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MGAT1  -  mannosyl (alpha-1,3-)-glycoprotein beta-1...

Homo sapiens

Synonyms: Alpha-1,3-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase, GGNT1, GLCNAC-TI, GLCT1, GLYT1, ...
 
 
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Disease relevance of MGAT1

  • Finally, an up-regulation of both MGAT2 protein expression and MGAT activity was observed in mice fed a high fat diet, implicating a role of MGAT2 in diet-induced obesity [1].
  • In order to improve the oligosaccharide processing properties of these cells we have used baculovirus vectors for expression of human (beta 1,2-N-acetylglucosaminyltransferase I (hGNT-I), the enzyme catalysing the crucial step in the pathway leading to complex type N-glycans in vertebrate cells [2].
  • To monitor hGNT-I activity in intact Sf9-cells, the glycosylation of coexpressed fowl plague virus hemagglutinin (HA) was investigated employing a galactosylation assay and chromatographic analysis of isolated HA N-glycans [2].
  • Characterization of the glycine transport system GLYT 1 in human placental choriocarcinoma cells (JAR) [3].
 

High impact information on MGAT1

  • However, MGAT1 was not expressed in the small intestine, implying the existence of a second MGAT gene [4].
  • Expression of the MGAT1 cDNA in insect cells markedly increased MGAT activity in cell membranes [4].
  • Acyl-CoA:monoacylglycerol acyltransferase (MGAT) catalyzes the synthesis of diacylglycerol, the precursor of physiologically important lipids such as triacylglycerol and phospholipids [4].
  • MGAT activity has also been reported in mammalian liver and white adipose tissue [4].
  • In addition, MGAT activity was proportional to the level of MGAT1 protein expressed, and the amount of diacylglycerol produced depended on the concentration of either of its substrates, oleoyl-CoA or monooleoylglycerol [4].
 

Biological context of MGAT1

  • The human GlcNAc-T I and II genes (MGAT1 and MGAT2) map to chromosome bands 5q35 and 14q21, respectively, by fluorescence in situ hybridization [5].
  • Previous work indicated the presence of at least two exons in the human GlcNAc-T I gene MGAT1, exon 2 containing part of the 5' untranslated region and the complete coding and 3' untranslated regions, and exon 1 with the remainder of the 5' untranslated region [6].
  • The present study reports further characterization of MGAT2, a newly identified intestinal MGAT (Cao, J., Lockwood, J., Burn, P., and Shi, Y. (2003) J. Biol. Chem. 278, 13860-13866) for its substrate specificity, requirement for lipid cofactors, optimum pH and Mg2+, and other intrinsic properties [7].
  • The ontogenic changes of lipid and lipoprotein synthesis are correlated with specific patterns of regulatory enzymes (HMG-CoA reductase, ACAT, MGAT) that are representative of key patterns such as the cholesterol pathway, cholesterol esterification, and neutral lipid pathway [8].
 

Anatomical context of MGAT1

  • Acyl-CoA:monoacylglycerol acyltransferase (MGAT) plays an important role in dietary fat absorption by catalyzing a rate-limiting step in the re-synthesis of diacylglycerols in enterocytes [7].
  • Immunohistochemical studies have demonstrated that, as well as being found in glial cells, GLYT1 is also associated with the pre- and postsynaptic aspects of glutamatergic synapses [9].
  • Membranes of insect cells and homogenates of mammalian cells overexpressing MFAT exhibited significantly increased MGAT, acyl-CoA:fatty acyl alcohol acyltransferase (wax synthase), and acyl-CoA:retinol acyltransferase (ARAT) activities, which catalyze the synthesis of diacylglycerols, wax monoesters, and retinyl esters, respectively [10].
  • 5'-Guanidinonaltrindole (GNTI) possesses 5-fold greater opioid antagonist potency (K(e)=0.04 nM) and an order of magnitude greater selectivity (selectivity ratios >500) than the prototypical kappa-opioid receptor antagonist, norbinaltorphimine, in smooth muscle preparations [11].
  • Acyl-CoA: monoglyceride acyltransferase (MGAT; EC 2.3.1.22) has been studied in human small intestinal mucosa by means of a spectrophotometric method based on the detection of liberated CoA employing 5,5'-dithiobis-(2-nitrobenzoic acid) [12].
 

Associations of MGAT1 with chemical compounds

  • Acyl coenzyme A:monoacylglycerol acyltransferase (MGAT) catalyzes the synthesis of diacylglycerol using 2-monoacylglycerol and fatty acyl coenzyme A. This enzymatic reaction is believed to be an essential and rate-limiting step for the absorption of fat in the small intestine [13].
  • Glycine (GLYT1) and small neutral amino-acid (SNAT) transporters, which regulate glycine levels, represent additional targets for drug development, and may represent a site of action of clozapine [14].
  • The finding that only the 5'-regioisomer (GNTI) possessed potent kappa-opioid antagonist activity and high affinity at kappa-receptors illustrates the importance of the 5'-position in orienting the guanidinium group to the proper recognition locus (Glu 297) for potent kappa-antagonist activity [15].
  • The importance of the indole scaffold of GNTI 3 in directing its address (5'-guanidinium group) to associate with the Glu297 residue of the kappa-opioid receptor was investigated by the synthesis and biological evaluation of its 4'- (4a), 6'- (4b), and 7'- (4c) regioisomers [15].
  • Both systems were Na+ -dependent; the high-affinity system proved also dependent on external Cl- and was inhibited by sarcosine, characteristic of GLYT1 transporters [16].
 

