Biochemistry - Unit III - Complex carb collagen

  1. Glycoproteins vs. Proteoglycans
    • both are Proteins conjugated to saccharides
    • Glycoprotein: protein >> carbohydrate; no repeat unit of saccharides
    • Proteoglycans: carb >> protein; polysaccharide w/ repeat units
  2. Proteoglycans are ________
    glycosaminoglycans and mucopolysaccharides
  3. Vast majority of glycoproteins and proteoglycans function in _______
    the extracellular matrix (ECM)
  4. Overview of glycoproteins:
    • carbohydrate chain short
    • no serial repeats
    • often branched, not linear
    • neutral or charged
    • variable amounts of carbs
    • wide range of functions
  5. Sample Glycoproteins
    • Structural molecule: Collagens
    • Lubricant: Mucins
    • Transport molecule: Transferrin, Ceruloplasmin
    • Immune: Immunoglobulins, Histocompatibility antigens, Blood group determinants (ABO)
    • Hormone: HCG, TSH
    • Enzymes: Alkaline phosphatase
    • Blood clotting: Fibrinogen
    • Cell surface recognition: Lectins
  6. There are two types of glycosidic links in glycoproteins:
    O-glycosidic link and N-glycosidic link
  7. O-glycosidic link
    • -OH + -OH -> -O- + H2O
    • between galactose or glucose and the hydroxyl group of hydroxylysine (collagen), OR
    • between N-acetyl galactosamine and serine or threonine (blood group substances and salivary mucins).
  8. N-glycosidic link
    • -OH + -NH2 -> -NH- + H2O
    • between N-acetylglucosamine and
    • asparagine. There are two types:
    • A. High mannose on the other side of the sugar
    • B. Complex. eg in addition to mannose they may contain N-acetylglucosamine, galactose, frucose and N-acetylneuraminic acid (sialic acid)
  9. Glycoproteins are synthesized on _______, then transported via ______ to the ____ for sorting
    • ribosomes attached to the RER
    • vesicles
    • Golgi
  10. saccharide units come from
    • UDP-glucuronic acid
    • UDP-N-acetylgalactosamine
    • GDPmannose
    • CMP-NANA (for Sialic acid)
    • All catalyzed by specific glycosyltransferases
  11. For synthesis of O-linked glycoproteins, addition is _____. For N-linked glycoproteins, the chain is _______ formed on ______ and then transferred to the protein.
    • direct
    • indirectly
    • dolichol pyrophosphate
  12. Degradation of the saccharide chains of glycoprotein is achieved by _____ enzymes present in _______. The enzymes act on ____ of the chains on a _______ basis.
    • hydrolytic
    • lysosomes
    • the ends
    • last-on-first-off
  13. Defect of glycoprotein degradation: _____
    cause
    symptoms
    • I-cell disease
    • deficiency in lysosomal enzymes, which do not aquire the targeting signal, mannose 6-phosphate.
    • Fibroblasts have dense inclusion bodies (I-cells)
    • lysosomes engorged with indigestible substrates
    • leading to death in infancy
  14. Proteoglycans are usually ______ components of the ________ (exception: ______); some have a ______ role, or ________ roles
    • structural
    • extracellular matrix
    • heparin (normally intracellular)
    • lubricant: bind large amounts of water
    • cell/cell signalling and adhesion
  15. The proteoglycans include
    • hyaluronic acid: GlcUA-β1,3-GlcNAc
    • heparin: GlcUA-α1,4-GlcN
    • chondroitin sulfate: GlcUA-β1,3-GalNAc
    • dermatan sulfate: IdUA-β1,3-GalNAc
    • heparan sulfate: GlcUA-α1,4-GlcN
    • keratan sulfate: Gal-β1,4-GlcNAc
  16. Proteoglycan monomers are _______ bound to _________ in association w/ _________ in a _______ arrangement.
    • non-covalently
    • a hyaluronic acid molecule
    • linker proteins
    • "bottle brush"
    • This is how the proteoglycan aggrecan forms.
