middle loop interact in response to ATP binding. This reduces their respective accessibility to polar reagents and restricts glucose release from the translocation pathway.



        Rotation Projects

        Potential Rotation Projects

         

        1. Mapping glucose transporter ligand binding sites.
        2. Mapping GLUT1 intramolecular contacts.
        3. How does cell shape regulate glucose transport?
        4. Using transporter chimeras to map specificity and functional domains.
        5. Development of a transwell model for blood brain barrier function.
        6. Site directed GLUT1 mutagenesis to test specific hypotheses for GLUT1 function.

         

        For specific details on each project, please e-mail me at:

                                        anthony.carruthers@umassmed.edu

         



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Sage JM, Carruthers A. Human erythrocytes transport dehydroascorbic acid and sugars using the same transporter complex. Am J Physiol Cell Physiol. 2014 May 15; 306(10):C910-7.
          View in: PubMed
        2. De Zutter JK, Levine KB, Deng D, Carruthers A. Sequence determinants of GLUT1 oligomerization: analysis by homology-scanning mutagenesis. J Biol Chem. 2013 Jul 12; 288(28):20734-44.
          View in: PubMed
        3. Vollers SS, Carruthers A. Sequence determinants of GLUT1-mediated accelerated-exchange transport: analysis by homology-scanning mutagenesis. J Biol Chem. 2012 Dec 14; 287(51):42533-44.
          View in: PubMed
        4. Cura AJ, Carruthers A. AMP kinase regulation of sugar transport in brain capillary endothelial cells during acute metabolic stress. Am J Physiol Cell Physiol. 2012 Oct 15; 303(8):C806-14.
          View in: PubMed
        5. Cura AJ, Carruthers A. Role of monosaccharide transport proteins in carbohydrate assimilation, distribution, metabolism, and homeostasis. Compr Physiol. 2012 Apr; 2(2):863-914.
          View in: PubMed
        6. Robichaud T, Appleyard AN, Herbert RB, Henderson PJ, Carruthers A. Determinants of ligand binding affinity and cooperativity at the GLUT1 endofacial site. Biochemistry. 2011 Apr 19; 50(15):3137-48.
          View in: PubMed
        7. Mangia S, DiNuzzo M, Giove F, Carruthers A, Simpson IA, Vannucci SJ. Response to 'comment on recent modeling studies of astrocyte-neuron metabolic interactions': much ado about nothing. J Cereb Blood Flow Metab. 2011 Jun; 31(6):1346-53.
          View in: PubMed
        8. Cura AJ, Carruthers A. Acute modulation of sugar transport in brain capillary endothelial cell cultures during activation of the metabolic stress pathway. J Biol Chem. 2010 May 14; 285(20):15430-9.
          View in: PubMed
        9. Carruthers A, DeZutter J, Ganguly A, Devaskar SU. Will the original glucose transporter isoform please stand up! Am J Physiol Endocrinol Metab. 2009 Oct; 297(4):E836-48.
          View in: PubMed
        10. Mangia S, Simpson IA, Vannucci SJ, Carruthers A. The in vivo neuron-to-astrocyte lactate shuttle in human brain: evidence from modeling of measured lactate levels during visual stimulation. J Neurochem. 2009 May; 109 Suppl 1:55-62.
          View in: PubMed
        11. Carruthers A, Naftalin RJ. Altered GLUT1 substrate selectivity in human erythropoiesis? Cell. 2009 Apr 17; 137(2):200-1; author reply 201-2.
          View in: PubMed
        12. Leitch JM, Carruthers A. alpha- and beta-monosaccharide transport in human erythrocytes. Am J Physiol Cell Physiol. 2009 Jan; 296(1):C151-61.
          View in: PubMed
        13. Blodgett DM, Graybill C, Carruthers A. Analysis of glucose transporter topology and structural dynamics. J Biol Chem. 2008 Dec 26; 283(52):36416-24.
          View in: PubMed
