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Section 6: Carbohydrate Metabolism

Section 6: Carbohydrate Metabolism. 2. Glycosides; polysaccharides; glycogen metabolism. 10/18/05. Reduction. carbohydrates with a free carbonyl group are also reducible, i.e., they are also oxidizing agents products called sugar alcohols like sugars, have a sweet taste

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Section 6: Carbohydrate Metabolism

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  1. Section 6: Carbohydrate Metabolism 2. Glycosides; polysaccharides; glycogen metabolism 10/18/05

  2. Reduction • carbohydrates with a free carbonyl group are also reducible, i.e., they are also oxidizing agents • products called sugar alcohols • like sugars, have a sweet taste • alternative sweeteners • xylitol: a sugar alcoholof 5-C sugar xylose • mild anticarieseffect 1

  3. Glycosides • derivatives of monosaccharides & alcohols or amines • unlike oxidation, reduction & glycation, reactant is a or b form • known as O-glycosides (e.g., polysaccharides) or N-glycosides (e.g., nucleotides) • linkage: – to the anomeric carbon – termed a glycosidic bond 2

  4. Glycosides • glycosides are not in rapid-equilibrium with an open-chain form or the other anomeric (a/b) form • by replacing the H atom of the C1 OH • ring opening is prevented • anomeric form is fixed • oxidation, reduction, glycation reactions prevented 3

  5. Disaccharides • monosaccharides connected by O-glycosidic bond ( ) • maltose • from hydrolysis of starch (polyglucose) • reducing end: • underivatized anomeric C(bonded to –OH or =O) • sugar has a, b,open-chain forms 4

  6. Disaccharides: lactose • also reducing sugar • many adults lactose intolerant • intestinal lactase absent or deficient • milk sugar • contains galactose epimer of glc(configurations differ at C4) 5

  7. Sucrose • anomeric C of both monosaccharides linked in glycosidic bond • nonreducing • high group-transfer potential for each glycosyl unit G'º hydrolysis = –7 kcal/mol (–4 kcal/mol for maltose & lactose) • activated precursor* of polysaccharides of dental plaque • building blocks don't have to be activated prior to transfer • polymerization catalyzed by bacteria-secreted enzymes 6 * see slide 10

  8. Glucose transport into cells • glc size & polarity cause simple diffusion across lipid bilayer of cell membranes to be very slow • transport by facilitated diffusion (carrier mediated) Model of carrier-mediated diffusion: from Hypercell binding site Vtransport [glc] KM 7

  9. Glucose transport proteins • GLUcose Transport proteins (GLUT1-5) • GLUT1 & 3 all cells“basal” uptake; low KM (KM < [glc]) • GLUT2liverhigh KM (KM > [glc] range, so uptake rate  [glc]) • GLUT4muscle, adiposepresence of GLUT4 in membrane is insulin-dependent • sugar transport in bacteria • several monosaccharides, disaccharides, sugar alcohols transported into cell, then phosphorylated by PEP (phosphoenolpyruvate) 8

  10. Phosphorylation of glucose 1 • after entering eucaryotic cells, glc (& other sugars) are phosphorylated • ATP phosphoryl group donor • usually first step in monosaccharide metabolism • sugars commonly metabolized in phosphorylated form • traps the sugar inside cell • catalyzed by phosphotransferases (aka kinases) • DG'º = –4 kcal/mol (effectively irreversible) glycolysispentose phosphate pathway glycogenesis 9

  11. Biopolymers: general features polymer monomer bond linking activated(repeating unit) monomers precursor* nucleic acid nucleotide phosphodiester nucleoside triphosphate protein amino acid peptide aminoacyl-tRNA polysaccharide monosacch glycosidic glycogen glucose " UDP-glucose amylose " " " dextran " " sucrose mutan " " " levan fructose " " * – can transfer part of itself exergonically (with –DG') – have high group-transfer potential – use allows bypass of endergonic reactions (+DG') 10

  12. Polysaccharides (glycans) glycan monomer main linkage branch linkage glucans glucose dextran a1,6 a1,2; a1,3 mutan a1,3 a1,4; a1,6 glycogen a1,4 a1,6 cellulose b1,4 none fructans fructose levan b2,6 b2,1 unbranched branched polymers 11

  13. Glycogen • average mol. wt.: 106 (~5000 glucosyl units) • function: storage form of glc units • location: cytosol (as granules) • muscle 250 g; role: supply intracellular glc units • liver 100 g; role: supply blood glc • branched structure • ~1 branch/10 glc units • more soluble • more sites for adding/removing glc units 12

  14. Glycogen synthesis: glycogenesis 2 glc 6-P® catabolism via glycolysis or pentose phosphate glycogenesis glycogenolysispathway glycogen • glc 1-P formation • preliminary to activating C1 • reversible; same reaction used in glycogenolysis 13