  17. STRUCTURE OF PROTEOGLYCANS (GAGs)
    Proteoglycans usually consist of _____ _____ linked to ______, which typically consists of __________ with _______.
    • a core protein
    • covalently
    • a glycosaminoglycan
    • a long polysaccharide chain
    • a repeating disaccharide motif
  18. STRUCTURE OF PROTEOGLYCANS (GAGs)
    Proteoglycans are poly_____, which comes from the ______ and/or ______ groups. The ______ group is on either _______ or _______.
    • anionic
    • carboxyl
    • sulfate
    • carboxyl
    • D-glucuronic acid
    • its epimer L-iduronic acid
  19. STRUCTURE OF PROTEOGLYCANS (GAGs)
    The repeating disaccharide is ______ linked to a ____ residue on the protein through a __________ sequence.
    • glycosidically
    • serine
    • galactose-galactose-xylose-serine
  20. Synthesis of proteoglycans
    where
    The units in the saccharide chains are elongated in _______, donated from ___ derivatives. Last step is _____ of some _____ sugars.
    Defects:
    defects
    Golgi

    • alternating acidic/amino sugars
    • UDP
    • sulfation
    • amino

    • Defects in sulfation -> chondrodystrophy
    • genetic defects affect proper developement and maintenance of the skeletal system
  21. DEGRADATION OF PROTEOGLYCANS
    Some proteoglycans must be _______ first
    Degradation of the saccharide chains is achieved by ______ enzymes present in ______. The enzymes act on the ends of the chains on a ______ basis.
    • phagocytosized
    • hydrolytic
    • lysosomes
    • last-on-first-off
  22. MUCOPOLYSACCHARIDOSES (MPS)
    • Rare inborn errors in the degradation of glycosaminoglycans
    • mental retardation and/or structural defects
    • Type I-IV, VI, and VII
  23. MPS Type I
    • Hurler’s syndrome
    • a deficiency of alpha-L-iduronidase
    • Heparan sulfate and dermatan sulfate accumulate. growth and mental retardation with characteristic facial changes
    • 1:100,000
  24. MPS Type II
    • Hunters syndrome
    • deficiency of iduronate sulfatase
    • X-linked inheritance (male only)
    • 1:100,000; only affects males
    • delayed tooth eruption and possible mental retardation
  25. MPS Type III
    • Sanfilipo’s syndrome
    • deficiency of one of four degradative enzymes: three hydrolases and one N-acetyltransferase.
    • severe mental retardation and mild structural features
    • 1:70,000
  26. MPS Type IV
    • Morquio Syndrome
    • Deficiency of galactose-6-sulfatase or betagalactosidase
    • accumulation of keratan sulfate
    • normal intelligence but severe deformity
  27. Fibrous proteins — _______
    solubility
    stability
    half-life
    mechanical property
    • collagens and elastin
    • • Insoluble
    • • Stable
    • • Long biological half-life
    • • High tensile strength and contractibility, respectively, resulting from their unique structures
  28. These proteins function in ________
    the extracellular matrix (ECM)
  29. ______ are the most abundant proteins in the human body, comprising ____% of all proteins. Almost __ have been identified! Genetics:
    • Collagens
    • 25-30
    • 30 (different collagens)
    • MANY genes throughout the genome
  30. Types of collagens
    • Fibril forming (rope-like; hallmark collagen): I-III, ...
    • Network forming (mesh-like): IV, VII, ...
    • Fibril associated (linking fibrils): IX, XII, ...
