Structural Biochemistry/Proteins/Protein O-GlcNAcylation by O-linked β-N-acetylglucosamine (O-GlcNAc)
O-GlcNAc[edit | edit source]
β-linked N-acetylglucosamine is also known as O-GlcNAc. It is an intercellular carbohydrate that dynamically modifies proteins in the nucleolus and cytoplasm on the Serine and Threonine residues (Hart). The regulation of O-GlcNAc is dependent on only two enzymes OGT and O-GlcNacase (Hart). The differences between O-GlcNAc and many forms of protein glycosylation are: a).O-GlcNAcylation occurs only in the cytoplasm and nucleus b). It is not an elongated structure c). It is attached and removed several times in the life of a (Hart). It was discovered in 1983 (Hart). It is present in all multicellular organisms, but not in yeast, for example, Saccharomyces cerevisiae (Hart).
O-GlcNAcylation[edit | edit source]
O-GlcNAcylation shares more similarities to phosphoylation than other forms of protein glycosylation. The interplay between O-GlcNAc and O-phosphate is fact, that protein phosphatase 1 catalytic subunit (PP1c). The enzyme that removes O-phosphate also regulates OGT. This suggests that the enzyme can remove the phosphate group and attach the O-GlcNAc. The monosaccharide B-N-Acetyl-glucosamine (GlcNAc) attaches to serine/threonine residues via an O-linked glycosidic bond.
O-GlcNAcylation in Alzheimers[edit | edit source]
O-GlcNAcylation regulation has been proven to been an important factor in Alzheimer Disease patients as shown in the article done by Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities. (F.Liu, K.Iqbal, I.Grundke-Iqbal, G.W. Hart, and Cheng-Xin Gong) A microtubule associated protein, Tau, is "hyperphosphorylated and aggregated into a neurofibillary tangle in Alzheimer diseased brain".The protein tau is modified by O-GlcNAcylation through process described in previous paragraph. The phosphoryl site-specificity of tau is both regulated in vitro and in vivo. Experiments were ran to show that the inverse affect that occurs when levels of O-GlcNAcylation occurs.
Starving Mouse Experiment[edit | edit source]
This experiment tested the affects of decreased glucose leading to decrease in O-GlcNAcylation. The mice starved for 48h as a result decreasing brain supply of glucose. The environment of the mouse was in a cage with prevention of coprophagy. There is a reduction in cellular concentration of UDP-Glucose consequently the protein of O-GlcNAcylation. In the experiment a I(125) Western blot is ran with anti-GlcNAcyl antibodies.The tau phosphorylation increases suggesting an overall inverse regulation of tau phosphorylation by O-GlcNAcylation. The mouse's brain neurofilaments had an increased level of tau phosphorylation due to the decrease of tau O-GlcNAcylation in the brain. This is the result of deficient glucose uptake and utilization.
O-GlcNAc Transferase[edit | edit source]
The catalyst that attaches O-GlcNAc from the UDP-GlcNAc substrate to either a Serine or Threonine residue forming a β-glycosidic linkage is the O-GlcNAc transferase (OGT) (Hart). Mammals seem to have only one gene that catalysis the OGT. There is a dependent relationship between OGT and viability of the embryonic stem cells. In the absence O-GlcNacylation in the mammalian cells is lethal (Hart). The complex regularion of OGT has not been clearly defined. But, it has been discovered that OGT is O-GlcNAcylated and phosphorylated (Hart).
O-GlcNAcase[edit | edit source]
Nucleocytoplasmic β-N-acetylglucosaminidase (O-GlcNAcase) is the enzyme that removes O-GlcNAc from a protein (Hart).
References[edit | edit source]
1-2.^ Fei Liu*, Khalid Iqbal*, Inge Grundke-Iqbal*, Gerald W. Hart†, and Cheng-Xin Gong*‡ "O-GlcNAcylation regulates phosphorylation of tau: A mechanism involved in Alzheimer’s disease", *Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities; and †Department of Biological Chemistry, The Johns Hopkins University School of Medicine, 2004.
3.Hart, Gerald and Akimoto, Yoshihiro. Essentials of Glycobiology. 2009.