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Buford L Nichols - One of the best experts on this subject based on the ideXlab platform.
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metabolic impacts of maltase deficiencies
Journal of Pediatric Gastroenterology and Nutrition, 2018Co-Authors: Buford L Nichols, Susan S Baker, Roberto QuezadacalvilloAbstract:: The mucosal maltase enzymes are characterized by an activity that produces glucose from linear glucose polymers, assayed with the disaccharide maltose. The related enzyme isomaltase produces glucose from branched glucose polymers, assayed with palatinose. Maltase and isomaltase activities are part of the 4 disaccharidases assayed from clinical duodenal biopsy homogenates. The reported maltase activities are more difficult to interpret than lactase or sucrase activities because both the sucrase-isomaltase and Maltase-Glucoamylase proteins have overlapping maltase activities. The early work of Dahlqvist identified 4 maltase activities from human small intestinal mucosa. On one peptide, sucrase (maltase Ib) and isomaltase (maltase Ia) activities shared maltase activities but identified the enzymes as sucrase-isomaltase. On the other peptide, no distinguishing characteristics of the 2 maltase activities (maltases II and III) were detected and the activities identified as Maltase-Glucoamylase. The nutritional/clinical importance of small intestinal maltase and isomaltase activities are due to their crucial role in the digestion of food starches to absorbable free glucose. This review focuses on the interpretation of biopsy maltase activities in the context of reported lactase, sucrase, maltase, and palatinase biopsy assay activity patterns. We present a classification of mucosal maltase deficiencies and novel primary maltase deficiency (Ib, II, III) and provide a clarification of the role of maltase activity assayed from clinically obtained duodenal biopsies, as a path toward future clinical and molecular genomic investigations.
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13c labeled starch breath test in congenital sucrase isomaltase deficiency
Journal of Pediatric Gastroenterology and Nutrition, 2018Co-Authors: Claudia C Robayotorres, Susan S Baker, Bruce R Hamaker, Antone R. Opekun, Marisela Diazsotomayor, Bruno P Chumpitazi, Buford L NicholsAbstract:ABSTRACTBackground and Hypotheses:Human starch digestion is a multienzyme process involving 6 different enzymes: salivary and pancreatic α-amylase; sucrase and isomaltase (from sucrose-isomaltase [SI]), and maltase and glucoamylase (from Maltase-Glucoamylase [MGAM]). Together these enzymes cleave st
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improved starch digestion of sucrase deficient shrews treated with oral glucoamylase enzyme supplements
Journal of Pediatric Gastroenterology and Nutrition, 2017Co-Authors: Buford L Nichols, Stephen E Avery, Roberto Quezadacalvillo, Shadi B Kilani, Amy Huimei Lin, Douglas G Burrin, Benjamin E Hodges, Shaji K ChackoAbstract:BACKGROUND AND OBJECTIVE Although named because of its sucrose hydrolytic activity, this mucosal enzyme plays a leading role in starch digestion because of its maltase and glucoamylase activities. Sucrase-deficient mutant shrews, Suncus murinus, were used as a model to investigate starch digestion in patients with congenital sucrase-isomaltase deficiency.Starch digestion is much more complex than sucrose digestion. Six enzyme activities, 2 α-amylases (Amy), and 4 mucosal α-glucosidases (maltases), including Maltase-Glucoamylase (Mgam) and sucrase-isomaltase (Si) subunit activities, are needed to digest starch to absorbable free glucose. Amy breaks down insoluble starch to soluble dextrins; mucosal Mgam and Si can either directly digest starch to glucose or convert the post-α-amylolytic dextrins to glucose. Starch digestion is reduced because of sucrase deficiency and oral glucoamylase enzyme supplement can correct the starch maldigestion. The aim of the present study was to measure glucogenesis in suc/suc shrews after feeding of starch and improvement of glucogenesis by oral glucoamylase supplements. METHODS Sucrase mutant (suc/suc) and heterozygous (+/suc) shrews were fed with C-enriched starch diets. Glucogenesis derived from starch was measured as blood C-glucose enrichment and oral recombinant C-terminal Mgam glucoamylase (M20) was supplemented to improve starch digestion. RESULTS After feedings, suc/suc and +/suc shrews had different starch digestions as shown by blood glucose enrichment and the suc/suc had lower total glucose concentrations. Oral supplements of glucoamylase increased suc/suc total blood glucose and quantitative starch digestion to glucose. CONCLUSIONS Sucrase deficiency, in this model of congenital sucrase-isomaltase deficiency, reduces blood glucose response to starch feeding. Supplementing the diet with oral recombinant glucoamylase significantly improved starch digestion in the sucrase-deficient shrew.
