Structural basis for substrate selectivity in human maltase-glucoamylase and sucrase-isomaltase N-terminal domains.
Human maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) are small intestinal enzymes that work concurrently to hydrolyze the mixture of linear alpha-1,4- and branched alpha-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 alpha-1,4-oligosaccharides, whereas N-terminal SI (ntSI) has a broader specificity for both alpha-1,4- and alpha-1,6-oligosaccharides. Here we present the crystal structure of the human ntSI, in apo form to 3.2 A and in complex with the inhibitor kotalanol to 2.15 A 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 alpha-1,6 substrates.
Sim
Lyann
L
Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, Toronto, Ontario M56 2M9, Canada.
Willemsma
Carly
C
Mohan
Sankar
S
Naim
Hassan Y
HY
Pinto
B Mario
BM
Rose
David R
DR
D000818:Animals; D002241:Carbohydrates / Q000737:chemistry; D018360:Crystallography, X-Ray / Q000379:methods; D003920:Diabetes Mellitus / Q000378:metabolism; D004330:Drosophila / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D009834:Oligo-1,6-Glucosidase / Q000737:chemistry*; D011134:Polysaccharides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D013393:Sucrase / Q000737:chemistry*; D000520:alpha-Glucosidases / Q000737:chemistry*
D002241:Carbohydrates; D011134:Polysaccharides; D009834:Oligo-1,6-Glucosidase; D000520:alpha-Glucosidases; D013393:Sucrase