Glycolysis
Glycolysis The conversion of glucose to pyruvate to yield 2ATP molecules 10 enzymatic steps Chemical interconversion steps Mechanisms of enzyme conversion and intermediates Energetics of conversions Mechanisms controlling the Flux of metabolites through the pathway
Pathway overview Glucose + 2NAD + + 2ADP +2Pi 2NAD + 2pyruvate + 2ATP + 2 2 + 4 +
exokinase C 2 Glucose Mg ++ C 2 P 3 2- + ATP + ADP + + Glucose-6-phosphate
Covalent modification-protein phosphorylation
Phosphoglucose Isomerase C 2 P 3 2- -2 3 PC 2 C 2
Phosphofructokinase -2 3 PC 2 C 2 Mg ++ -2 3 PC 2 C 2 P 3-2 + ATP + ADP Fructose-6-P 4 Fructose-1,6-bisphosphate
C 2 P 3-2 C Aldolase -2 C 2 P 3 C C Dihydroxyacetone phosphate (DAP) C C + C C 2 P 3-2 Fructose -1,6-bisphosphate (FBP) C C 2 P 3-2 Glyceraldehyde-3- phosphate (GAP) Aldol cleavage (retro aldol condensation)
Front half of glycolysis
Glyceraldehyde-3-phosphate dehydrogenase The first high-energy intermediate P 3 2- C + NAD + + Pi C + NAD C 2 P 3 2- C 2 P 3 2- Uses inorganic phosphate to create 1,3 bisphosphoglycerate
Phosphoglycerate Kinase: First ATP generation step P 3 2- - C + ADP C + ATP C 2 P 3 2- C 2 P 3 2-1,3 BPG 3 PG
Phosphoglycerate mutase - - C C P 3-2 3 PG C 2 P 3 2- C - P 3-2 C 2 2PG C 2 P 3 2-2,3 BPG
Enolase generation of a second high energy intermediate - - C P 3-2 C P 3-2 + 2 C 2 Phosphoglycerate Phosphoenol pyruvate
Pyruvate kinase: Second ATP generation step
The second half of glycolysis
The metabolic fate of pyruvate
The Citric acid cycle
The Citric acid cycle verall reaction 3NAD+ + FAD + GDP + Pi + acetyl-coa 3NAD + FAD + GTP + CoA + 2C 2
verview
The citric acid cycle enzymes are found in the matrix of the mitochondria Substrates have to flow across the outer and inner parts of the mitochondria
The five reactions of the pyruvate dehydrogenase multi enzyme complex
Citrate Synthase C 2 C + 3 C C SCoA C 2 C C 2
Induced fit needs binding of oxaloacetate before Acetyl CoA can bind. CoAS C C 3 Acetyl-CoA CoAS C C 2 Proposed intermediate CoAS C 2 C C 3 CoAS C 2 Acetonly CoA (ground-state analog) Carboxymethyl-CoA (transition state analog)
Aconitase C 2 C C 2 C 2 C C C 2 C C Citrate Cis-Aconitate Isocitrate The double bond is placed on the Pro-R arm
NAD + - Dependent Isocitrate dehydrogenase NAD + NAD
a-ketoglutarate dehydrogenase NAD + C 2 2 C C 2 C 2 C NAD C 2 CoAS
Succinyl-CoA Synthetase or succinate thiokinase
Succinate dehydrogenase C 2 C 2 C C + 2e - + 2 + The FAD on the enzyme itself is reduced
Succinate dehydrogenase is the only membrane bound enzyme in the citrate cycle Succ dh--fad 2 + Ubiquinone or Coenzyme Q 3 C 3 C C 3 C 3 C 2 n xidized form n = 6-10 3 C C 3 3 C C 3 C 2 n Reduced form
Fumarase
Malate dehydrogenase 2 C NAD 2 C C C NAD +
Citric acid cycle intermediates are always in flux
Fig 19-2 Mitochondrion Double membrane, with inner membrane very impermeable TCA occurs in the matrix ETC in the inner membrane
Chemiosmotic Mechanism Electron transport chain sets up an + gradient (proton motive force). Energy of the pmf is harnessed to make ATP.
Electron transport chain
Gluconeogenesis
verview of Glucose Metabolism
Gluconeogenesis
Pyruvate is converted to oxaloacetate before being changed to Phosphoenolpyruvate
The Core Cycle
The glyoxylate pathway
Phosphopentose pathway 3G-6-P + 6NADP + + 3 2 6NADP + 6+ 3C 2 + 2F6P + GAP
The pathway consists of three parts 1. xidative reactions: G-6-P + 6NADP + + 3 2 6NADP + 3C 2 + 3Ribulose-5-P 4 2. Isomerization and epimerization reactions: 3Ribulose-5-P 4 Ribose -5-P 4 + 2Xylulose-5-P 4 3. A series of C-C bond cleavage and formations: Ribose-5-P 4 + 2Xyluose-5-P 4 2F-6-P + GAP
Glucose-6 phosphate dehydrogenase
Phosphogluconate dehydrogenase
Ribulose-5-P 4 isomerase
Glycogen Storage Glycogen is a D-glucose polymer a(1 4) linkages a(1 6) linked branches every 8-14 residues
Glycogen Breakdown or Glycogenolysis Three steps Glycogen phosphorylase Glycogen + Pi <-> glycogen + G1P (n residues) (n-1 residues) Glycogen debranching Phosphofructomutase
Glycogen Phosphorylase Requires Pyridoxal-5 -phosphate PLP
Glycogen Debranching Enzyme
Phosphofructomutase
Glycogen Syntheisis
UDP-glucose Pyrophorylase
Glycogen Synthase