        14. Khera PK, Joiner CH, Carruthers A, Lindsell CJ, Smith EP, Franco RS, Holmes YR, Cohen RM. Evidence for interindividual heterogeneity in the glucose gradient across the human red blood cell membrane and its relationship to hemoglobin glycation. Diabetes. 2008 Sep; 57(9):2445-52.
          View in: PubMed
        15. Blodgett DM, De Zutter JK, Levine KB, Karim P, Carruthers A. Structural basis of GLUT1 inhibition by cytoplasmic ATP. J Gen Physiol. 2007 Aug; 130(2):157-68.
          View in: PubMed
        16. Simpson IA, Carruthers A, Vannucci SJ. Supply and demand in cerebral energy metabolism: the role of nutrient transporters. J Cereb Blood Flow Metab. 2007 Nov; 27(11):1766-91.
          View in: PubMed
        17. Leitch JM, Carruthers A. ATP-dependent sugar transport complexity in human erythrocytes. Am J Physiol Cell Physiol. 2007 Feb; 292(2):C974-86.
          View in: PubMed
        18. Graybill C, van Hoek AN, Desai D, Carruthers AM, Carruthers A. Ultrastructure of human erythrocyte GLUT1. Biochemistry. 2006 Jul 4; 45(26):8096-107.
          View in: PubMed
        19. Friedman JR, Thiele EA, Wang D, Levine KB, Cloherty EK, Pfeifer HH, De Vivo DC, Carruthers A, Natowicz MR. Atypical GLUT1 deficiency with prominent movement disorder responsive to ketogenic diet. Mov Disord. 2006 Feb; 21(2):241-5.
          View in: PubMed
        20. Levine KB, Robichaud TK, Hamill S, Sultzman LA, Carruthers A. Properties of the human erythrocyte glucose transport protein are determined by cellular context. Biochemistry. 2005 Apr 19; 44(15):5606-16.
          View in: PubMed
        21. Blodgett DM, Carruthers A. Quench-flow analysis reveals multiple phases of GluT1-mediated sugar transport. Biochemistry. 2005 Feb 22; 44(7):2650-60.
          View in: PubMed
        22. Blodgett DM, Carruthers A. Conventional transport assays underestimate sugar transport rates in human red cells. Blood Cells Mol Dis. 2004 May-Jun; 32(3):401-7.
          View in: PubMed
        23. Levine KB, Cloherty EK, Hamill S, Carruthers A. Molecular determinants of sugar transport regulation by ATP. Biochemistry. 2002 Oct 22; 41(42):12629-38.
          View in: PubMed
        24. Cloherty EK, Levine KB, Graybill C, Carruthers A. Cooperative nucleotide binding to the human erythrocyte sugar transporter. Biochemistry. 2002 Oct 22; 41(42):12639-51.
          View in: PubMed
        25. Cloherty EK, Diamond DL, Heard KS, Carruthers A. Regulation of GLUT1-mediated sugar transport by an antiport/uniport switch mechanism. Biochemistry. 1996 Oct 8; 35(40):13231-9.
          View in: PubMed
        26. Zottola RJ, Cloherty EK, Coderre PE, Hansen A, Hebert DN, Carruthers A. Glucose transporter function is controlled by transporter oligomeric structure. A single, intramolecular disulfide promotes GLUT1 tetramerization. Biochemistry. 1995 Aug 1; 34(30):9734-47.
          View in: PubMed
        27. Carruthers A. Mechanisms for the facilitated diffusion of substrates across cell membranes. Biochemistry. 1991 Apr 23; 30(16):3898-906.
          View in: PubMed
        28. Carruthers A, Helgerson AL. Inhibitions of sugar transport produced by ligands binding at opposite sides of the membrane. Evidence for simultaneous occupation of the carrier by maltose and cytochalasin B. Biochemistry. 1991 Apr 23; 30(16):3907-15.
          View in: PubMed
        29. Carruthers A, Helgerson AL. The human erythrocyte sugar transporter is also a nucleotide binding protein. Biochemistry. 1989 Oct 17; 28(21):8337-46.
          View in: PubMed
        30. Carruthers A. ATP regulation of the human red cell sugar transporter. J Biol Chem. 1986 Aug 25; 261(24):11028-37.
          View in: PubMed
        31. Carruthers A. Anomalous asymmetric kinetics of human red cell hexose transfer: role of cytosolic adenosine 5'-triphosphate. Biochemistry. 1986 Jun 17; 25(12):3592-602.
          View in: PubMed
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