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About Sickkids
About SickKids

Harry Schachter, MD, PhD, FRSC

Research Institute
Senior Scientist Emeritus
Molecular Medicine

University of Toronto
Professor Emeritus
Dept. of Biochemistry


Phone: 416-813-5915
Fax: 416-813-5022
Email: harry.schachter@sickkids.ca

Brief Biography

University Education:

1955 - BA (Physiology and Biochemistry), University of Toronto
1959 - MD, University of Toronto
1959 - 1960 Rotating General Internship, Toronto General Hospital
1964 - PhD (Biochemistry), University of Toronto (Supervisor, Gordon DIXON)

Staff Appointments:

Department of Biochemistry, University of Toronto:

1964 - 1965, Assistant Professor
1965 - 1972, Associate Professor
1972 - 1998, Professor
1984 - 1989, Chairman
1998 - present, Emeritus Professor

Division of Structural Biology and Biochemistry,
The Hospital for Sick Children, Toronto:

1976 - 1989, Head
1976 - 1998, Senior Scientist
1998 - present, Emeritus Scientist

Research Interests

  • Glycosyltransferases
  • Glycoprotein synthesis
  • Developmental biology
  • Caenorhabditis elegans
  • Drosophila melanogaster
  • Functional glycoproteomics

Research Activities

Summary of Research Contributions

  • (PhD project) - Active site of chymotrypsin. Identification of the methionine involved in the active center of chymotrypsin.
  • Research on the biosynthesis of glycoconjugates, primarily on the mechanisms of protein glycosylation.
  • Pathway of L-fucose catabolism in mammalian liver and enzymatic assay for L-fucose.
  • Synthesis of radioactive GDP-Fucose.
  • Intracellular localization of glycosyltransferases in a Golgi-rich fraction. First biochemical evidence supporting Leblond's histochemical data showing that the Golgi apparatus is a major site of glycosylation.
  • Serum contains glycosyltransferase activities involved in N-glycan and human blood group antigen synthesis. This work facilitated the study of blood group genetics at a time when the cloned glycosyltransferases were not yet available.
  • Qualitative differences in the N-acetyl-D-galactosaminyltransferases produced by human blood group A1 and A2 genes.
  • Branch specificity of ß4-Gal-transferase.
  • Discovery, characterization and synthesis of testis-specific sulfogalactoglycerolipid.
  • Glycoprotein glycosyltransferase levels during spermatogenesis.
  • Carbohydrate-binding specificities of various lectins.
  • Discovery and characterization of a rat liver Golgi α-D-mannosidase dependent on the prior action of UDP-N-acetylglucosamine: α-D-mannoside ß-2-N-acetylglucosaminyltransferase I. This activity was also described by the groups of Kornfeld and Touster and was subsequently named α-mannosidase II.

Discovery and characterization of novel glycosyltransferase activities.

This area has for many years been our major research interest. Among the important contributions in this area have been the discovery of several new glycosyltransferase activities, the naming of these enzymes (GnT I to VI and the core 1 to 4 O-glycan glycosyltransferases) and the delineation of ordered pathways of synthesis involving allowed ("GO") and non-allowed ("NO GO") steps in the pathway. Although we named GnT V, this enzyme was first described by Cummings and Kornfeld.

N-glycan synthesis:

  • N-glycan core α6- and α3-fucosyltransferase
  • ß2-GlcNAc-transferase I
  • ß2-GlcNAc-transferase II
  • ß4-GlcNAc-transferase III
  • ß4-GlcNAc-transferase IV
  • ß4-GlcNAc-transferase VI

O-glycan synthesis:

  • Core 1 ß3-Gal-transferase
  • Core 2 ß6-GlcNAc-transferase
  • Core 3 ß3-GlcNAc-transferase
  • Core 4 ß6-GlcNAc-transferase
  • Extension ß3-GlcNAc-transferase

Snail glycosyltransferases
Substrate specificity studies with synthetic substrates and analogues.

Studies on glycosyltransferase genes

  • Cloning and characterization of the gene encoding ß1,2-GlcNAc-transferase I.
  • Cloning and characterization of the gene encoding ß1,2-GlcNActransferase II.
  • Cloning and characterization of the gene encoding ß1,2-GlcNAc-transferase I.2. This enzyme was subsequently re-named Protein O-Mannosyl ß1,2-GlcNAc-transferase I (POMGnTI).
  • Determination of the crystal structure of ß1,2-GlcNAc-transferase I, in collaboration with Jim Rini.

Studies on the functions of N-glycans

  • Glycosyltransferases in various cancer systems.
  • Characterization of mice with null mutations in GlcNAc-transferase genes I, II and III, in collaboration with Jamey Marth.
  • Carbohydrate-Deficient Glycoprotein Syndrome type IIa is due to a defective GlcNAc-transferase II gene, in collaboration with Jaak Jaeken.
  • Structural and functional consequences of an N-glycosylation mutation in hereditary erythroblastic multinuclearity with a positive acidified serum test (HEMPAS) affecting human erythrocyte membrane glycoproteins, in collaboration with RAF Reithmeier.

Recent work on the role of glycosylation in development.