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contribution of the individual small intestinal α glucosidases to digestion of unusual α linked glycemic disaccharides
Journal of Agricultural and Food Chemistry, 2016Co-Authors: David R Rose, Roberto Quezadacalvillo, Buford L Nichols, Bruce R HamakerAbstract:The mammalian mucosal α-glucosidase complexes, maltase–glucoamylase (MGAM) and sucrase–isomaltase (SI), have two catalytic subunits (N- and C-termini). Concurrent with the desire to modulate glycemic response, there has been a focus on di-/oligosaccharides with unusual α-linkages that are digested to glucose slowly by these enzymes. Here, we look at disaccharides with various possible α-linkages and their hydrolysis. Hydrolytic properties of the maltose and sucrose isomers were determined using rat intestinal and individual recombinant α-glucosidases. The individual α-glucosidases had moderate to low hydrolytic activities on all α-linked disaccharides, except trehalose. Maltase (N-terminal MGAM) showed a higher ability to digest α-1,2 and α-1,3 disaccharides, as well as α-1,4, making it the most versatile in α-hydrolytic activity. These findings apply to the development of new glycemic oligosaccharides based on unusual α-linkages for extended glycemic response. It also emphasizes that mammalian mucosal α-...
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Milk glucosidase activity enables suckled pup starch digestion
Molecular and cellular pediatrics, 2016Co-Authors: Buford L Nichols, Susan S Baker, Bruce R Hamaker, Shaji K Chacko, M. Diaz-sotomayor, S. E. Avery, D. L. Hadsell, H. M. Lin, Like Yan, R. Quezada-calvilloAbstract:ᅟ Starch requires six enzymes for digestion to free glucose: two amylases (salivary and pancreatic) and four mucosal maltase activities; sucrase-isomaltase and Maltase-Glucoamylase. All are deficient in suckling rodents.
Bruce R Hamaker - One of the best experts on this subject based on the ideXlab platform.
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13c labeled starch breath test in congenital sucrase isomaltase deficiency
Journal of Pediatric Gastroenterology and Nutrition, 2018Co-Authors: Claudia C Robayotorres, Susan S Baker, Bruce R Hamaker, Antone R. Opekun, Marisela Diazsotomayor, Bruno P Chumpitazi, Buford L NicholsAbstract:ABSTRACTBackground and Hypotheses:Human starch digestion is a multienzyme process involving 6 different enzymes: salivary and pancreatic α-amylase; sucrase and isomaltase (from sucrose-isomaltase [SI]), and maltase and glucoamylase (from Maltase-Glucoamylase [MGAM]). Together these enzymes cleave st
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contribution of the individual small intestinal α glucosidases to digestion of unusual α linked glycemic disaccharides
Journal of Agricultural and Food Chemistry, 2016Co-Authors: David R Rose, Roberto Quezadacalvillo, Buford L Nichols, Bruce R HamakerAbstract:The mammalian mucosal α-glucosidase complexes, maltase–glucoamylase (MGAM) and sucrase–isomaltase (SI), have two catalytic subunits (N- and C-termini). Concurrent with the desire to modulate glycemic response, there has been a focus on di-/oligosaccharides with unusual α-linkages that are digested to glucose slowly by these enzymes. Here, we look at disaccharides with various possible α-linkages and their hydrolysis. Hydrolytic properties of the maltose and sucrose isomers were determined using rat intestinal and individual recombinant α-glucosidases. The individual α-glucosidases had moderate to low hydrolytic activities on all α-linked disaccharides, except trehalose. Maltase (N-terminal MGAM) showed a higher ability to digest α-1,2 and α-1,3 disaccharides, as well as α-1,4, making it the most versatile in α-hydrolytic activity. These findings apply to the development of new glycemic oligosaccharides based on unusual α-linkages for extended glycemic response. It also emphasizes that mammalian mucosal α-...
