Mapping the intestinal alpha-glucogenic enzyme specificities of starch digesting maltase-glucoamylase and sucrase-isomaltase

Jones, Kyra; Sim, Lyann; Mohan, Sankar; Jayakanthan, Kumarasamy; Liu, Hui; Avery, Stephen; Naim, Hassan Y.; Quezada‐Calvillo, Roberto; Nichols, Buford L.; Pinto, B. Mario; Rose, David R.

doi:10.1016/j.bmc.2011.05.033

Cited by 80 publications

(86 citation statements)

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“…0.03-0.19 M) compared with acarbose (1) (K i ϭ 62 Ϯ 13 M) (23)(24)(25)(26)(27)(28). In addition, the de-O-sulfonated compounds (6 -9) were either equivalent or better inhibitors than the parent sulfonated compounds (2-5) (14,29,54). We have also synthesized the C-3Ј-␤-maltose-extended de-O-sulfonated ponkoranol analog (10) and C-5Ј-␤-maltose-extended de-Osulfonated ponkoranol (11) (Fig.…”

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confidence: 83%

“…Enzyme Preparation-Methods for cloning, expression, and purification of human ntMGAM (7) and ntSI (30) from Drosophila S2 cells, as well as mouse ctMGAM, and ctSI, were reported previously (14).…”

Section: Methodsmentioning

confidence: 99%

“…acarbose (1) (see Fig. 1A) (13), leading to the hypothesis that one might regulate individual ␣-glucosidase activities with certain inhibitors by partially or wholly inhibiting one, two, or three of the four ␣-glucosidase activities while leaving the remaining one or more subunits active, a concept we advanced as "toggling" (14,15). That is, through the judicious action of selective inhibitors, a fast digesting subunit or subunits can be inhibited to place the onus of digestion on slower digesting subunits.…”

mentioning

confidence: 99%

“…Therefore, an objective of this work was to explore the role of different inhibitors in MGAM and SI enzyme activities against LM/␣LDx structures. Furthermore, we wanted to elucidate whether specific inhibitors could affect glucogenesis by selective inhibition of the different enzymes, having shown this property with maltose as a substrate (14,15), and to investigate how slow starch digestion or slow glucose delivery to the body might be achieved using this concept. We have chosen, as representative inhibitors, acarbose (1), de-O-sulfonated kotalanol (6), C-3Ј-␤-maltose-extended de-O-sulfonated ponkoranol analog (10), and C-5Ј-␤-maltose-extended de-O-sulfonated ponkoranol (11), and we report here their inhibitory effects on recombinant human MGAM and SI using a mixture of the ␣-amylase degradation products (LM/␣LDx) as a substrate.…”

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confidence: 99%

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Modulation of Starch Digestion for Slow Glucose Release through “Toggling” of Activities of Mucosal α-Glucosidases

Lee

Eskandari

Jones

et al. 2012

Journal of Biological Chemistry

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For digestion of starch, α‐amylase first hydrolyzes the starch structure to α‐limit dextrins (αLDx's). Complete hydrolysis to glucose then takes place through the combined action of mucosal maltase‐glucoamylase (MGAM) and sucrase‐isomaltase (SI), which have two subunits each (N‐ and C‐ terminal). In this study, we applied the concept of “toggling” through differential inhibition of subunits to examine control of glucogenesis from αLDx's with the aim of attaining slow glucose delivery to the body. Mammalian recombinant MGAM and SI subunits were individually reacted with αLDx's with varying concentrations of acarbose, a well known α‐glucosidase inhibitor. Released glucose amounts were analyzed for hydrolysis activity. Notably, results showed selective inhibitory effect on C‐terminal subunits by acarbose for starch digestion. Furthermore, Ki values of C‐terminal subunits were lower than human α‐amylases which can be applied that certain amount of acarbose had inhibitory effect on the hydrolysis of αLDx's by C‐terminal subunits but not on α‐amylase for moderating glucogenesis. This result supports the concept of controlling starch digestion rate for slow glucose release through the “toggling” of activities of the mucosal α‐glucosidases by selective enzyme inhibition. Conceivably this approach could be used to treat Type II diabetes by extending postprandial blood glucose delivery to the body, and may apply as well to other metabolic syndrome‐associated diseases and conditions. This research was supported from Whistler Center for Carbohydrate Research and USDA/AFRI.

