Disease relevance of Gcs1

• Contrary to our original expectations, the most influential gene was the one on chromosome (chr.) 15, Gastric cancer susceptibility gene 1 (Gcs1), which confers susceptibility to stomach carcinogenesis (LOD, 3.8) with a dominant BUF allele by promoting conversion from adenomas to carcinomas [1].
• Glucosidase inhibition. A new approach to the treatment of diabetes, obesity, and hyperlipoproteinaemia [2].
• Since these changes could be produced with an amount of glucosidase inhibitor which did not prevent normal rate of weight gain, the possibility arises that this approach may be useful in the treatment of various hypertriglyceridemic states in man [3].
• Normal rat kidney (NRK) cells transformed by the v-sis oncogene of simian sarcoma virus (SSV) were treated with the glucosidase I inhibitor castanospermine [4].

High impact information on Gcs1

• We also could not find any evidence of Golgi-associated processing of the Asn-linked oligosaccharide chains of two well-characterized ER membrane glycoprotein enzymes (glucosidase II and hexose-6-phosphate dehydrogenase), or of the oligosaccharides attached to the bulk of the glycoproteins of the ER membrane [5].
• In contrast, two glucosidase I inhibitors (castanospermine [CA] and N-methyl-1-deoxynojirimycin [MdN]) blocked carbohydrate remodeling at an early stage within the endoplasmic reticulum and prevented cell surface expression of v-fms proteins [6].
• An alternate glucosidase II-independent deglucosylation pathway exists, in which endo-alpha-mannosidase cleaves internally the glucose-substituted mannose residue of oligosaccharides [7].
• Double immunogold labeling established a mutually exclusive distribution of endomannosidase and glucosidase II, whereas calreticulin was observed in endomannosidase-reactive sites (17.3% in intermediate compartment, 5.7% in Golgi apparatus) in addition to the ER (77%) [7].
• Trimming of N-linked oligosaccharides by endoplasmic reticulum (ER) glucosidase II is implicated in quality control of protein folding [7].

Chemical compound and disease context of Gcs1

• Effects of a glucosidase inhibitor (acarbose, BAY g 5421) on the development of obesity and food motivated behavior in Zucker (fafa) rats [8].

Biological context of Gcs1

• These results indicate that glucosidase I is a transmembrane protein with a luminally oriented catalytic domain [9].
• This domain appeared to contain the active site of the enzyme and had the ability to bind to glucosidase I-specific affinity gel [9].
• Glucosidase II from rat liver microsomes. Kinetic model for binding and hydrolysis [10].
• Of the three glucosidase inhibitors examined, 1-deoxynojirimycin inhibited not only oligosaccharide trimming but also glycosylation de novo of newly synthesized proteins, resulting in the formation of alpha 1PI with two and three (normally carrying three) and alpha 1AGP with two to five (normally carrying six) oligosaccharide side chains [11].
• The regulation of lipogenesis in vivo in the lactating mammary gland of the rat during the starved-refed transition. Studies wtih acarbose, a glucosidase inhibitor [12].

Anatomical context of Gcs1

• Based on trypsin digestion pattern and the data on membrane topography, glucosidase I constitutes a single polypeptide chain of 85 kDa with two contiguous domains: a membrane-bound domain that anchors the protein to the endoplasmic reticulum and a luminal domain [9].
• Role of sulfhydryl groups in the function of glucosidase I from mammary gland [13].
• Intestinal brush border enzyme activities in the rats treated with urogastrone-epidermal growth factor were restored to those seen in the orally fed rats except for alpha glucosidase activity in the proximal gut [14].
• Acarbose is a potent intestinal glucosidase inhibitor which could have an anti-obesity property by reducing postprandial plasma glucose and insulin levels, potentially responsible for high rates of lipid synthesis in adipose tissue [15].
• Brush border gamma glutamyltransferase and alpha glucosidase activities were reduced by up to 50% throughout the small intestine of the animals fed intravenously [14].

Associations of Gcs1 with chemical compounds

• We have analyzed the functional domain structure of rat mammary glucosidase I, an enzyme involved in N-linked glycoprotein processing, using biochemical and immunological approaches [9].
• One of these glucosidases removes the distal glucose from Glc3Man9GlcNAc, and the other glucosidase sequentially removes glucose from Glc2Man9GlcNAc and Glc1Man9GlcNAc [16].
• The fully core-glycosylated form of Mr = 41,000, which was detected after inhibition of glucosidase I with 1-deoxynojirimycin, was converted into a Mr = 39,000 intermediate, and upon further trimming, into a Mr = 36,000 endo-H-sensitive form [17].
• Glucosidase I initiates the processing of asparagine-linked glycoproteins by excising the distal alpha 1,2-linked glucosyl residue from the Glc3Man9GlcNAc2 oligosaccharide, soon after its en bloc transfer from the lipid-linked donor to the nascent polypeptide [13].
• The results on hormonal regulation of glucosidase I indicate that the synthesis of the enzyme is stimulated by a combination of insulin, hydrocortisone, and prolactin; additionally, epidermal growth factor may play a role in this regulation [18].

Regulatory relationships of Gcs1

• The interaction of calnexin with newly synthesized type-I IP(3)R was transient and inhibited by treatment of the cells with dithiothreitol or the glucosidase inhibitor N-methyldeoxynojirimicin [19].
• Secretion of rat hepatic lipase is blocked by inhibition of oligosaccharide processing at the stage of glucosidase I [20].

Other interactions of Gcs1

• Addition of glucosidase inhibitors prevented the association of calnexin with in vitro translated type-I TM construct [19].
• The binding could be modulated in vitro by incubation of substrate with purified preparations of the glycan modifying enzymes glucosidase II and the UDP-glucose:glycoprotein glucosyltransferase, thus recapitulating the regulation of calreticulin-binding by glycan modification that occurs in vivo [21].
• Different effects of the glucosidase inhibitors 1-deoxynojirimycin, N-methyl-1-deoxynojirimycin and castanospermine on the glycosylation of rat alpha 1-proteinase inhibitor and alpha 1-acid glycoprotein [11].
• The LG fraction was enriched in certain acid hydrolases including glucosidase, acid phosphatase, phospholipases A, and sphingomyelinase; other acid hydrolases, i.e., amino-glycosidases, glactosidase and aryl sulfatase (pH 5.5), and steroid sulfatase were not preferentially localized in this fraction [22].
• alpha-Glucosidase inhibitors in diabetes: lessons from animal studies [23].

Analytical, diagnostic and therapeutic context of Gcs1

• Depression of carbohydrate digestion by oral administration of acarbose, a glucosidase inhibitor, led to a 75% inhibition of the re-activation of lipogenesis in vivo in the mammary gland of 18 h-starved lactating rats refed with 5 g of chow diet [12].
• Lysosomal enzyme levels such as acid phosphatase, glucosidase, glucuronidase and dipeptidyl aminopeptidase in the serum of hemodialysis patients were higher than those of normal individuals [24].
• The glucosidase which acts on (Glc)2(Man)9(GlcNAc)2 could be purified with a Concanavalin-A--Sepharose column following by electrofocusing [25].
• No change in GLU or GLR activity was detected after treatment [26].
• The lysosomal glucosidase activities and glycogen degradation in newborn rat liver were studied by using biochemical assays, electron microscopy and quantitative morphometry [27].

References