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Milk glucosidase activity enables suckled pup starch digestion
Molecular and Cellular Pediatrics, 2016Co-Authors: B. L. Nichols, Bruce R Hamaker, M. Diaz-sotomayor, S. E. Avery, S. K. Chacko, D. L. Hadsell, S. S. Baker, L. K. Yan, H. M. Lin, R. Quezada-calvilloAbstract:ᅟ Starch requires six enzymes for digestion to free glucose: two amylases (salivary and pancreatic) and four mucosal maltase activities; sucrase-isomaltase and Maltase-Glucoamylase. All are deficient in suckling rodents. Objective The objective of this study is to test ^13C-starch digestion before weaning by measuring enrichment of blood ^13C-glucose in Maltase-Glucoamylase-null and wild-type mice. Methods Maltase-Glucoamylase gene was ablated at the N-terminal. Dams were fed low ^13C-diet and litters kept on low ^13C-diet. Pups were weaned at 21 days. Digestion was tested at 13 and 25 days by intragastric feeding of amylase predigested ^13C-α-limit dextrins. Blood ^13C-glucose enrichment was measured by gas chromatography combustion isotope ratio mass spectrometry (GCRMS) using penta-acetate derivatives. Results Four hours after feeding, blood ^13C-glucose was enriched by 26 × 10^3 in null and 18 × 10^3 in wild-type mice at 13 days and 0.3 × 10^3 and 0.2 × 103 at 25 days (vs. fasting p = 0.045 and p = 0.045). By jejunal enzyme assay, immunohistochemistry, or Western blots, there was no maltase activity or brush border staining with Maltase-Glucoamylase antibodies at 13 days, but these were fully developed in the wild-type mice by 25 days. In 13-day null mice, luminal contents were stained by Maltase-Glucoamylase antibodies. Lactating the mammary gland revealed Maltase-Glucoamylase antibody staining of alveolar cells. Reverse transcription/polymerase chain reaction (RT/PCR) of lactating glands revealed a secreted form of Maltase-Glucoamylase. Conclusions (1) ^13C-α-limit dextrins were rapidly digested to ^13C-glucose in 13-day mice independent of Maltase-Glucoamylase genotype or mucosal maltase activity. (2) This experiment demonstrates that a soluble maltase activity is secreted in mouse mother’s milk which enables suckling pup starch digestion well before brush border enzyme development. (3) This experiment with ^13C-α-limit dextrins needs to be repeated in human breast fed infants.
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Milk glucosidase activity enables suckled pup starch digestion
Molecular and cellular pediatrics, 2016Co-Authors: Buford L Nichols, Susan S Baker, Bruce R Hamaker, Shaji K Chacko, M. Diaz-sotomayor, S. E. Avery, D. L. Hadsell, H. M. Lin, Like Yan, R. Quezada-calvilloAbstract:ᅟ Starch requires six enzymes for digestion to free glucose: two amylases (salivary and pancreatic) and four mucosal maltase activities; sucrase-isomaltase and Maltase-Glucoamylase. All are deficient in suckling rodents.
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dietary phenolic compounds selectively inhibit the individual subunits of maltase glucoamylase and sucrase isomaltase with the potential of modulating glucose release
Journal of Agricultural and Food Chemistry, 2015Co-Authors: Meric Simsek, Mario G. Ferruzzi, Roberto Quezadacalvillo, Buford L Nichols, Bruce R HamakerAbstract:In this study, it was hypothesized that dietary phenolic compounds selectively inhibit the individual C- and N-terminal (Ct, Nt) subunits of the two small intestinal α-glucosidases, Maltase-Glucoamylase (MGAM) and sucrase-isomaltase (SI), for a modulated glycemic carbohydrate digestion. The inhibition by chlorogenic acid, caffeic acid, gallic acid, (+)-catechin, and (−)-epigallocatechin gallate (EGCG) on individual recombinant human Nt-MGAM and Nt-SI and on mouse Ct-MGAM and Ct-SI was assayed using maltose as the substrate. Inhibition constants, inhibition mechanisms, and IC50 values for each combination of phenolic compound and enzymatic subunit were determined. EGCG and chlorogenic acid were found to be more potent inhibitors for selectively inhibiting the two subunits with highest activity, Ct-MGAM and Ct-SI. All compounds displayed noncompetitive type inhibition. Inhibition of fast-digesting Ct-MGAM and Ct-SI by EGCG and chlorogenic acid could lead to a slow, but complete, digestion of starch for impr...