Work done in many laboratories, including ours, indicates the essential role of complex N-glycans in mammalian embryogenesis. This has led us to study the roles of complex N-glycans in the development of Caenorhabditis elegans and Drosophila melanogaster. We have cloned and characterized three C.elegans genes and one D.melanogaster gene encoding alpha-Mannoside GlcNAc-transferase I and one gene encoding C.elegans alpha-Mannoside GlcNAc-transferase II. We have reported on the phenotypes of worms with null mutations in the three GlcNAc-transferase I genes and flies with a null mutation in the GlcNAc-transferase I gene. Point mutations in the POMGnTI gene (first cloned by our group) have been shown by others to be responsible for a form of human congenital muscular dystrophy called Muscle-Eye-Brain (MEB) disease. We have developed an enzymatic diagnostic test for MEB using cultured cells.

Future Research Interests

Functional Glycoproteomics using Caenorhabditis elegans and Drosophila melanogaster as model organisms. These projects will attempt to determine the precise molecular mechanisms whereby protein-bound N-glycans function in the development of a multicellular organism.

External Funding

Canadian Institutes of Health Research (CIHR)

Achievements

2001 - The Pan-American Association for Biochemistry and Molecular Biology (PABMB) Plenary Lecturer Award, ASBMB Annual Meeting, Orlando, Florida, April 3, 2001.
2000 - Elected to the Johns Hopkins University Society of Scholars, Baltimore MD
1998 - Karl Meyer Award of the Society for Glycobiology.
1998 - Honorary degree, Universität der Bodenkultur (BOKU), Vienna, Austria.
1989,1990, 1992 - Visiting Professor, Universitat der Bodenkultur, Vienna, Austria.
1995 - Elected as a Fellow of the Royal Society of Canada
1989 - Sandoz Lecture, Clinical Research Society of Toronto.
1989 - Visiting Professor, Donders Chair, University of Utrecht, The Netherlands.
1985 - Boehringer-Mannheim Prize in Biochemistry
1964 - Starr Medal
1966 - 1968 - National Cystic Fibrosis Research Foundation Fellow
1960 - 1964 - Medical Research Council Post-doctoral Fellow
1959 - Cody Silver Medal

Publications

Publications search on Pubmed

Shi H, Tan J, Schachter H. N-glycans are involved in the response of Caenorhabditis elegans to bacterial pathogens. Methods in Enzymology (2006) 417:359-389.

Sarkar M, Leventis PA, Silvescu CI, Reinhold VN, Schachter H, Boulianne GL. Null mutations in Drosophila N-acetylglucosaminyltransferase I produce defects in locomotion and a reduced lifespan. J. Biol. Chem. (2006) 281 (18):12776-12785

Vajsar J, Zhang W, Dobyns WB, Biggar D, Holden KR, Hawkins C, Ray P, Olney AH, Burson CM, Srivastava AK, Schachter H. Carriers and patients with muscle-eye-brain disease can be rapidly diagnosed by enzymatic analysis of fibroblasts and lymphoblasts. Neuromuscular Disorders (2006) 16 (2): 132-136.

Fan X, She Y, Bagshaw RD, Callahan JW, Schachter H, Mahuran DJ. Identification of the hydrophobic glycoproteins of Caenorhabditis elegans. Glycobiology (2005) 15:952-964.

Zhu S, Hanneman A, Reinhold VN, Spence AM, Schachter H. Caenorhabditis elegans triple null mutant lacking UDP-N-acetyl-D-glucosamine:α-3-D-mannoside β1,2-N-acetylglucosaminyltransferase I. Biochem.J. (2004) 382: 995-1001.

Fan X, She Y, Bagshaw RD, Callahan JW, Schachter H, Mahuran DJ. A method for proteomic identification of membrane-bound proteins containing Asn-linked oligosaccharides. Analytical Biochem. (2004) 332: 178-186.

Barresi R, Michele DE, Kanagawa M, Harper HA, Dovico SA, Satz JS, Moore SA, Zhang W, Schachter H, Dumanski JP, Cohn RD, Nishino I, Campbell KP. LARGE can functionally bypass α-dystroglycan glycosylation defects in distinct congenital muscular dystrophies. Nat. Med. (2004) 10: 696-703 abstract.

Zhang W, Vajsar J, Cao P, Breningstall G, Diesen C, Dobyns W, Herrmann R, Lehesjoki A-E, Steinbrecher A, Talim B, Toda T, Topaloglu H, Voit T, Schachter H. Enzymatic diagnostic test for Muscle-Eye-Brain type Congenital Muscular Dystrophy using commercially available reagents. Clinical Biochemistry. (2003) 36 (5): 339-344.

Zhang W, Cao P, Chen S, Spence AM, Zhu S, Staudacher E, Schachter H. Synthesis of paucimannose N-glycans by Caenorhabditis elegans requires prior actions of UDP-N-acetyl-D-glucosamine:α-3-D-mannoside β1,2-N-acetylglucosaminyltransferase I, α3,6-mannosidase II and a specific membrane-bound β-N-acetylglucosaminidase. Biochem.J. (2003) 372(1): 53-64.

Zhang W, Betel D, Schachter H. Cloning and Expression of a Novel UDP-GlcNAc:α-D-Mannoside ß1,2-N-Acetylglucosaminyltransferase Homologous to UDP-GlcNAc:α-3-D-Mannoside ß1,2-N-Acetylglucosaminyltransferase I. Biochemical J. (2002), 361:153-162.