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confidence: 83%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Modulation of Starch Digestion for Slow Glucose Release through “Toggling” of Activities of Mucosal α-Glucosidases

Lee

Eskandari

Jones

et al. 2012

Journal of Biological Chemistry

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“…On the other hand, this difference was quite small in the case of neosalacinol. Although substrate specificities of the domains of the rat enzyme have not been investigated, the C-terminal domains of human alpha-glucosidase are known to be the site of hydrolysis of, not only disaccharides, but also tri-saccharides [29]; therefore, large ligands prefer C-terminal domains over N-terminal domains. The chemical size of acarbose corresponds to that of large tetra-saccharides, whereas the size of neosalacinol corresponds to that of small disaccharides.…”

Section: Binding Affinity Predictionmentioning

confidence: 99%

Computational Study on the Comparative Differences in the Activity of Inhibitors of Human versus Rat Alpha-Glucosidase

Nakamura¹,

Shimada²,

Tanabe³

et al. 2017

OJMC

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Differences between the inhibitory activities of specific compounds on analogous enzymes isolated from different animal species are one of the critical issues to evaluate when exploring structure-activity relationships. The activity of acarbose is about ten times stronger in rat than in human, and that of neosalacinol is similar in both species. Binding affinities of acarbose and neosalacinol to four catalytic domains of alpha-glucosidases in human and rat were compared to investigate the cause of activity differences among species. Species difference was brought about complicatedly by the balance of interaction with four domains, and the result was indicated that larger ligand would show larger species difference in activity.

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Biochemical and In Silico Aspects of Active Compounds From Nyctanthes arbor‐tristis Flower As Antidiabetic Agent

ALNadhari,

Alsakkaf,

Albarakat

2024

Biotech and App Biochem

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Targeting alpha‐glucosidase (maltase‐glucoamylase [MGAM] and sucrase‐isomaltase [SI]) under diabetes conditions is important to overcome hyperglycemia. Moreover, it is necessary to mitigate hyperglycemia‐mediated oxidative stress to evade the progression of diabetes‐associated secondary complications. Hence, in the present study, under‐explored Nyctanthes arbor‐tristis flowers (NAFs) were studied for inhibition of alpha‐glucosidase activities. The NAF methanolic extract (NAFME) was prepared. Through liquid chromatography/electrospray ionization tandem mass spectrometry (LC–ESI/MS/MS) analysis, various phytocompounds belonging to different classes—flavonoids, iridoid glycosides, proanthocyanidin, anthocyanin, polyphenol, phenolic acid, fatty acid ester, and carotenoid—were identified. NAFME showed in vitro antioxidant activity. NAFME inhibited maltase, sucrase, glucoamylase, and isomaltase in mixed mode with Ki values of 179.93, 176.38, 126.03, and 201.56 µg/mL, respectively. In silico screening of phytocompounds identified in NAFME indicated that hinokiflavone (HKF), pelargonidin‐3‐O‐glucoside (PG), isorhamnetin‐3‐glucoside‐7‐rhamnoside (IGR), and petunidin‐3‐rutinoside (PR) showed better interactions with different subunits of human alpha‐glucosidase, namely, N‐terminal (Nt‐MGAM and Nt‐SI) and C‐terminal (Ct‐MGAM and Ct‐SI). Molecular dynamics (MD) simulation, binding free energy study (molecular mechanics–generalized Born surface area [MM/GBSA]), and post‐MD simulation studies (principal component analysis [PCA] and dynamic cross‐correlation matrix [DCCM]) provided an in‐depth understanding of these ligands’ interactions with proteins. The overall efficacy of NAFME against oxidative stress and alpha‐glucosidase in vitro is understood. Moreover, in silico analysis has shown the possible potential of HKF, PG, IGR, and PR to act as alpha‐glucosidase inhibitors. Further studies on the antidiabetic potential of NAFME, HKF, PG, IGR, and PR in in vivo conditions are required to fully unveil the applicability of NAFME in the management of T2DM as a complementary medicine.

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Mapping the intestinal alpha-glucogenic enzyme specificities of starch digesting maltase-glucoamylase and sucrase-isomaltase

Cited by 80 publications

References 35 publications

Modulation of Starch Digestion for Slow Glucose Release through “Toggling” of Activities of Mucosal α-Glucosidases

Modulation of Starch Digestion for Slow Glucose Release through “Toggling” of Activities of Mucosal α-Glucosidases

Computational Study on the Comparative Differences in the Activity of Inhibitors of Human versus Rat Alpha-Glucosidase

Biochemical and In Silico Aspects of Active Compounds From Nyctanthes arbor‐tristis Flower As Antidiabetic Agent

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