Erwin E. Sterchi - One of the best experts on this subject based on the ideXlab platform.
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luminal starch substrate brake on maltase glucoamylase activity is located within the glucoamylase subunit
Journal of Nutrition, 2008Co-Authors: Claudia C Robayotorres, Zihua Ao, Andrea Quaroni, Gary D Brayer, Erwin E. Sterchi, David R Rose, Roberto Quezadacalvillo, Bruce R Hamaker, Buford L NicholsAbstract:The detailed mechanistic aspects for the final starch digestion process leading to effective alpha-glucogenesis by the 2 mucosal alpha-glucosidases, human sucrase-isomaltase complex (SI) and human Maltase-Glucoamylase (MGAM), are poorly understood. This is due to the structural complexity and vast variety of starches and their intermediate digestion products, the poorly understood enzyme-substrate interactions occurring during the digestive process, and the limited knowledge of the structure-function properties of SI and MGAM. Here we analyzed the basic catalytic properties of the N-terminal subunit of MGAM (ntMGAM) on the hydrolysis of glucan substrates and compared it with those of human native MGAM isolated by immunochemical methods. In relation to native MGAM, ntMGAM displayed slower activity against maltose to maltopentose (G5) series glucose oligomers, as well as maltodextrins and alpha-limit dextrins, and failed to show the strong substrate inhibitory "brake" effect caused by maltotriose, maltotetrose, and G5 on the native enzyme. In addition, the inhibitory constant for acarbose was 2 orders of magnitude higher for ntMGAM than for native MGAM, suggesting lower affinity and/or fewer binding configurations of the active site in the recombinant enzyme. The results strongly suggested that the C-terminal subunit of MGAM has a greater catalytic efficiency due to a higher affinity for glucan substrates and larger number of binding configurations to its active site. Our results show for the first time, to our knowledge, that the C-terminal subunit of MGAM is responsible for the MGAM peptide's "glucoamylase" activity and is the location of the substrate inhibitory brake. In contrast, the membrane-bound ntMGAM subunit contains the poorly inhibitable "maltase" activity of the internally duplicated enzyme.
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human intestinal maltase glucoamylase crystal structure of the n terminal catalytic subunit and basis of inhibition and substrate specificity
Journal of Molecular Biology, 2008Co-Authors: Roberto Quezadacalvillo, Erwin E. Sterchi, Buford L Nichols, David R RoseAbstract:Human Maltase-Glucoamylase (MGAM) is one of the two enzymes responsible for catalyzing the last glucose-releasing step in starch digestion. MGAM is anchored to the small-intestinal brush-border epithelial cells and contains two homologous glycosyl hydrolase family 31 catalytic subunits: an N-terminal subunit (NtMGAM) found near the membrane-bound end and a C-terminal luminal subunit (CtMGAM). In this study, we report the crystal structure of the human NtMGAM subunit in its apo form (to 2.0 A) and in complex with acarbose (to 1.9 A). Structural analysis of the NtMGAM-acarbose complex reveals that acarbose is bound to the NtMGAM active site primarily through side-chain interactions with its acarvosine unit, and almost no interactions are made with its glycone rings. These observations, along with results from kinetic studies, suggest that the NtMGAM active site contains two primary sugar subsites and that NtMGAM and CtMGAM differ in their substrate specificities despite their structural relationship. Additional sequence analysis of the CtMGAM subunit suggests several features that could explain the higher affinity of the CtMGAM subunit for longer maltose oligosaccharides. The results provide a structural basis for the complementary roles of these glycosyl hydrolase family 31 subunits in the bioprocessing of complex starch structures into glucose.
