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Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
Aliases | SI , sucrase-isomaltase | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 609845; MGI: 1917233; HomoloGene: 37424; GeneCards: SI; OMA:SI - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Sucrase-isomaltase is a bifunctional glucosidase (sugar-digesting enzyme) located on the brush border of the small intestine, encoded by the human gene SI. It is a dual-function enzyme with two GH31 domains, one serving as the isomaltase, the other as a sucrose alpha-glucosidase. [5] [6] [7] It has preferential expression in the apical membranes of enterocytes. [8] 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. [9]
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. [10] The enzyme is anchored in the intestinal brush border membrane by a hydrophobic segment located near the N-terminus of the isomaltase subunit. [11] 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. [12] [13] In addition, there is a segment that is both O-linked glycosylated and Ser/Thr-rich. [14] 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. [15] Sucrase-isomaltase’s mechanism results in a net retention of configuration at the anomeric center. [15]
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. [15] 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. [15]
The interactions between the active site of sucrase-isomaltase and the following compounds have been identified:
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. [15]
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. [6] [16] [17]
A deficiency is responsible for sucrose intolerance. Congenital sucrase-isomaltase deficiency (CSID), also called genetic sucrase-isomaltase deficiency (GSID), and sucrose intolerance, is a genetic, intestinal disorder that is caused by a reduction or absence of sucrase and isomaltase [13] Explanations for GSID include:
Furthermore, a relationship between mutations in sucrase-isomaltase and chronic lymphocytic leukemia (CLL) has been identified. These mutations cause a loss of enzyme function by blocking the biosynthesis of SI at the cell surface. [8]