  15. Glycogenesis: UDP-glucose formation 3 • activated precursor of glycogen glc units • glc unit transferable with – DG' • UDP serves as a carrier of glycosyl units which are to be linked to other molecules • PPi hydrolysis makes reaction irreversible ¯H2O2 Pi 14

  16. Glycogenesis: glc unit addition to glycogen 4 glc unit added at a nonreducing end of a pre-existing glycogen 15

  17. Glycogenolysis 5 • glc units removed 1 at a time by phosphorolysis • bond cleavage with Pi (hydrolysis: with H2O) • resulting glc unit • already phosphorylated • source of ATPvia glycolysis • trapped in cell(most tissues;liver anexception) 16

  18. Glycogenolysis: fate of glucosyl units 2 • glc 1-P  glc 6-P (reaction ) • in muscle, glc 6-P catabolized to produce ATP via glycolysis (next lecture: L3) • in liver, glc 6-P converted to glc byglc 6-P phosphatase (absent in muscle) • glc to blood via facilitated diffusion carrier: GLUT2 • result: blood [glc] maintained despite rapid use by brain • liver also converts pyruvate, lactate, most amino acids to glc (gluconeogenesis: L4) glc 6-P + H2O¯glc + Pi 17

  19. Stoichiometries 2 4 3 5 2 • glycogenesis: glc 6-P →glc 1-P →UDP-glc → glycogen (reactions ) (glc)n + glc 6-P + UTP + H2O → UDP + (glc)n+1 + 2 Pieq1 • glycogenolysis: glycogen → glc 1-P →glc 6-P (reactions )(glc)n+1 + Pi → (glc)n + glc 6-P eq2 net: UTP + H2O →UDP + Pi (sum of eqs 1 & 2) • hydrolysis of 1 UTP is the cost of storing 1 glc unit • if both processes occur without control, result would be large waste of high-energy phosphates (futile cycling) 18

  20. Control: general factors (see S4L4sl 1-2) allosteric control of enzyme activity • noncovalent binding of effector (modulator: Mi & Ma) (less active) Mi·ET↔ ET ↔ ER↔ Ma·ER(more active) • covalent modification, usually by phosphorylation of a specific OH side chain (ser, thr or tyr side chains) on E • phosphorylation reaction:E + ATP E-P + ADP (catalyst: a protein kinase) • result: activity of E changed (increased/decreased) • reversed by dephosphorylation • dephosphorylation reaction:E-P + H2O E + Pi (catalyst: a protein phosphatase) • result:E restored to initial state 19

  21. Control of glycogen metabolism • glycogenesis: since role is fuel storage • activated when glc units plentiful • inhibited when glc units scarce/in demand • control enzyme: glycogen synthase • glycogenolysis: since role is supplying glc units • inhibited when glc units plentiful • activated when glc units in demand • control enzyme: glycogen phosphorylase • control coordinated & reciprocal (when 1 turned on, other turned off) 20

  22. Activation & inhibition of the control enzymes • glycogen synthasenoncovalent covalent activation: glc 6-P dephosphorylation inhibition: phosphorylation • glycogen phosphorylase noncovalent covalent activation: AMP, ADP phosphorylation inhibition: ATP, glc, glc 6-P dephosphorylation • hormones coordinate control among cells (Section 9) • epinephrine & glucagon stimulate above phosphorylations • insulin stimulates above dephosphorylations 21

  23. Overview of bacterial carbohydrate metabolism • oral bacteria among organisms that use carbs • fuel, including fuel storage • adhesive scaffolding • carbon source fructans glucans glc sucrose frc phosphorylgroup donor:PEP glc 6-P sucrose 6-P frc 1-P glycolysis, etc. (next lecture) 22

  24. Dental plaque polysaccharides • provide for oral microorganisms: • stored fuel • adhesive surface • anaerobic (cariogenic) environment • synthesis • sucrose main precursor • already activated (DG'° hydrolysis = –7 kcal/mol) • minimal input of energy by bacteria • extracellular • amount that can be made not limited by bacteria's intracellular volume • product provides meshwork for bacterial adhesion 23

  25. Plaque polysaccharide synthesis dextransucrase* • catalyzed by bacteria-secreted enzymes called glycosyl transferases (sucrases) G-F + G-G-G-G~ F + G-G-G-G-G~ fructose dextran (G)n+1 sucrose dextran (G)n mutan sucrase* G-F + G-G-G-G~ F + G-G-G-G-G~ fructose mutan (G)n+1 sucrose mutan (G)n levan sucrase* G-F + F-F-F-F~ G + F-F-F-F-F~ glucose levan (F)n+1 sucrose levan (F)n • anticaries vaccine targeting a glucosyl transferase is being developed *aka glucosyl (or fructosyl) transferases 24

  26. Next:3. Glycolysis

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