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the maltase glucoamylase gene common ancestry to sucrase isomaltase with complementary starch digestion activities
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Buford L Nichols, Dagmar Hahn, Stephen E Avery, Dallas M. Swallow, Erwin E. SterchiAbstract:Brush-border Maltase-Glucoamylase (MGA) activity serves as the final step of small intestinal digestion of linear regions of dietary starch to glucose. Brush-border sucrase-isomaltase (SI) activity is complementary, through digestion of branched starch linkages. Here we report the cloning and sequencing of human MGA gene and demonstrate its close evolutionary relationship to SI. The gene is ≈82,000 bp long and located at chromosome 7q34. Forty-eight exons were identified. The 5′ gene product, when expressed as the N-terminal protein sequence, hydrolyzes maltose and starch, but not sucrose, and is thus distinct from SI. The catalytic residue was identified by mutation of an aspartic acid and was found to be identical with that described for SI. The exon structures of MGA and SI were identical. This homology of genomic structure is even more impressive than the previously reported 59% amino acid sequence identity. The shared exon structures and peptide domains, including proton donors, suggest that MGA and SI evolved by duplication of an ancestral gene, which itself had already undergone tandem gene duplication. The complementary human enzyme activities allow digestion of the starches of plant origin that make up two-thirds of most diets.
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congenital maltase glucoamylase deficiency associated with lactase and sucrase deficiencies
Journal of Pediatric Gastroenterology and Nutrition, 2002Co-Authors: Buford L Nichols, Dagmar Hahn, Wikrom Karnsakul, Ursula Luginbuehl, Stephen E Avery, Dallas M. Swallow, Farook Jahoor, Erwin E. SterchiAbstract:Background: Multiple enzyme deficiencies have been reported in some cases of congenital glucoamylase, sucrase, or lactase deficiency. Here we describe such a case and the investigations that we have made to determine the cause of this deficiency.Methods and Results: A 2.5 month-old infant, admitted with congenital lactase deficiency, failed to gain weight on a glucose oligomer formula (Nutramigen(R)). Jejunal mucosal biopsy at 4 and 12 months revealed normal histology with decreased Maltase-Glucoamylase, sucrase-isomaltase, and lactase-phlorizin hydrolase activities. Testing with a C-13-starch/breath (CO2)-C-13 loading test confirmed proximal starch malabsorption. Sequencing of Maltase-Glucoamylase cDNA revealed homozygosity for a nucleotide change (C1673T) in the infant, which causes an amino acid substitution (S542L) 12 amino acids after the N-terminal catalytic aspartic acid. The introduction of this mutation into "wildtype" N-terminus Maltase-Glucoamylase cDNA was not associated with obvious loss of Maltase-Glucoamylase enzyme activities when expressed in COS 1 cells and this amino-acid change was subsequently found in other people. Sequencing of the promoter region revealed no nucleotide changes. Maltase-Glucoamylase, lactase, and sucrase-isomaltase were each normally synthesized and processed in organ culture.Conclusions: The lack of evidence for a causal nucleotide change in the Maltase-Glucoamylase gene in this patient, and the concomitant low levels of lactase and sucrase activity, suggest that the depletion of mucosal Maltase-Glucoamylase activity and starch digestion was caused by shared, pleiotropic regulatory factors.
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contribution of villous atrophy to reduced intestinal maltase in infants with malnutrition
Journal of Pediatric Gastroenterology and Nutrition, 2000Co-Authors: Buford L Nichols, Andrea Quaroni, Erwin E. Sterchi, Stephen E Avery, Veda N Nichols, Margaret Putman, J K Fraley, Margot Shiner, Francisco R CarrazzaAbstract:ABSTRACTBackgroundIt has been known for many years that small intestinal maltase activities are reduced in malnourished infants and in other patients with villous atrophy. The recent availability of human Maltase-Glucoamylase cDNA provides the opportunity to test the hypothesis that villous atrophy
Toshinao Goda - One of the best experts on this subject based on the ideXlab platform.
