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David R. Rose

Professor (Department Chair)

David R. RoseBachelor of Arts (BA) Pennsylvania, Doctor of Philosophy (DPhil) Oxford

Email:  david.rose@uwaterloo.ca

Telephone: (519) 888-4567 ext. 35208

Office: Earth Sciences Building (ESC) 349

Lab: ESC 244, ext. 31217

Research interests

Structural Studies of Glycoside Hydrolases
This major area of research involves enzymes that recognize and act upon carbohydrates, including especially glycosidases involved in the protein glycosylation pathway and the process of starch digestion.

Golgi α-mannosidase II
Insights from these results are now being applied to enzymes in the mammalian glycosylation pathway. A key component in this pathway, Golgi α-mannosidase II, is a target for inhibition by compounds that can decrease the size and aggressiveness of many tumour types. We have solved the structure of the Drosophila homologue as a model to study the interaction of known inhibitors and the design of new inhibitors to α-mannosidase II. This structure of the glycoside hydrolase family 38 enzyme displays a novel folding pattern and acts through a fascinating catalytic process that allows two glycosidic bonds to be cleaved successively in the same catalytic site.

Lysosomal α-mannosidase
Related to the Golgi enzyme, inhibition of the lysosomal Family 38 mannosidase is thought to contribute to the side effects of clinical trials of Golgi mannosidase inhibitors. We have produced the lysosomal enzyme in our Drosophila system and are analyzing its enzymatic and inhibitory properties. We are also working towards the structural analysis of this homologue.

Intestinal Maltase-Glucoamylase and Sucrase-Isomaltase (MGAM and SI)
MGAM and SI are involved in starch breakdown in mammalian cells. Inhibition of these and other alpha-glucosidases is proposed to be a novel approach to treatment of Type II Diabetes. We have expressed these Family GH31 enzymes in Drosophila cells and studied the activities of a series of specific inhibitors under development as anti-diabetics. We have determined the crystallographic structure of two of the four GH31 domains of these enzymes.

Gut commensal microbial glycoside hydrolases
The human intestine is populated by many bacterial species in a symbiotic partnership. One of the roles for these bacteria is in the digestion of resistant starches that have survived the intestinal MGAM/SI processing, as a source of nutrition for both the host and the bacteria. We are interested in a structural approach to studying the mechanism of recognition of resistant starch structures by the bacterial glycoside hydrolases. Of the gut bacteria with known genomes, Bacteroides thetaiotamicron has the largest number and variety of predicted glycoside hydrolases, suggesting that it plays a key role in salvaging resistant polysaccharides such as starch. We are building on our results on the intestinal enzymes to express and purify family GH31 enzymes from Bacteroides thetaiotamicron with the goal of studying their substrate specificities and, hence, defining their role in nutrition.

