COMPLEX CARBOHYDRATES

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COMPLEX CARBOHYDRATES

• Medical Biochemistry, Lecture 44

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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

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Lecture 44, Text Sources

• Marks, Marks and Smith Chapter 30, primary
  source, Harpers Ch 56 supersecondary source.
  Review Ch. 15,16 for sugar and lipid structural
  properties

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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

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UDP-Glucose Glycosyltranserase Reaction
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Sugar Nucleotide Conversions
Figure 29.12a, MMS
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Sugar Nucleotide Conversions (cont.)
Figure 29-12b, MMS
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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.

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Proteoglycans (cont.)

• Major components of the extracellular matrix,
  also in joint synovial fluid, vitreous humor of
  the eye, arterial walls, bone and cartilage

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The main classes of disaccharide repeats found in
glycosaminoglycans attached to protein
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GAG-Carbohydrate Core Linkage
to Protein
Figure 30.3, MMS
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Sequential Biosynthetic Pathway for GAGs
Figure 30.4, MMS
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Figure 30.8
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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 glycosylphosphatidylinosit
  ol (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.

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Three Main Types of Glycoprotein Structures
GPI-linked
O-linked
GPI glycosylphosphatidylinositol
N-linked
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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
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Dolichol-linked Donor Oligosaccharide Synthesis
for N-linked Glycoproteins
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Figure 30.
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O-linked Glycoproteins (Mucins most common)
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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

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Glycolipid Structural Components
Sulfate donor
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R protein or ceramide
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Bacteria sp. with binding proteins (lectins) for
Lactosylceramide
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I-Cell Disease Summary
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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.