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• W2912270660 abstract "Carbohydrates are essential components of the human diet and are broken down into their building monosaccharides during transit through the gastrointestinal tract. The monosaccharides, mainly glucose, can then be utilized as energy sources for the human body. Sucrase-isomaltase (SI) is an enzyme complex anchored in the small intestinal brush border membrane that essentially contributes to the final step of carbohydrate digestion and the release of glucose. SI is a highly glycosylated type II integral membrane protein that consists of two functional subunits, isomaltase and sucrase. The SI protein is synthesized in the rough endoplasmic reticulum and is transported along the secretory pathway to the cell surface. Defects of SI cause carbohydrate malabsorption that oftentimes goes along with a clinical onset of osmotic-fermentative diarrhea, abdominal pain and cramps in patients. Congenital sucrase-isomaltase deficiency (CSID) is a form of carbohydrate malabsorption elicited by genetic alterations in the SI gene. The disease is described as rare autosomal recessively inherited disorder that is characterized by reduced or absent activities of SI. The molecular processes underlying dietary carbohydrate digestion in human health and disease with focus on SI are not fully understood and will be studied in this thesis. The first part of this thesis investigates the molecular pathogenesis of 15 SI mutations, found in CSID patients with reduced or absent α-glyosidic activities of SI, in a cellular in vitro model system. The 15 single nucleotide polymorphisms target the coding region of the SI gene and result in protein variants with single amino acid exchanges and in two cases in the introduction of a chain termination codon. The effect of the genetic alteration on the SI protein function, involving different cellular processes like protein trafficking and folding into an active conformation, was reflected by the definition of three biosynthetic phenotypes in our study. With a complete loss of in vitro SI protein function by intracellular blockage and enzymatic inactivation, that is matching to absent activities in patients’ biopsies, mutations grouped in biosynthetic phenotype III had the highest molecular pathogenic potential. Mutations grouped in biosynthetic phenotypes I and II lead to mild to intermediate effects on the SI function by reduced activities and a normal to delayed trafficking to the cell surface. Some mutations from phenotype II and III were enzymatically active but not properly trafficked, rendering them as potential candidates to test chemical or pharmacological chaperone therapy for CSID in future, alternatively or additionally to enzyme replacement therapy or nutritional restrictions to restore the SI activities at the cell surface. The second part of the thesis elucidates the SI catalytic site properties under physiological conditions in a cellular system. Here, the focus was on two aspartic acid residues (D) at amino acid positions 604 (D604) and 1500 (D1500) within the isomaltase and sucrase catalytic sites, with predicted proton donor functions. The experimental mutational replacement of aspartic acid in the conserved catalytic site motifs of SI led to a complete loss of activities of the targeted SI subunit, while the activities of the respective other subunit was not influenced. These data indicate that D604 and D1500 in the two catalytic sites of SI have an essential role in substrate catalysis by SI and prove the proton donor function of these residues. The generated single active site variants of SI provided a good model to study enzymatic capacities of both SI subunits separately. The proportion of maltose digestion carried out by each subunit was not known so far. The sucrase subunit showed a higher maltose digestive capacity compared to the isomaltase subunit. Increased combined activities of both single-active site variants lead to the investigation of product inhibition of SI. In fact, analysis of SI activities in human brush border membrane preparations revealed a reduction of both sucrase and isomaltase activities under addition of glucose, suggesting product inhibition as new mechanism for SI. This so far undescribed mechanism of SI may function to regulate the glucose release from carbohydrate digestion in the intestine and balance the blood glucose level. Taken together, this thesis provides insights into the catalytic properties and mechanisms of human SI during carbohydrate digestion and into the molecular basis of an impaired human SI function during the pathogenesis of CSID and may help to find new targets for therapy." @default.
• W2912270660 created "2019-02-21" @default.
• W2912270660 creator A5065856944 @default.
• W2912270660 date "2016-01-01" @default.
• W2912270660 modified "2023-09-23" @default.
• W2912270660 title "Molecular basis of the heterogeneity in congenital sucrase-isomaltase deficiency" @default.
• W2912270660 hasPublicationYear "2016" @default.
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