Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & & Glycogen Metabolism Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc. Polysaccharides are degraded and the resulting Glc is stored as glycogen in muscle and liver. glycogen PPP The pentose phosphate pathway (PPP) is the source of ribose (deoxyribose), and NADPH. Glc also syn from pyruvate (lactate and amino acids) Liver/kidney Glc needed in brain/muscle NADPH is required for biosynthesis.
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Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc.
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Low [Glc]: glucagon increases protein kinase A (activates Fru-2,6-bisP phosphatase) lowering [Fru-2,6-bisP].
Activate Glc synandLoss of glycolysis stim
Modulate one enzyme effect 2 opposing pathways Inhibit PFK-1 ….. stim Glc syn
Dec the net flux of a pathwayBut allows a point for reg flux
neg reg pyruvate kinase
Regulation of Phosphofructokinase-1Regulation of Phosphofructokinase-1
Citrate - feedback inhibitor - regulates supply of pyruvate - links Glycolysis and CAC
Fru-2,6-bisphosphate - strong activator - produced by PFK-2 when excess fru-6-phosphate - indirect means of substrate stimulation or feed forward activation
ATP - product of pathway - allosteric inhibitor
AMP - allosteric activator - relieves inhibition by ATP
Large oligomeric enzyme bacteria/mammals - tetramer yeast - octamer
Regulation of Pyruvate KinaseRegulation of Pyruvate Kinase
High blood [Glc]
Allosteric (feed-forward) activation Fructose-1,6-bisphosphate -allosterically activates -produced in step three -links control steps together
+ F 1,6 BP
Inactivation by covalent modification -blood [Glc] drops, glucagon released -liver protein kinase A (PKA) turned on -PKA phosphorylates pyruvate kinase
Allosteric inhibition by ATP -product of pathway and CAC
Low blood [Glc]
Regulation of Phosphofructokinase-1Regulation of Phosphofructokinase-1Produced in pancreas in response to low [Glc]
Dual activities of PFK-2 regsteady-state conc of Fru-2,6-bisP
Glycogen MetabolismGlycogen MetabolismGlycogen is the storage form of Glc found in muscles and liver. (Plants: stored as Starch)
Glycogen complex: single glycogenin molecule (Tyr -OH) and >50,000 glucose residues
Stores of Glc in time of plenty and supplies it in times of need
Muscle: fuel for contraction
Liver: produce Glc…released to Bldstream to other tissues
All regulated by hormones: Glucagon, Epinephrin and Insulin
Glycogen MetabolismGlycogen Metabolism
Synthesis: Different enzymes for syn and degradation
Driven by PPi hydrolysis
Major regulatory step
UDP-Glc synthases in protists, animals, and fungi.ADP-Glc synthase in plants.Primer of 4 to 8 Glc on a Tyr (-OH) of glycogenin. 1st Glc from UDP-Glc via Glc transferase. Remaining Glc’s tranferred by glycogenin.Amylo-(1,4 1,6)-transglycolase catalyzes the branch point. (Alpha 1-6 link)
(hormonally regulated)
Pre-existingGlycogenin primer
Key regulationby phosphorylation
Degradation:
Phosphorolysis rxn. Generates phosph-sugar not free glc
Two subunits, two catalytic sites, allosteric sites.AMP- activator; ATP & Glc-6-P – inhibitor.
Phosphorylation: active (phosphorylase a).Dephosphorylated: less active (phosphorylase b).
Primary regulation
Reg by ATP and G-6-P
Primarily by phosphorylation
phosphorolytic
hydrolytic
Branching inc speed ofsyn and degradation
Sequential removal of GlcFrom non-reducing end
Stops 4 Glc from branch pt
Energy yield from glycogenHigher than from glc
Regulation of Glycogen MetabolismRegulation of Glycogen MetabolismHormonal Regulation:
Via cAMP
Via PIP3
Fed statefasting
Insulin: secreted by pancreas when Glc high inc rate of transport into cell and glycogen syn
Glucagon: secreted when Glc low
Epi: released by adrenal gland in response to neural signal (flight or flight)
Sudden energy response
GLUT4
Decreaseglycolysis
phosphatase
Intracellular Regulation of Glycogen Metabolism by Interconvertible Enzymes:
Low [Glc]Simultaneouseffect
cAMP
AMP
phosphodiesterase
Low glc activate kinase and breakdown
Regulation of Phosphofructokinase-1Regulation of Phosphofructokinase-1Produced in pancreas in response to low [Glc]
Dual activities of PFK-2 regsteady-state conc of Fru-2,6-bisP