  31. Collagen structure
    • All triple-helically structured
    • Each chain has the amino acid sequence Gly-X-Y
    • X is usually proline
    • Y is usually (hydroxy)-proline and (hydroxy)-lysine
    • Gly has small side chain, tolerate the structure
  32. Synthesis of collagen
    • prepro-a chain translated (RER)
    • signal sequence cleaved, forming pro-a chain
    • lys and pro residules are selectively hydroxylated
    • some hydroxylys are modified w/ glucose and/or galactose
    • three pro-a chains assemble: C-terminals form inter- and intra-chain disulfide bonds; tripple-helix forms
    • triple-helix pro-a secreted to ECM from golgi vacuole
    • extracellular enzyme procollagen peptidase cleaves off the terminals to form collagen
    • collagen self assemble (in a regularly staggered way) and later on cross link to form the fibrils
  33. Staggered packing of collagen
    • w/ negative staining, a banding pattern is generated
    • where there is a gap becomes darker; places w/o gap are lighter
  34. Hydroxylation of proline and lysine
    enzyme
    co-factor
    • prolyl hydroxylase and lysyl hydroxylase
    • Fe2+ and ascorbic acid
  35. Cross-linking between the collagens require
    enzyme _______ and co-factor ______
    • lysyl oxidase
    • Cu2+
  36. Deficiency of Cu2+ causes ________, and ______ results from too much Cu2+ accumulated in the body.
    • Menkes disease
    • Wilson's disease
  37. Scurvy
    • A non-genetically based collagen disorder
    • Directly results from ascorbic acid deficiency.
    • Frequently presents as easily bruised skin,bleeding gums, loosened teeth, “corkscrew hairs”,poor wound healing.
  38. Genetically-based collagen disorders:
    • Osteogenesis imperfecta (OI; “brittle bone disease” since bones easily fracture; four types)
    • Ehlers-Danlos syndrome
  39. Type I OI
    • splice site mutation resulting in mRNA not being made properly, premature stop codon, etc.
    • Usually there’s no mutation of glycine
    • Collagen that is formed is ok, there’s less of it though
    • least severe
    • presents in infancy or early childhood
  40. Type II-IV
    • Severity: II>III>IV>I
    • Most mutations are substitutions in the gene for COL1A1 or COL1A2 that result in the change from Gly to another amino acid with a bulky side chain in type I collagens, preventing correct folding into the triple helix
    • Fractures appear in utero for type II OI
    • Dentiogenesis imperfecta too
  41. Common symptom in eyes of OI patients
    • blue eye
    • the membranes in the eye so thin
    • seeing vessels underneath
    • not every patient has the symptom
  42. Ehlers-Danlos Syndrome (EDS):
    • A collection of defects
    • Stretchy skin and joint hypermobility are common
  43. Elastin: a ______ tissue protein
    -can be stretched to ________ in _____
    -found in ________
    -is an insoluble protein polymer synthesized from the precursor, ______
    -______ genetic type
    • rubbery connective
    • several times their normal length
    • any direction
    • the walls of large arteries, lungs, and elastic ligaments
    • tropoelastin
    • only one
  44. Elastin:
    -AAs composition: ________
    -is secreted by cells into ______
    -interacts with _____, mutations of which are responsible for ________
    • rich in glycine, proline and lysine, only has a little hydroxyproline and no hydroxylysine
    • extracellular space
    • fibrillin
    • Marfan syndrome
  45. Marfan syndrome is an autosomal _____ disorder that has been linked to the ___ gene on chromosome __.
    The disease affects many structures, including _____, and is characterized by _______, and is believed to have affected _____.
    • dominant
    • FBN1
    • 15
    • the skeleton,lungs, eyes, heart and blood vessels
    • unusually long limbs
    • Abraham Lincoln
  46. FBN1 encodes _____, which is essential for the formation of _____ found in connective tissue.
    • fibrillin
    • elastic fibers
  47. Without the structural support provided by fibrillin, many tissues are weakened, which can have severe consequences, for example, ________.
    ruptures in the walls of major arteries
  48. In elastin, some lysyl side chains are ______ by ______, forming ______, ___ of which and one unmodified lysyl side chain from the same or nearby polypeptide form a _____, which helps make elastin an _______.
    • oxidatively deaminated
    • lysyl oxidase, Cu2+ required
    • allysine residues
    • three
    • desmosine cross-link
    • extensively interconnected rubbery network
Author
akhan
ID
317749
Card Set
Biochemistry - Unit III - Complex carb collagen
Description
Biochemistry - Unit III - Complex carb, collagen
Updated