Structural Basis for Substrate Selectivity in Human Maltase-Glucoamylase and Sucrase-Isomaltase N-terminal Domains |
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| Authors: | Lyann Sim Carly Willemsma Sankar Mohan Hassan Y. Naim B. Mario Pinto David R. Rose |
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| Affiliation: | From the ‡Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M56 2M9, Canada.;the §Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.;the ¶Department of Physiological Chemistry, University of Veterinary Medicine, D-3059 Hannover, Germany, and ;the ‖Department of Biology, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada |
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| Abstract: | Human maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) are small intestinal enzymes that work concurrently to hydrolyze the mixture of linear α-1,4- and branched α-1,6-oligosaccharide substrates that typically make up terminal starch digestion products. MGAM and SI are each composed of duplicated catalytic domains, N- and C-terminal, which display overlapping substrate specificities. The N-terminal catalytic domain of human MGAM (ntMGAM) has a preference for short linear α-1,4-oligosaccharides, whereas N-terminal SI (ntSI) has a broader specificity for both α-1,4- and α-1,6-oligosaccharides. Here we present the crystal structure of the human ntSI, in apo form to 3.2 Å and in complex with the inhibitor kotalanol to 2.15 Å resolution. Structural comparison with the previously solved structure of ntMGAM reveals key active site differences in ntSI, including a narrow hydrophobic +1 subsite, which may account for its additional substrate specificity for α-1,6 substrates. |
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| Keywords: | Carbohydrate/Polysaccharide Carbohydrate/Processing Diseases/Diabetes Enzymes/Kinetics Enzymes/Structure Methods/X-ray Crystallography |
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