Selected recent publications

  • Sim L, Jayakanthan K, Mohan S, Nasi R, Johnston BD, Pinto BM, Rose DR (2010) ‘New glucosidase inhibitors from an Ayurvedic herbal treatment for type 2 diabetes: structures and inhibition of human intestinal maltase-glucoamylase with compounds from Salacia reticulata’,  Biochemistry, 49:443-451.
  • Mohan S, Jayakanathan K, Nasi R, Kuntz DA, Rose DR, Pinto BM (2010) ‘Synthesis and Biological Evaluation of Heteroanalogues of Kotalanol and de-O-Sulfonated Kotalanol’, Org Lett, 12:1088-1091.
  • Sim L, Willemsma C, Naim H, Pinto BM, Rose DR (2010) ‘Structural Basis for substrate selectivity in human GH31 intestinal glucosidases: Comparison of N-terminal maltase-glucoamylase and sucrase-isomaltase’, J. Biol. Chem. 285:17763-17770.
  • Eskandari R, Kuntz DA, Rose DR, Pinto BM (2010) ‘Potent Glucosidase Inhibitors: De-O-sulfonated ponkoranol and its stereoisomer’, Org Lett, 12:1632-1635.
  • Eskandari R, Jayakanthan K, Kuntz DA, Rose DR, Pinto BM (2010) ‘Synthesis of a biologically active isomer of kotalanol, a naturally occurring glucosidase inhibitor’, Bioorg Med Chem, 18:2829-2835.
  • Eskandari R, Jones K, Rose DR, Pinto BM (2010) ‘Probing the active-site requirements of human intestinal N-terminal maltase glucoamylase:  The effect of replacing the sulfate moiety by a methyl  ether in ponkoranol, a naturally occurring a-glucosidase inhibitor’ Bioorg Med Chem, 20:5686-5689.
  • Mohan S, Sim L, Rose DR, Pinto BM (2010) ‘Probing the active-site requirements of human intestinal N-terminal maltase glucoamylase: Synthesis and enzyme Inhibitory activities of a Six-membered ring nitrogen analogue of kotalanol and its de-O-sulfonated derivative’ Bioorg Med Chem, 18:7794-7798.
  • Jones K, Sim L, Mohan S, Kumarasamy J, Liu H, Avery S, Naim HH, Quezada-Calvillo R, Nichols BL, Pinto M, Rose DR (2011) ‘Mapping the intestinal alpha-glucogenic enzyme specificities of starch digesting maltase-glucoamylase and sucrase-isomaltase’, Bioorg Med Chem., 19:3929-3934.
  • Barker MK, Wilkinson BL, Faridmoayer S, Scaman CH, Fairbanks AJ, Rose DR (2011) ‘Production and Crystallization of processing alpha-glucosidase i: P. pastoris expression and a two-step purification toward structural determination’, Prot. Expr. Purif., 79:96-101.
  • Eskandari R, Jones K, Rose DR, Pinto BM (2011) ‘The effect of heteroatom substitution of sulfur for selenium in glucosidase inhibitors on intestinal α-glucosidase activities’, Chem. Commun., 47:9134-9136.
  • Eskandari R, Jones K, Rose DR, Pinto BM (2011) ‘Selectivity of 3'-O-methylponkoranol for inhibition of N- and C-terminal maltase glucoamylase and sucrase isomaltase, potential therapeutics for digestive disorders or their sequelae’, Bioorganic & Medicinal Chemistry Letters, 21:6491-6494.
  • Eskandari R, Jones K, Kongara RR, Jayakanthan K, Chaudet M, Rose DR, Pinto BM (2011) ‘Probing the intestinal alpha-glucosidase specificities of starch-digesting maltase-glucoamylase and sucrase-isomaltase: Synthesis and inhibitory properties of 3’- and 5’- maltose-extended de-O-sulfonated ponkoranol’, Chemistry-A European Journal, 17:14817-14825.
  • Neufeld JD, Engel K, Cheng J, Moreno-Hagelsieb G, Rose DR, Charles TC (2011) ‘Public Domain Metagenomics’, Standards in Genomic Sciences. 5:203-210.
  • Broom AR, Doxey AC, Lobsanov Y, Berthin LG, Rose DR, Howell PL, McConkey BJ, Meiering EM (2012) ‘Modular evolution and the origins of symmetry: reconstruction of a threefold symmetric globular protein’, Structure, 20:161-171.
  • Lin AH, Nichols BL, Ao Z, Quezada-Calvillo R, Avery S, Sim L, Rose DR, Naim H, Hamaker BR (2012) ‘Unexpected high digestion rate of cooked starch by the Ct-maltase-glucoamylase small intestinal mucosal α-glucosidase subunit’, PLoS One, 7(5):e35473.
  • Lee B-H, Quezada-Calvillo R, Nichols BL, Rose DR, Hamaker BR (2012) ‘Inhibition of Maltase-glucoamylase activity to hydrolyze a-1,4 linkages by the presence of undigested sucrose’, J Pediatric Gastroenterology & Nutrition, in press.
  • Ao Z, Quezada-Calvillo R, Nichols BL, Rose DR, Strerchi EE, Hamamker BR (2012) ‘The nature of raw starch digestion’, J Pediatric Gastroenterology & Nutrition, in press.
  • Jones K, Eskandari R, Naim H, Pinto BM, Rose DR, Nichols BL (2012) ‘Investigations of the structures and inhibitory properties of maltase-glucoamylase and sucrose-isomaltase’, J Pediatric Gastroenterology & Nutrition in press.
  • Lee BH, Eskandari R, Jones K, Reddy RK, Nichols BL, Rose DR, Hamaker BR, Pinto BM (2012) ‘Modulation of starch digestion for slow glucose release through “toggling” of activities of mucosal α-glucosidases’, J. Biol. Chem., doi:10.1074/jbc.M112.351858.
  • Chaudet MM, Allen J-L (Jacobs), Rose DR (2012) ‘Expression and purification of two family 31 α-glucosidases from Bacteroides thetaiotaomicron’, Protein Expression and Purification, in press.
Affiliation: 
University of Waterloo

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