nov 23 2018.ppt [kompatibilitätsmodus] - limes-institut-bonn · figure 11-5 the anomeric...
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Gerhild van Echten-Deckert
Tel. 73 2703E-mail: [email protected]
Glycolysis
Biochemistry
Metabolism
22.11.2018 – 11.12.2018
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FMN and FAD are able to sequentially transfer one e-
Biochemistry. Voet & Voet
(Vit. B2)
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Lehninger Principles of Biochemistry. 5th Ed.Nelson & Cox
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Figure 11-4 Cyclization reactions for hexoses.
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hemiketal
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Figure 11-5 The anomeric monosaccharides -D-glucopyranose and -D-glucopyranose, drawn as both Haworth projections and ball-and-stick models.
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Non-enzymatic glucosylation of proteins
Reversible generation of a Schiff base
Irreversible Amadori-rearrangement
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Glycolysis - overview
Not an one-way road but a branched metabolic network!!!
Preparatory phase:
Payoff phase:
Berg, Tymoczko, Stryer: Biochemistry
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Energetics of glycolysis
Berg, Tymoczko, Stryer: Biochemistry
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Glycolytic steps: Phosphorylation catalysed by hexokinase
• ubiquitous• unspecific (catalyses phosphorylation of several hexoses)• co-substrate Mg-ATP-complex • KMGlc < 100 µM !!!
•Note: in the liver Glucokinase:KMGlc = 10 mM
Induced fit
„Isoenzyme“
Berg, Tymoczko, Stryer: Biochemistry
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Glycolytic steps: Isomerisation catalysed by glucose phosphate isomerase
Reaction mechanism:
General acid/base catalysis
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Glycolitic steps: Phosphorylation catalysed by phosphofructokinase (PFK)(rate-limiting step)
Allosteric modulators of PFK: ATP, AMP, Citrate, H+, F-2,6-BP (Activators, Inhibitors)
Regulation of F1,6BPase is mirror-inverted but opposite !!!
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PFK2: a bifunctional (tandem)-enzyme
Hormone regulation of the enzyme istissue-specific!!!
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cAMP-mediated hormonal regulation of PFK via F2,6BP
Berg, Tymoczko, Stryer: Biochemistry
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General mechanism of the activation of effector proteins associated with GPCRs
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Lodish et al. Molecular Biology of the Cell
Hormone-induced activation and inhibition of adenylyl cyclase in adipocytes
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PLC-
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Adenylyl cyclase generates the second messenger cAMPusing ATP as a substrate
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Protein kinase A (PKA)
Structure and activation of Protein kinase A by cAMP
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Berg, Tymoczko, Stryer: Biochemistry, 2002
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Termination/desensitization of the signal transduction process
3. Phosphodiesterase (PDE) catalyses hydrolysis of cAMP (calcium-dependent)4. GTP-hydrolysis
Berg, Tymoczko, Stryer: Biochemistry, 2002
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CREB links cAMP signals to transcription
Lodish et al. Molecular Biology of the Cell
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Glycolytic steps: Aldol cleavage catalysed by aldolase
Berg, Tymoczko, Stryer: Biochemistry
96%
4%
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Glyolytic steps: Isomerisation catalysed by triose phosphate isomerase (TIM)
-Barrel
•catalysis via an endiol-intermediate•Mech: general acid/base catalysis•K=[GAP]/[DHAP]=4,7x10-2
[DHAP]>> [GAP]•Enzyme works diffusion controlled•kcat/KM = 2x108 M-1s-1
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Glycolysis
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Glycolytic steps: Oxidative phosphorylation catalysed by GAP-DH
Two-step-reaction:
exergonicG0’= –43,1 kJ/mol
endergonicG0’= +49,4 kJ/mol
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Mechanism of the GAP-DH catalysed reaction
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Glycolytic steps: Phosphorylation catalysed by phosphoglycerate kinase
The phosphoglycerate kinase reaction generates the first ATP molecules:
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Glycolytic steps: Phosphoglycerate mutase catalyzes a phosphoryl group transfer from C3 to C2
• Rationale for this reaction in glycolysis: It repositions the phosphate to make PEP (high energy molecule) in the following reaction (enolase)
• Note the phospho-histidine intermediates- a bit of 2,3-BPG (Hb) is required to phosphorylate His (discovered by Zelda Rose)
• Nomenclature note: a “mutase” catalyzes migration of a functional group within a substrate
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Textbook of Biochemistry with Clinical Correlations, 7e edited by Thomas M. Devlin © 2011 John Wiley & Sons, Inc.
The reactions of 2,3‐bisphosphotglycerate (2,3‐BPG) shunt are catalyzed by the bifunctional enzyme, 2,3‐BPG mutase/phosphatase.
The 2,3‐BPG Shunt
2,3 BPG can prevent tissue hypoxia in conditions of low [O2].
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Glycolytic steps: Dehydration catalysed by enolase
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Glycolytic steps: phosphorylation catalysed by pyruvate kinase
• enzyme requires Mg2+ or Mn2+
• in mammals allosterically regulated:- Activators: F-1,6-BP, PEP- Inhibitors: ATP, Citrate, Ala
The pyruvate kinase reaction converts PEP to pyruvate, driving synthesis of ATP. Pyruvate kinase generates 2 ATP (debt was paid in the phosphoglycerate kinase reaction so both ATPs are a gain of energy).