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COMPLEX CARBOHYDRATES

COMPLEX CARBOHYDRATES. Medical Biochemistry, Lecture 44. Lecture 44, What to Study:. - Know the structural components and differences between the glycoconjugate types - Know the general biosynthetic and catabolic strategies and molecules involved

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COMPLEX CARBOHYDRATES

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  1. COMPLEX CARBOHYDRATES Medical Biochemistry, Lecture 44

  2. Lecture 44, What to Study: - Know the structural components and differences between the glycoconjugate types - Know the general biosynthetic and catabolic strategies and molecules involved - Know the general function of each class of glycoconjugate - Know the general biochemical principles associated with diseases resulting from defects in the catabolic pathways of the glycoconjugates

  3. Lecture 44, Text Sources • Marks, Marks and Smith Chapter 30, primary source, Harper’s Ch 56 supersecondary source. Review Ch. 15,16 for sugar and lipid structural properties

  4. General Biosynthetic and Catabolic Themes for Glycoconjugates • An initial sugar residue is attached to a core protein or lipid, usually through a serine or asparagine residue. • Sugar residues are added sequentially from nucleotide diphosphate sugar donors by specific glycosyltransferases in the endoplasmic reticulum and golgi. • Glycosidases (sugar specific hydrolases) in the lysosome are responsible for degradation and catabolism • Almost all diseases related to glycoconjugates result from defective lysosomal glycosidase function

  5. UDP-Glucose Glycosyltranserase Reaction

  6. Sugar Nucleotide Conversions Figure 29.12a, MMS

  7. Sugar Nucleotide Conversions (cont.) Figure 29-12b, MMS

  8. Proteoglycans • Consist of a core protein, that is either transmembranous or secreted. Via serine residues, long, unbranched, repeating disaccharides of uronic acid (glucuronic or iduronic) and hexosamine (N-acetylglucosamine or N-acetylgalactosamine) are covalently attached to the protein on the (on the extracellular surface if membrane attached). • These residues are frequently sulfated following polymer formation. Thus they possess a large net negative charge, are highly hydrated, and occupy a large amount of space extracellularly (good for their role as lubricants and molecular sieves). They also provide a large surface area for binding of other matrix components and some growth factors.

  9. Proteoglycans (cont.) • Major components of the extracellular matrix, also in joint synovial fluid, vitreous humor of the eye, arterial walls, bone and cartilage

  10. The main classes of disaccharide repeats found in glycosaminoglycans attached to protein

  11. GAG-Carbohydrate Core Linkage to Protein Figure 30.3, MMS

  12. Sequential Biosynthetic Pathway for GAGs Figure 30.4, MMS

  13. Figure 30.8

  14. Glycoproteins There are three major classes of glycoproteins – those with carbohydrate chains that are N-linked (via an Asn), O-linked (via Ser or Thr) or linked via a glycosylphosphatidylinositol (GPI) lipid. These are primarily transmembranous proteins with the carbohydrates positioned extracellularly, and they are also secreted. • For N-linked, the carbohydrate core structure is synthesized processively on an activated lipid carrier, dolichol phosphate, and transferred co-translationally to membrane proteins synthesized in the endoplasmic reticulum.

  15. Three Main Types of Glycoprotein Structures GPI-linked O-linked GPI = glycosylphosphatidylinositol N-linked

  16. Also:targeting signal for removal of damaged or mis-folded proteins from the cell And: generally function to aid in the proper conformation and stability of membrane-associated proteins

  17. Dolichol-linked Donor Oligosaccharide Synthesis for N-linked Glycoproteins

  18. Figure 30.

  19. O-linked Glycoproteins (Mucins most common)

  20. Glycolipids • Carbohydrates are attached to ceramide (a sphingolipid: sphingosine plus fatty acid). Involved in cell-cell contact/interactions. The terminal carbohydrates can frequently be identical to carbohydrate chains on glycoproteins (Ex: blood group antigens) • Cerebrosides – glycolipids with one or two sugars (glucose and galactose); if sulfated, are termed sulfatides, found in high concentrations in the brain  • Gangliosides – glycolipids that contain sialic acid residues, longer and branched relative to cerebrosides

  21. Glycolipid Structural Components Sulfate donor

  22. R = protein or ceramide

  23. Bacteria sp. with binding proteins (lectins) for Lactosylceramide

  24. I-Cell Disease Summary

  25. Tay-Sachs Disease (Ex.) • The most common form of GM2 gangliosidosis; the GM2 ganglioside accumulates due to a defect in hexosaminidase A. Causes swelling and loss of ganglion cells in the cerebral cortex, proliferation of glial cells, and demyelination of peripheral nerves. • Rare defect in general population, but occurs 1 in every 3600 births in the U.S. Jewish population descended from Eastern Europe (ex: 1 in 28 Ashkenazi Jews carry the defect). • No effective treatments; genetic counseling and screening are the primary approaches used to minimize occurrence.

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