page_title: Sucrase-isomaltase
section_title: Structure
hierarchical_section_title: Sucrase-isomaltase / Structure
caption_attribution_description: English: Key residues that interact with substrate where turquoise residues correspond to interactions with Man2GlcNAc2, pink residues correspond to interactions with kotalonal, and magenta residues corresponds to interactions with both Man2GlcNAc2 and kotalonal. Generated from 3LPO
context_page_description: Sucrase-isomaltase is a glucosidase enzyme located on the brush border of the small intestine. It is a dual-function enzyme with two GH31 domains, one serving as the isomaltase, the other as a sucrose alpha-glucosidase. It has preferential expression in the apical membranes of enterocytes. The enzyme’s purpose is to digest dietary carbohydrates such as starch, sucrose and isomaltose. By further processing the broken-down products, energy in the form of ATP can be generated.
context_section_description: Sucrase-isomaltase consists of two enzymatic subunits: sucrase and isomaltase.  The subunits originate from a polypeptide precursor, pro-SI. By heterodimerizing the two subunits, the sucrase-isomaltase complex is formed. The enzyme is anchored in the intestinal brush border membrane by a hydrophobic segment located near the N-terminal of the isomaltase subunit. Before the enzyme is anchored to the membrane, pro-SI is mannose-rich and glycosylated; it moves from the ER to the Golgi, where it becomes a protein complex that is N- and O- glycosylated. The O-linked glycosylation is necessary to target the protein to the apical membrane. In addition, there is a segment that is both O-linked glycosylated and Ser/Thr-rich. A similarly-arranged enzyme is the maltase-glucoamylase, also a member of GH31.
  Sucrase-isomaltase is composed of duplicated catalytic domains, N- and C-terminal. Each domain displays overlapping specificities. Scientists have discovered the crystal structure for N-terminal human sucrase-isomaltase (ntSI) in apo form to 3.2 Å and in complex with the inhibitor kotalanol to 2.15 Å resolution. Sucrase-isomaltase’s mechanism results in a net retention of configuration at the anomeric center.
  The crystal structure shows that sucrase-isomaltase exists as a monomer. The researchers claim that the observance of SI dimers is dependent on experimental conditions. ntSI’s four monomers, A, B, C, and D are included in the crystal asymmetric unit and have identical active sites. The active site is composed of a shallow-substrate binding pocket including -1 and +1 subsites.  The non-reducing end of substrates binds to the pocket. While the non-reducing sugar ring has interactions with the buried -1 subsite, the reducing ring has interactions with the surface exposed +1 subsite.
  The interactions between the active site of sucrase-isomaltase and the following compounds have been identified:
  Man2GlcNAc2 glycan: Within the active site, Man2GlcNAc2 hydrogen bonds with hydroxyl side chains of Asp231 and Asp571. Furthermore, hydrophobic interactions with Leu233, Trp327, Trp435, Phe479, Val605, and Tyr634 provide additional stabilization for Man2GlcNAc2.
  Kotalonal, the inhibitor: It interacts with the catalytic nucleophile Asp472 and acid base catalyst Asp571.  In addition, ntSI residues His629, Asp355, Arg555, Asp231, Trp435, and Phe479 bind to the substrate.
  Currently, there are no crystal structures of ntSI in complex with an α-1,6-linked substrate or inhibitor analogue. In order to predict isomaltose binding in sucrase-isomaltase structure, a model was produced by hand. Within the -1 subsite, isomaltose’s non-reducing glucose ring was aligned to that of acarbose.
  Not only has the structure of human sucrase-isomaltase been studied, but also sucrase-isomaltase’s structure in sea lions and pigs have also been analyzed.
caption: Key residues that interact with substrate where turquoise residues correspond to interactions with Man2GlcNAc2, pink residues correspond to interactions with kotalonal, and magenta residues corresponds to interactions with both Man2GlcNAc2 and kotalonal. Generated from 3LPO[10]
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