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    • A computational protocol to model organophosphonate CWAs and their simulants
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  • Galactosemia – protein misfolding diseases which result in cellular stress

Galactosemia – protein misfolding diseases which result in cellular stress

Galactosemia is a rare, inherited metabolic disease which results from mutations in the genes encoding enzymes of galactose metabolism. The mildest cases are almost asymptomatic, but the most severe are life-threatening. There is no cure. We are seeking to understand the molecular basis of this disease by studying recombinant enzymes from the Leloir pathway of galactose metabolism. Typically we recapitulate disease-associated variants and study the biochemical and enzymological effects. In addition, we also conduct in silico studies. The dramatic effects of severe forms of galactosemia suggest that inhibition of these enzymes in pathogens may be a viable strategy for therapy. Therefore, we have studied some of these enzymes from parasitic worms with a longer term aim of identifying novel inhibitors of these enzymes. We have also attempted to expand the substrate range of galactokinase so that it can be used in the biocatalytic site- and stereo-specific phosphorylation ofa range of monosaccharides.

The work is conducted with a range of excellent collaborators and we are always open to new collaborations. We are also interested in extending the approaches taken to understand galactosemia to other inherited metabolic diseases.

Project timeframe

This project commenced in 2001 and will end when we fully understand the molecular basis of galactosemia.

Project aims

  • To understand how disease-associated variant forms of galactokinase, galactose 1-phosphate uridylyltransferase and UDP-galactose 4’-epinerase fail to function
  • To undertake in silico studies to identify other variants which may have reduced stability compared to the wild-type
  • To identify small molecular which may act as “pharmacological chaperones” to correct the folding of disease-associated variants
  • To study Leloir pathway enzymes from pathogens and to discover compounds which inhibit these
  • To exploit Leloir pathway enzymes in biocatalysis
  • To extend the approaches pioneered for galactosemia to other inherited metabolic diseases

 

 

Project findings and impact

  • Protein misfolding lies at the heart of UDP-galactose 4’-epimerase and galactose 1-phosphate uridylyltransferase deficiency
  • Enzymological impairment approximately correlates with disease severity