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the regulation of jejunal induction of the maltase glucoamylase gene by a high starch low fat diet in mice
Molecular Nutrition & Food Research, 2010Co-Authors: Kazuki Mochizuki, Kazue Honma, Masaya Shimada, Toshinao GodaAbstract:: Maltase and glucoamylase are derived from the same mRNA and are responsible for digestion of starch in the small intestine. Their jejunal activities in rodents are induced by a high-starch/low-fat (HS)-diet. However, it is unknown whether jejunal expression of the Maltase-Glucoamylase (Mgam) gene is enhanced by the HS-diet. In this study, we found that jejunal Mgam mRNA was increased by a HS-diet in mice. We showed that the HS-diet increased acetylation of histones, bindings of a coactivator, Creb binding protein (CREBBP), and the transcriptional factors caudal type homeobox 2 (CDX2) and HNF1 homeobox (HNF1) in the promoter/enhancer and transcriptional regions of Mgam gene. This suggests that the increase in the jejunal activity of maltase and glucoamylase caused by a HS-diet in mice is regulated at the mRNA level through histone acetylation and binding of CREBBP, CDX2 and HNF1 in the promoter/enhancer and transcriptional regions of Mgam gene.
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The regulation of jejunal induction of the maltase–glucoamylase gene by a high‐starch/low‐fat diet in mice
Molecular nutrition & food research, 2010Co-Authors: Kazuki Mochizuki, Kazue Honma, Masaya Shimada, Toshinao GodaAbstract:Maltase and glucoamylase are derived from the same mRNA and are responsible for digestion of starch in the small intestine. Their jejunal activities in rodents are induced by a high-starch/low-fat (HS)-diet. However, it is unknown whether jejunal expression of the Maltase-Glucoamylase (Mgam) gene is enhanced by the HS-diet. In this study, we found that jejunal Mgam mRNA was increased by a HS-diet in mice. We showed that the HS-diet increased acetylation of histones, bindings of a coactivator, Creb binding protein (CREBBP), and the transcriptional factors caudal type homeobox 2 (CDX2) and HNF1 homeobox (HNF1) in the promoter/enhancer and transcriptional regions of Mgam gene. This suggests that the increase in the jejunal activity of maltase and glucoamylase caused by a HS-diet in mice is regulated at the mRNA level through histone acetylation and binding of CREBBP, CDX2 and HNF1 in the promoter/enhancer and transcriptional regions of Mgam gene.
David R Rose - One of the best experts on this subject based on the ideXlab platform.
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phylogenetic analysis reveals key residues in substrate hydrolysis in the isomaltase domain of sucrase isomaltase and its role in starch digestion
Biochimica et Biophysica Acta, 2019Co-Authors: Marcia M Chaudet, Hassan Y. Naim, Mahdi Amiri, Nathalie Marth, David R RoseAbstract:Abstract Background Starch constitutes one of the main sources of nutrition in the human diet and is broken down through a number of stages of digestion. Small intestinal breakdown of starch-derived substrates occurs through the mechanisms of small intestinal brush border enzymes, Maltase-Glucoamylase and sucrase-isomaltase. These enzymes each contain two functional enzymatic domains, and though they share sequence and structural similarities due to their evolutionary conservation, they demonstrate distinct substrate preferences and catalytic efficiency. The N-terminal isomaltase domain of sucrase-isomaltase has a unique ability to actively hydrolyze isomaltose substrates in contrast to the sucrase, maltase and glucoamylase enzymes. Methods Through phylogenetic analysis, structural comparisons and mutagenesis, we were able to identify specific residues that play a role in the distinct substrate preference. Mutational analysis and comparison with wild-type activity provide evidence that this role is mediated in part by affecting interactions between the sucrase and isomaltase domains in the intact molecule. Results The sequence analysis revealed three residues proposed to play key roles in isomaltase specificity. Mutational analysis provided evidence that these residues in isomaltase can also affect activity in the partner sucrase domain, suggesting a close interaction between the domains. Major conclusions The sucrase and isomaltase domains are closely interacting in the mature protein. The activity of each is affected by the presence of the other. General Significance: There has been little experimental evidence previously of the effects on activity of interactions between the sucrase-isomaltase enzyme domains. By extension, similar interactions might be expected in the other intestinal α-glucosidase, Maltase-Glucoamylase.
