UIUC MCB 450 - mcb450 lecture 1 (42 pages)
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mcb450 lecture 1
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- Pages:
- 42
- School:
- University of Illinois at Urbana, Champaign
- Course:
- Mcb 450 - Introductory Biochemistry
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7 1 MCB 450 Lecture 7 O Glycoconjugates Proteoglycans Glycoproteins Glycan Synthesis Examples of Importance of Glycans 7 2 Glycoconjugates NOTE THE MODIFICATIONS WITH SUGARS ARE ALL ON EXTRACYTOPLASMIC PORTIONS OF PROTEINS AND LIPIDS PROTEIN 7 3 Definitions proteoglycan vs glycoprotein Proteoglycan Protein Uronic acid and or SO42 containing polysaccharide glycosaminoglycan Protein Glycosaminoglycan GAG Glycoprotein Protein Oligosaccharide not GAG covalently attached to peptide backbone 7 4 Glycosaminoglycan repeats 1 One sugar always GalNAc GlcNAc or GlcN often esterified with sulfate The other usually a uronic acid e g glucuronate GlcA GalNAc 7 5 Glycosaminoglycan repeats 2 Ionized carboxyl sulfate groups give molecule a ve charge Assume e x t e n d e d c o n f o r m a t i o n in solution Repeating disaccharide HYALURONIC ACID disaccharide repeats chain GlcA 50 000 GlcNAc CHONDROITIN SULFATE GlcA GalNAc KERATAN SULFATE GlcNAc Gal 20 60 25 7 6 Glycosaminoglycans in vertebrates HYALURONIC ACID CHONDROITIN SULFATE KERATAN SULFATE Highly hydrated Forms viscous solution is lubricant in joints also structural component of extracellular matrix of vertebrate cells In cartilage tendons ligaments aorta walls No uronic acid In cartilage bone nails horn hoofs 7 7 Cartilage proteoglycan Central filament of hyaluronate SUPRAMOLECULAR COMPLEX OF GLYCOSAMINOGLYCAN CHAINS PROTEINS Aggrecan Electron micrograph Mass 2 x 106 daltons 7 8 Cartilage proteoglycan Can spring back after being deformed so cartilage can cushion compressive forces HIGHLY HYDRATED 7 9 Definitions proteoglycan vs glycoprotein Proteoglycan Protein Uronic acid and or SO42 containing oligosaccharide glycosaminoglycan Protein Glycosaminoglycan Glycoprotein Protein Oligosaccharide not GAG covalently attached to peptide backbone Two major types of linkage to extracytoplasmic domains of proteins Occur with variations in all eukaryotes Examples in bacteria and archaea 7 10 Two major types of protein saccharide linkage in glycoproteins GlcNAc ADDED IN ER GalNAc ADDED IN Golgi 7 11 N linked glycoproteins HUGE VARIETY OF STRUCTURES CAN BE BUILT UP ON N LINKED GlcNAc DIFFERENT SUGARS BRANCHING 7 12 Asparagine linked N glycoproteins Glycan is added to proteins in lumen of rough ER The GlcNAc is actually added as part of a larger branched oligosaccharide a2 a6 a2 a3 a3 a2 a3 a2 a6 a2 b4 b4 a3 GlcNAc is the first sugar of a branched oligosaccharide GlcNAc Man Glc N glycosidic linkage involving Asn amide N 7 13 A great variety of N linked glycan structures can be generated in the Golgi a2 a6 to varying degrees a3 a2 a2 a3 a3 a2 a2 a6 Oligosacch trimmed back b4 b4 a3 a2 Different sugars added back a6 a3 b4 b4 a3 a2 in many linkages in Golgi Great structural diversity possible w different sugars different linkages between them and branching VaRiability between protein cell tissue type developmental stage organism important in intermolecular recognition information rich also for stability of some proteins NAc b3 b3 b3 b3 b3 b3 b3 b3 b3 b3 b3 b3 b6 b2 a 6 b2 a3 b4 b4 NAc Fucose 7 14 Complex glycans with sialic acid a k a N acetylneuraminic acid HO l ll H C C N l H OH OH OH O COO OH OH C 2 anomeric C 7 15 N linked glycans are important Help promote proper folding of freshly translated polypeptides in the lumen of the ER Can help stabilize protein conformation and protect against proteolysis Can help direct proteins to various membrane compartments e g lysosome in mammalian cells Complete inability to attach any N linked glycans is embryonically lethal in mice Even subtle underglycosylation of asparagines i e an Asn glycosylation site is missed is associated with human developmental defects Congenital Disorders of Glycosylation 7 16 O linked glycoproteins Mostly added to proteins in lumen of Golgi Single sugar transferred initially Subsequent ones added individually 7 17 Mucins are heavily O glycosylated major components of the mucus secreted by epithelial cells that line respiratory digestive urogenital tracts RICH IN Ser Thr Variable number tandem repeats 7 18 Mucins polymerize S S bonding The highly glycosylated domains of mucins dimerization are l o n g e x t e n d e d structures much less flexible than unglycosylated random coils Oligosaccharides contribute to stiffness by limiting rotation around peptide bonds charge repulsion among neighboring vely charged oligosacch groups O linked saccharides Long extended mucin molecules have a much greater solution volume than native proteins w little or no carbohydrate Mucins therefore form viscous solutions or gels that protect against infection by microbes that bind cell surface carbohydrates Perez Vilar J Hill R L 1999 J Biol Chem 274 31751 7 19 Contribution of carbohydrate to protein structure Protein covalently attached sugar chain N glycosidically linked Glycolipid anchors glycoprotein in membrane covalently attached sugars O glycosidically linked force protein into extended conformation 7 20 Energetics of glycosidic bond formation Formation of a glycosidic bond between two sugars Sugar Sugarn Sugarn 1 energetically unfavorable General strategy for making glycans use an activated sugar donor compounds in which anomeric carbon is activated by attachment to a nucleotide through a phosphodiester linkage e g UDP glucose a ed k lin 7 21 Different sugar nucleotides serve as sugar donors for different glycosyltransferases UDP Glc UDP GlcNAc UDP Gal GDP Man CMP sialic acid Luis Leloir Nobel Prize in Chemistry 1970 for his discovery of sugar nucleotides and their role in the biosynthesis of carbohydrates 7 22 Elongation of an a1 4 linked glycogen chain Glc added at non reducing end of chain UDP Nucleophilic displacement of UDP from C 1 of UDPGlc by C 4 OH of glucose at non reducing end of chain UDP excellent leaving group facilitates nucleophilic attack by activating the sugar carbon to which it is attached 7 23 Nucleophiles and leaving groups Nucleophile from nucleus loving or ve charge loving reactant that provides a pair of electrons to form a new covalent bond ENZYME TAKES THE H CH2OH H O O R a Leaving group accepts the electron pair from the nucleophile http www masterorganicchemistry com 2012 06 05 nucleophiles and electrophiles P P l N R O MAKES NUCLEOPHILIC ATTACK ACTIVATION BY UDP MAKES C 1 WANT TO ACCEPT ELECTRONS 7 24 Cellulose synthase catalyzes repeated Glc transfers extrudes growing cellulose chain through a transmembrane translocation domain GROWING CELLULOSE CHAIN TRANSLOCATION DOMAIN
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MCB 450: Exam 2
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