Analytical, diagnostic and therapeutic context of MGAT1

  • The discovery that the 6'-regioisomer of GNTI was a potent kappa-agonist, together with the results of site-directed mutagenesis studies that are consistent with association between the 6'-guanidinium group and Glu297, suggest that the transition from an inactive to an active state of the kappa-receptor involves a conformational change of TM6 [15].

References

  1. A predominant role of acyl-CoA:monoacylglycerol acyltransferase-2 in dietary fat absorption implicated by tissue distribution, subcellular localization, and up-regulation by high fat diet. Cao, J., Hawkins, E., Brozinick, J., Liu, X., Zhang, H., Burn, P., Shi, Y. J. Biol. Chem. (2004) [Pubmed]
  2. Elongation of the N-glycans of fowl plague virus hemagglutinin expressed in Spodoptera frugiperda (Sf9) cells by coexpression of human beta 1,2-N-acetylglucosaminyltransferase I. Wagner, R., Liedtke, S., Kretzschmar, E., Geyer, H., Geyer, R., Klenk, H.D. Glycobiology (1996) [Pubmed]
  3. Characterization of the glycine transport system GLYT 1 in human placental choriocarcinoma cells (JAR). Liu, W., Leibach, F.H., Ganapathy, V. Biochim. Biophys. Acta (1994) [Pubmed]
  4. Identification of a gene encoding MGAT1, a monoacylglycerol acyltransferase. Yen, C.L., Stone, S.J., Cases, S., Zhou, P., Farese, R.V. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  5. The human UDP-N-acetylglucosamine: alpha-6-D-mannoside-beta-1,2- N-acetylglucosaminyltransferase II gene (MGAT2). Cloning of genomic DNA, localization to chromosome 14q21, expression in insect cells and purification of the recombinant protein. Tan, J., D'Agostaro, A.F., Bendiak, B., Reck, F., Sarkar, M., Squire, J.A., Leong, P., Schachter, H. Eur. J. Biochem. (1995) [Pubmed]
  6. Organization of the human beta-1,2-N-acetylglucosaminyltransferase I gene (MGAT1), which controls complex and hybrid N-glycan synthesis. Yip, B., Chen, S.H., Mulder, H., Höppener, J.W., Schachter, H. Biochem. J. (1997) [Pubmed]
  7. Properties of the mouse intestinal acyl-CoA:monoacylglycerol acyltransferase, MGAT2. Cao, J., Burn, P., Shi, Y. J. Biol. Chem. (2003) [Pubmed]
  8. Developmental aspects of lipid and lipoprotein synthesis and secretion in human gut. Levy, E., Ménard, D. Microsc. Res. Tech. (2000) [Pubmed]
  9. The scaffolding protein PSD-95 interacts with the glycine transporter GLYT1 and impairs its internalization. Cubelos, B., González-González, I.M., Giménez, C., Zafra, F. J. Neurochem. (2005) [Pubmed]
  10. A human skin multifunctional O-acyltransferase that catalyzes the synthesis of acylglycerols, waxes, and retinyl esters. Yen, C.L., Brown, C.H., Monetti, M., Farese, R.V. J. Lipid Res. (2005) [Pubmed]
  11. 5'-Guanidinonaltrindole, a highly selective and potent kappa-opioid receptor antagonist. Jones, R.M., Portoghese, P.S. Eur. J. Pharmacol. (2000) [Pubmed]
  12. Triacylglycerol biosynthesis in human small intestinal mucosa. Acyl-CoA: monoglyceride acyltransferase. Bierbach, H. Digestion (1983) [Pubmed]
  13. Identification of acyl coenzyme A:monoacylglycerol acyltransferase 3, an intestinal specific enzyme implicated in dietary fat absorption. Cheng, D., Nelson, T.C., Chen, J., Walker, S.G., Wardwell-Swanson, J., Meegalla, R., Taub, R., Billheimer, J.T., Ramaker, M., Feder, J.N. J. Biol. Chem. (2003) [Pubmed]
  14. Glutamate as a therapeutic target in psychiatric disorders. Javitt, D.C. Mol. Psychiatry (2004) [Pubmed]
  15. Transformation of a kappa-opioid receptor antagonist to a kappa-agonist by transfer of a guanidinium group from the 5'- to 6'-position of naltrindole. Sharma, S.K., Jones, R.M., Metzger, T.G., Ferguson, D.M., Portoghese, P.S. J. Med. Chem. (2001) [Pubmed]
  16. Characterization of glycine transport in cultured Müller glial cells from the retina. Gadea, A., López, E., López-Colomé, A.M. Glia (1999) [Pubmed]
 
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