Research Team

David Timson

Output

  • Timson DJ & Reece RJ (2003). Functional analysis of disease-causing mutations in human galactokinase. European Journal of Biochemistry 270, 1767-1774.
  • Timson DJ & Reece RJ (2003). Sugar recognition by human galactokinase. BMC Biochemistry 4:16.
  • Holden HM, Thoden JB, Timson DJ & Reece RJ (2004) Galactokinase – structure, function and role in type II galactosemia. Cellular and Molecular Life Sciences 61, 2471-2484.
  • Thoden JB, Timson DJ, Reece RJ & Holden HM (2005) Molecular structure of human galactokinase: Implications for type II galactosemia. Journal of Biological Chemistry 280, 9662-9670.
  • Timson DJ (2005) Functional analysis of disease-causing mutations in human UDP-galactose 4-epimerase. FEBS Journal 272, 6170-6177.
  • Timson DJ (2006) The structural and molecular biology of type III galactosemia. IUBMB Life 58, 83-89.
  • Timson DJ (2007) GHMP kinases – structures, mechanisms and potential for therapeutically relevant inhibition. Current Enzyme Inhibition. 3, 77-94.
  • Chhay JS, Vargas CA, McCorvie TJ, Fridovich-Keil JL & Timson DJ (2008) Analysis of UDP-galactose 4’-epimerase mutations associated with the intermediate form of type III galactosemia. Journal of Inherited Metabolic Disease 31, 108-116.
  • Timson DJ, Reece RJ, Thoden JB & Holden HM (2008) Galactokinase deficiency, in Encyclopedic Reference of Molecular Mechanisms of Disease Lang F (Ed), Springer (Germany).
  • Megarity CF, Huang M, Warnock C & Timson DJ (2011) The role of the active site residues in human galactokinase: implications for the mechanisms of GHMP kinases. Bioorganic Chemistry. 39, 120-126.
  • McCorvie TJ, Wasilenko J, Liu Y, Fridovich-Keil JL & Timson DJ (2011) In vivo and in vitro function of human UDP-galactose 4′-epimerase variants. Biochimie. 93, 1747-1754.
  • McCorvie TJ & Timson DJ (2011) The structural and molecular biology of type I galactosemia: enzymology of galactose 1-phosphate uridylyltransferase. IUBMB Life 63, 694-700.
  • McCorvie TJ & Timson DJ (2011) Structural and molecular biology of type I galactosemia: disease-associated mutations. IUBMB Life 63, 949-954.
  • Friedman AJ, Durrant JD, Pierce LCT, McCorvie TJ, Timson DJ & McCammon JA (2012) The molecular dynamics of Trypanosoma brucei UDP-galactose 4'-epimerase: a drug target for African sleeping sickness. Chemical Biology & Drug Design. 80, 173-181.
  • McCorvie TJ, Liu Y, Frazer A, Gleason TJ, Fridovich-Keil JL & Timson DJ (2012) Altered cofactor binding affects stability and activity of human UDP-galactose 4’-epimerase: implications for type III galactosemia. Biochimica et Biophysica Acta – Molecular Basis of Disease. 1822, 1516-1526.
  • McCorvie TJ & Timson DJ (2013) In silico investigation of the molecular basis of type III galactosemia: towards a predictive framework for novel mutations. Gene. 524, 95-104.
  • McCorvie TJ, Gleason TJ, Fridovich-Keil JL & Timson DJ (2013) Misfolding of galactose 1-phosphate uridylyltransferase can result in type I galactosemia Biochimica et Biophysica Acta – Molecular Basis of Disease. 1832, 1279-1293.
  • Huang M, Li X, Zou JW & Timson DJ (2013) The Role of Arg228 in the phosphorylation of galactokinase: the mechanism of GHMP kinases by QM/MM studies. Biochemistry. 52, 4858−4868.
  • Timson DJ & Lindert S (2013) Comparison of dynamics of wildtype and V94M human UDP-Galactose 4’-Epimerase – A computational perspective on severe Epimerase-deficiency Galactosemia. Gene. 526, 318-324.
  • McCorvie TJ & Timson DJ (2014) UDP-galactose 4-epimerase (GALE), in Handbook of Glycosyltransferases and Related Genes Taniguchi N, Honke K, Fukuda M, Narimatsu H, Yamaguchi Y & Angata T (ed.s) Springer.
  • Timson DJ (2014) Purple sweet potato colour – a potential therapy for galactosemia? International Journal of Food Sciences and Nutrition. 65, 391-393.
  • Pey AL, Padín-Gonzalez E, Mesa-Torres N & Timson DJ (2014) The metastability of human UDP-galactose 4ʹ-epimerase (GALE) is increased by variants associated with type III galactosemia but decreased by substrate and cofactor binding Archives of Biochemistry and Biophysics. 562, 103-114.
  • Zinsser VL, Lindert S, Banford S, Hoey EM, Trudgett A & Timson DJ (2015) UDP-galactose 4’-epimerase from the liver fluke, Fasciola hepatica: biochemical characterisation of the enzyme and identification of inhibitors. Parasitology 142, 463-472.
  • Browne C & Timson DJ (2015) In silico prediction of the effects of mutations in the human mevalonate kinase gene: towards a predictive framework for mevalonate kinase deficiency. Annals of Human Genetics. 79, 451-459.
  • Timson DJ (2016) The molecular basis of galactosemia – past, present and future. Gene. 589, 133-141.
  • McAuley M, Kristiansson H, Huang M, Pey AL & Timson DJ (2016) Galactokinase promiscuity: a question of flexibility? Biochemical Society Transactions. 44, 116-122.
  • Paul S, McCorvie TJ, Zschocke J & Timson DJ (2016) Disturbed cofactor binding by a novel mutation in UDP-galactose 4’-epimerase results in a type III galactosemia phenotype at birth RSC Advances. 6, 17297-17301.
  • Fuchs JE, Muñoz IG, Timson DJ & Pey AL (2016) Experimental and computational evidence on conformational fluctuations as a source of catalytic defects in genetic diseases. RSC Advances. 6, 58604-58612.
  • McAuley M, Huang M & Timson DJ (2017) Insight into the mechanism of galactokinase: role of a critical glutamate residue and helix/coil transitions. Biochimica et Biophysica Acta – Proteins and Proteomics. 1865, 321-328.
  • Timson DJ (2017) Molecular genetics of galactosaemia, in: eLS. John Wiley and Sons, Chichester.

Partners

Dr Angel Pey, University of Grenada

Prof Estela Rubio-Gozalbo, University of Maastricht

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