The absorption of dietary flavonoid glycosides in humans involves a critical deglycosylation step that is mediated by epithelial beta-glucosidases (LPH and CBG). The significant variation in beta-glucosidase activity between individuals may be a factor determining variation in flavonoid bioavailability.
The mammalian HSP90 family of proteins is a cluster of highly conserved molecules that are involved in myriad cellular processes. Their distribution in various cellular compartments underlines their essential roles in cellular homeostasis. HSP90 and its co-chaperones orchestrate crucial physiological processes such as cell survival, cell cycle control, hormone signaling, and apoptosis. Conversely, HSP90, and its secreted forms, contribute to the development and progress of serious pathologies, including cancer and neurodegenerative diseases. Therefore, targeting HSP90 is an attractive strategy for the treatment of neoplasms and other diseases. This manuscript will review the general structure, regulation and function of HSP90 family and their potential role in pathophysiology.
Human maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) are small intestinal enzymes that work concurrently to hydrolyze the mixture of linear ␣-1,4-and branched ␣-1,6-oligosaccharide substrates that typically make up terminal starch digestion products. MGAM and SI are each composed of duplicated catalytic domains, N-and C-terminal, which display overlapping substrate specificities. The N-terminal catalytic domain of human MGAM (ntMGAM) has a preference for short linear ␣-1,4-oligosaccharides, whereas N-terminal SI (ntSI) has a broader specificity for both ␣-1,4-and ␣-1,6-oligosaccharides. Here we present the crystal structure of the human ntSI, in apo form to 3.2 Å and in complex with the inhibitor kotalanol to 2.15 Å resolution. Structural comparison with the previously solved structure of ntMGAM reveals key active site differences in ntSI, including a narrow hydrophobic ؉1 subsite, which may account for its additional substrate specificity for ␣-1,6 substrates.In humans, six enzyme activities (two ␣-amylase and four ␣-glucosidase activities) are involved in the breakdown of dietary starches and sugars into glucose. The ␣-glucosidase activities are associated with two small intestinal membrane-bound enzymes: maltase-glucoamylase (MGAM) 3 and sucrase-isomaltase (SI) (for a review, see Refs. 1 and 2). MGAM and SI are composed of duplicated catalytic domains: an N-terminal membrane-proximal domain (ntMGAM and ntSI) and a C-terminal luminal domain (ctMGAM and ctSI). The domains are anchored to the small intestinal brush-border membrane via an O-glycosylated stalk stemming from the N-terminal domain. Given that MGAM and SI genes arose from duplication and divergence of an ancestral gene, which itself has undergone tandem duplication (3), the N-terminal domains of MGAM and SI are more similar to one another in sequence, as are the C-terminal domains (ϳ60% sequence identity), than are the N-and C-terminal domains associated with the same enzyme (ϳ40% sequence identity).Within the carbohydrate-active enzymes (CAZY) classification system (36), which groups enzymes based on sequence similarity and reflects the functional and structural similarities of family members, N-and C-terminal MGAM and SI domains are members of the glycoside hydrolase 31 family (GH31). The four domains exhibit exo-glucosidase activities against ␣-1,4-linked maltose substrates (Fig. 1A) but display different specificities for malto-oligosaccharides of various lengths (4 -6). ntSI and ctSI subunits have additional activity for the ␣-1,6 linkages of starch branch points (and isomaltose substrates; Fig. 1A) and the ␣-1,2 linkage of sucrose, respectively (7), and are historically referred to as isomaltase and sucrase.As they are involved in the breakdown of dietary sugars and starches, MGAM and SI are attractive targets for inhibition by ␣-glucosidase inhibitors as a means of controlling blood glucose levels in individuals with type 2 diabetes (8). Acarbose (Fig. 1B) is the most widely used ␣-glucosidase inhibitor currently on the market and h...
The biosynthesis and maturation of the human intestinal lactase-phlorizin hydrolase (LPH; EC 3.2.1.23-3.2.1.62) has been studied in cultured intestinal biopsies and mucosal explants. Short time pulse labelling revealed on high mannose intermediate of Mr 215,000 which was converted upon endo-beta-N-acetylglucosaminidase H (endo-H) digestion to a polypeptide of Mr 200,000. The brush border form of LPH was revealed after longer pulse periods and has Mr 160,000. It possesses mainly complex oligosaccharide chains and, owing to its partial endo-H sensitivity, at least one chain of the high mannose type. Leupeptin partially inhibited the appearance of the Mr-160,000 polypeptide. Monensin treatment of biopsies resulted in the modification of the Mr-160,000 species to the Mr-140,000 molecule, which was endo-H sensitive. Pulse-chase analysis indicated a slow post-translational processing of the high mannose precursor (Mr 215,000) to yield the mature brush-border form (Mr 160,000) of LPH. Our results further indicate that LPH is synthesized as a single polypeptide precursor which is intracellularly cleaved to yield the mature brush border of LPH. The data presented suggest that this cleavage occurs during the translocation of the molecule across the Golgi complex.
Cholesterol present in the plasma membrane of target cells has been shown to be important for the infection by SARS-CoV. We show that cholesterol depletion by treatment with methyl-beta-cyclodextrin (m beta CD) affects infection by SARS-CoV to the same extent as infection by vesicular stomatitis virus-based pseudotypes containing the surface glycoprotein S of SARS-CoV (VSV-Delta G-S). Therefore, the role of cholesterol for SARS-CoV infection can be assigned to the S protein and is unaffected by other coronavirus proteins. There have been contradictory reports whether or not angiotensin-converting enzyme 2 (ACE2), the cellular receptor for SARS-CoV, is present in detergent-resistant membrane domains. We found that ACE2 of both Vero E6 and Caco-2 cells co-purifies with marker proteins of detergent-resistant membranes supporting the notion that cholesterol-rich microdomains provide a platform facilitating the efficient interaction of the S protein with the cellular receptor ACE2. To understand the involvement of cholesterol in the initial steps of the viral life cycle, we applied a cell-based binding assay with cells expressing the S protein and cells containing angiotensin-converting enzyme 2 (ACE2). Alternatively, we used a soluble S protein as interaction partner. Depletion of cholesterol from the ACE2-expressing cells reduced the binding of S-expressing cells by 50% whereas the binding of soluble S protein was not affected. This result suggests that optimal infection requires a multivalent interaction between viral attachment protein and cellular receptors.
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