Don Mahuran, PhD
Research Institute
Senior Scientist
Genetics & Genome Biology
University of Toronto
Professor
Department of Laboratory Medicine and Pathobiology
Phone: 416-813-6161
Fax: 416-813-8700
e-mail: hex@sickkids.ca
Brief Biography
Don Mahuran graduated from Wartburg College in Waverly, Iowa, with a B.A. degree in chemistry, in 1971. He then attended the University of Windsor, Ontario, and was awarded a Ph.D. degree in chemistry, in 1976. His thesis title was "Characterization of Fumarylacetoacetate Fumarylhydrolase" (the enzyme defective in the French Canadian variant of Tyrosinemia).
Dr. Mahuran's postdoctoral training was in the Division of Neurosciences at The Hospital for Sick Children, from 1977-1979. From 1981-1982 Dr. Mahuran travelled to the Chemical Pathology Department at Adelaide Children's Hospital in South Australia as part of a Hospital Scientist Exchange Program.
Research Interests
- lysosomal storage diseases
- organelle-specific proteomics
- chemical chaperones
- protein trafficking
Research Activities
The hydrolysis of GM2 ganglioside requires the correct synthesis, targeting and combination of three gene products. Two of these, the á and â subunits of â-hexosaminidase A, combine in the endoplasmic reticulum and the third, the GM2 activator protein, acts as a substrate specific co-factor that removes GM2 from its membranous environment and presents it to Hex A for hydrolysis in the lysosome. Reduction of any of these proteins to >=5% of normal results in Tay-Sachs, Sandhoff or the AB-variant form of GM2 gangliosidosis, respectively. Our resent crystallization of human Hex has allowed us to model the active quaternary complex.
My laboratory is determining the validity of the model through site directed mutagenesis, cellular expression and biochemical analyses. Since many naturally occurring mutations produce unstable proteins that are degraded before they reach the lysosome, we are investigating known inhibitors and other small molecules as chemical chaperones for the treatment of chronic GM2 gangliosidosis. Finally we are using proteomic techniques to study the composition of the lysosomal membrane in normal and disease states.
External Funding
2009 - 2014: CIHR Emerging Team Grant in Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC): From Genes to Proteins, Cells, Tissues and Patients.
2007 - 2012: CIHR Team Grant in Lysosomal Storage Disease Pharmaco Therapeutics
2010 - 2012: The Sanfilippo Children's Research Foundation
Publications
Schitter G, Scheucher E, Steiner AJ, Stütz AE, Thonhofer M, Tarling CA, Withers SG, Wicki J, Fantur K, Paschke E, Mahuran D, Rigat B, Tropak M, Wrodnigg TM. Synthesis of lipophilic 1-deoxygalactonojirimycin derivatives as d-galactosidase Inhibitors, Beilstein J Org Chem 6, (21): doi:10.3762 (2010)
Khanna R, Benjamin ER, Pellegrino L, Schilling A, Rigat BR, Soska R, Nafar H, Ranes BE, Lun Y, Powe AC, Palling DJ, Wustman BA, Schiffmann R, Mahuran DJ, LockhartDJ, Valenzano KJ. The pharmacological chaperone isofagomine increases activity of the Gaucher Disease L44P mutant form of β-glucosidase, FEBS 1-21: doi:10.1111 (2010)
Zhang HW, Mahuran DJ, Callahan JW, Identification of proteins in the ceroid-like autofluorescent aggregates from liver lysosomes of Beige, a mouse model for human Chediak-Higashi syndrome, Molecular Genetics and Metabolism 99, 389-395 (2010)
Tropak MB, Bukovac SW, Rigat BA, Yonekawa S, Wakarchuk W, Mahuran DJ. A sensitive fluorescence-based assay for monitoring GM2 ganglioside hydrolysis in live patient cells and their lysates,Glycobiology 20 (3): 356-365 (2010)
Steiner AJ, Schitter G, Stuetz AE, Wrodnigg TM, Tarling CA, Withers SG, Mahuran DJ, Tropak MB, 2-Acetamino-1,2-dideoxynojirimycin-lysine hybrids as hexosaminidase inhibitors, Tetrahedron-Asymmetry 20, 832-835 (2009)
Sinici I, Tropak MB, Ozkara HA, Mahuran DJ, Inhibition of endoplasmic reticulum associated degradation of mutant pro-beta subunits of beta-hexosaminidase by kifunensine and lactacystin, Turkish Journal of Biochemistry-Turk Biyokimya Dergisi 34, 160-166 (2009)
Rigat B, Yeger H, Shehnaz D, Mahuran D. GM2 activator protein inhibits platelet activating factor signaling in rats, Biochem. Biophys. Resear. Commun. 385, 576-580 (2009)
Ramachandran N, Munteanu I, Wang P, Aubourg P, Rilstone JJ, Israelian N, Naranian T, Paroutis P, Guo R, Ren ZP, Nishino I, Chabrol B, Pellissier JF, Minetti C, Udd B, Fardeau M, Tailor CS, Mahuran DJ, Kissel JT, Kalimo H, Levy N, Manolson MF, Ackerley CA, Minassian BA. VMA21 deficiency causes an autophagic myopathy by compromising V-ATPase activity and lysosomal acidification, Cell 137, 235-46 (2009)
Rigat B, Mahuran D. Diltiazem, a L-type Ca2+ channel blocker, also acts as a pharmacological chaperone in Gaucher patient cells, Mol Genet Metab 96, 225-232 (2009).
Callahan JW, Bagshaw RD, Mahuran DJ. The integral membrane of lysosomes: its proteins and their roles in disease, J Proteomics 72, 23-33 (2009).