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contribution of the individual small intestinal α glucosidases to digestion of unusual α linked glycemic disaccharides
Journal of Agricultural and Food Chemistry, 2016Co-Authors: David R Rose, Roberto Quezadacalvillo, Buford L Nichols, Bruce R HamakerAbstract:The mammalian mucosal α-glucosidase complexes, maltase–glucoamylase (MGAM) and sucrase–isomaltase (SI), have two catalytic subunits (N- and C-termini). Concurrent with the desire to modulate glycemic response, there has been a focus on di-/oligosaccharides with unusual α-linkages that are digested to glucose slowly by these enzymes. Here, we look at disaccharides with various possible α-linkages and their hydrolysis. Hydrolytic properties of the maltose and sucrose isomers were determined using rat intestinal and individual recombinant α-glucosidases. The individual α-glucosidases had moderate to low hydrolytic activities on all α-linked disaccharides, except trehalose. Maltase (N-terminal MGAM) showed a higher ability to digest α-1,2 and α-1,3 disaccharides, as well as α-1,4, making it the most versatile in α-hydrolytic activity. These findings apply to the development of new glycemic oligosaccharides based on unusual α-linkages for extended glycemic response. It also emphasizes that mammalian mucosal α-...
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Substrate selectivity of C-terminal sucrase isomaltase and maltase glucoamylase
Acta Crystallographica Section A, 2014Co-Authors: Kyra Jones, David R RoseAbstract:Carbohydrates make up a significant component of the human diet. One approach to controlling blood glucose and serum insulin levels in individuals with type II diabetes is inhibition of intestinal α-glucosidases and pancreatic α-amylases. Two intestinal α-glucosidases, sucrase isomaltase (SI) and maltase glucoamylase (MGAM), are responsible for the final step of starch hydrolysis in mammals in the small intestine: the release of free glucose. Each enzyme consists of two catalytic subunits: N-terminal sucrase isomaltase (ntSI) and C-terminal sucrase isomaltose (ctSI); and N-terminal maltase glucoamylase (ntMGAM) and C-terminal maltase glucoamylase (ctMGAM). Here, residues hypothesized to impact substrate specificity of ctSI and ctMGAM will be presented, enhancing our understanding of the functionality of these enzymatic subunits as well as their overlapping substrate specificity.
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The effect of heteroatom substitution of sulfur for selenium in glucosidase inhibitors on intestinal α-glucosidase activities
Chemical communications (Cambridge England), 2011Co-Authors: Razieh Eskandari, Kyra Jones, David R Rose, B. Mario PintoAbstract:The synthesis of selenium analogues of de-O-sulfonated ponkoranol, a naturally occurring sulfonium-ion glucosidase inhibitor isolated from Salacia reticulata, and their evaluation as glucosidase inhibitors against two recombinant intestinal enzymes maltase glucoamylase (MGAM) and sucrase isomaltase (SI) are described.
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probing the active site requirements of human intestinal n terminal maltase glucoamylase the effect of replacing the sulfate moiety by a methyl ether in ponkoranol a naturally occurring α glucosidase inhibitor
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Razieh Eskandari, David R Rose, Kyra Jones, Mario B PintoAbstract:Abstract Ponkoranol is a naturally occurring glucosidase inhibitor isolated from the plant Salacia reticulata. The compound comprises a sulfonium ion with an internal sulfate counter ion. We report here an efficient synthetic route to 3′-O-methyl ponkoranol to test the hypothesis that occupation of a hydrophobic pocket by a methyl group instead of the polar sulfate ion within the active site of human N-terminal maltase glucoamylase would be beneficial. The synthetic strategy relies on the nucleophilic attack of 2,3,5-tri-O-benzyl-1,4-anhydro-4-thio- d -arabinitol at the C-6 position of benzyl 6-O-p-toluenesulfonyl β- d -glucopyranoside, followed by deprotection using boron trichloride and reduction with sodium borohydride. The target compound inhibited the N-terminal catalytic domain of intestinal human maltase glucoamylase (ntMGAM) with a Ki value of 0.50 ± 0.04 μM, higher than those of de-O-sulfonated ponkoranol (Ki = 43 ± 3 nM), or its 5′-stereoisomer (Ki = 15 ± 1 nM). We conclude that the interaction of the methyl group with hydrophobic residues in the active site is not as beneficial to inhibition of ntMGAM as the other interactions of the polyhydroxylated chain with active-site residues.