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Glycosyltransferases and Glycosidases

This text provides an overview of glycosyltransferases and glycosidases, including their catalytic mechanisms, structural characteristics, and roles in degradation pathways. It covers N-linked glycan synthesis, mechanisms of glycosyltransferases, and the diverse functions of glycosidases. Additionally, it includes information on the upcoming test and recommended reading materials.

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Glycosyltransferases and Glycosidases

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  1. Glycosyltransferases and Glycosidases • TEST Next Thursday--only individuals signed up for a letter grade • Problem Set Hand Out Today--Will go over in class Tuesday • Also Tuesday--1st clinical correlation (Lance presenting) - read papers BEFORE class & have 2 questions to hand in regarding the papers at the BEGINNING of class • Rearrangement of presenters • 2nd clinical correlation paper will be posted before the weekend • Refresher of Tuesday’s lecture

  2. GlcNAc Sialic acid Glucose Mannose Fucose Galactose newly synthesized N-linked glycan

  3. GlcNAcT-III ß4 GlcNAcT-II ß2 GlcNAcT-I ß2 GlcNAcT-V ß6 GlcNAcT-IV ß4 GlcNAcT-VI ß4 GlcNAc Sialic acid Glucose Mannose Fucose Galactose N-linked glycan synthesis: branching via GlcNAc addition branch = antennae

  4. Ser/Thr Mechanisms of Glycosyltransferases  Two main catalytic mechanisms can be envisioned for glycosyltransferases : inversion of the anomeric configuration (for instance UDP-glucose -> b-glucoside) or retention of the anomeric configuration (for instance UDP-glucose -> a-glucoside). glycosyltransferases (EC 2.4.x.y) Core 3 GlcNAcT b3 Ser/Thr UDP-GlcNAc UDP -most have divalent ion requirement and prefer neutral to acidic pH

  5. Mammals utilize only 9 (?) sugar nucleotide donors for glycosyltransferases: UDP-glucose, UDP-galactose, UDP-GlcNAc, UDP-GalNAc, UDP-xylose, UDP-glucuronic acid, GDP-mannose, GDP-fucose, and CMP-sialic acid. Other organisms have an extensive range of sugar nucleotide donors. Many glycosyltransferases in higher and lower organisms use lipid linked glycosyl donors where the lipid is frequently a terpenoid such as dolichol or polyprenol.

  6. STRUCTURE OF GLYCOSYLTRANSFERASES --vast majority fall into 3 types of folds -- CAZy ~ Carbohydrate-Active enZymes glycosyltransferases into over 86 families (structure, mechanism, substrate, acceptor)

  7. Type II Transmembrane Proteins --couple of exceptions in Man-6-P lysosomal targeting pathway

  8. Many Transferases are Expressed in Soluble Forms and/or Processed and Secreted-----Why?????

  9. Strict acceptor substrate requirements One-linkage-one-enzyme paradigm

  10. Exceptions to the Paradigm • Specific linkage can be product of several related gene products (2-8 sialytransferase family) • Rarely a glycosyltransferase can synthesize 2 different linkages (FucT-III 1-3 and 1-4) • Acceptor specificity modulation (GlcNAc to Glc for b4-galactosyltransferase by lactalbumin) • Glycosyltransferase that catalze two stepwise reactions (copolymerases of GAG chains)

  11. Glycosidases • Two Mechanisms--inverting/retention • Very Diverse in Primary and Tertiary Structure • Most localized to lysosome

  12. Retention of Configuration (EC 3.2.1.-) http://afmb.cnrs-mrs.fr/CAZY/index.html

  13. Inversion of Configuration

  14. Degradation of N-linked Proteins--both reducing & non-reducing end degradations

  15. Glycosphingolipid Degradation -terminal in lysosomes -some cleavages require SAPs (sphingolipid activator proteins)

  16. HA Degradation Non-reducing end degradation

  17. Degradation of Heparan Sulfate Non-reducing end degradation

  18. Keratan Sulfate Degradation Non-reducing end breakdown

  19. For the Test Next Week • Read Essentials and Go Over Presentations • Nomenclature (Three letter glycans, linkage, etc..) • Major Types of Glycosylation (N-linked, O-linked, Lipid linked, Proteoglycans)

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