chapter 12: gluconeogenesis, pentose phosphate pathway, & glycogen metabolism glucose catabolism...
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Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen MetabolismGlycogen 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.
PathwayPathway
Gluconeogenesis - glycolysis going backwards
- 3 places differ- control points in glycolysis - 4 new enzymes (eukaryotes)
- importance of near equilibrium reactions
- ATP energy, NADH reducing equivalents consumed
#3
#10
#1
**Gluconeogenesis Net Reaction:**2 Pyruvate + 4 ATP + 2 GTP + 2 NADH + 2 H+ + 6 H2O Glucose + 4 ADP + 2 GDP+ 2 NAD+ + 6 Pi
Glycolysis Net Reaction:Glucose + 2 ADP + 2 NAD+ + 2 Pi 2 Pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O
GluconeogenesisGluconeogenesis
6 ATP needed total
4 needed to overcome barrier of production of 2 mol of PEP
Gluconeogenesis: The Irreversible StepsGluconeogenesis: The Irreversible Steps
Pyruvate PEP; reversing the pyruvate kinase step of glycolysis.
4 subunitsBiotin
Allosteric+ acetyl CoA
Transcriptional regulation
+ glucagon (fasting)- Insulin (fed state)
Indicates CACBacked-up
No allosteric reg
Hormonal induction
GluconeogenesisGluconeogenesis
No ATP needed sinceFru-1,6-bisP not high energy intermediate
Fru-1,6-biP Fru-6-P; reversing the PFK-1 step of glycolysis.
Large – G and irreversible
Allosteric modulation- AMP- 2,6-Fru bisP (opposing effect in glycolysis)
Glc-6 Glc; reversing the Glc hexokinase step of glycolysis.
IrreversibleAllosteric modulation - AMP
Enzyme found only in liver, kidneys, small intestine.Bound to ER lumen…leads to release of Glc into bldstream
Most cases Glc-6-P is end product---used in other pathways (glycogen syn)
Get to brainAnd muscle
Gluconeogenesis: PrecursorsGluconeogenesis: PrecursorsMajor precurser in mammals: Lactate and Amino Acids,
Lactate
Cori cycle
Amino Acids
Lactate to pyruvate in liver
Since the body does not transfer pyruvate
Pyruvate in tissues must go to liverFirst converted to alanine
Major source of C for Glc syn during fasting
Amino arise from muscle protein breakdownActive muscle-- lactate
Provide temporary and readily available supply of Glc to muscle (exercise)
Gluconeogenesis -glucose biosynthesis found in all organisms
Some tissues require glucose -brain, muscles
After 16-24 hrs, glucose and glycogen reserves depleted
Some tissues synthesis glucose from non-carbohydrate precursor -liver, kidney -lactate, alanine
Easiest to start with pyruvate -converted from lactate or a.a.
GluconeogenesisGluconeogenesis
Gluconeogenesis: RegulationGluconeogenesis: Regulation
Substrate Cycle
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
Dec F-2,6-bisPPFK-1 less active…..dec glycolysis
Increased glycolysisFruc-6P inc….inc F-2,6-bisPStim PFK-1
Activate Protein Kinase A
Dec glycolysis Inc glc syn
Stimulate glycogen breakdown Figure 11-17
PFK-1 and pyruvate kinase
glycogen PPP
The pentose phosphate pathway (PPP) is the source of ribose (deoxyribose), and NADPH.
NADPH is required for biosynthesis.
Pentose Phosphate PathwayPentose Phosphate Pathway Shunt
Pentose Phosphate PathwayPentose Phosphate Pathway
Synthesize 3 pentose phosphates
Ribulose 5-P
Xylulose 5-P
Ribose 5-P (DNA/RNA)
And NADPH
Or
NADPH and glycolytic intermediates
Rapidly dividing cells need lots of NADPH and DNA
High PPP activity
Shunt
(for the reduction of RNA to DNA)
The Oxidation Stage of PPP
Allosteric- NADPH
Loss of Carbon
Major reg step
The Non-Oxidation Stage of PPP
All equilibruim rxns
When cells need lot of NADPH and nucleotides - ribulose 5-phosphate ribose 5-phosphate - end of pathway
The Non-Oxidation Stage of PPP
Convert 5C sugars into glycolytic intermediates
Can be used in glycolysis of Gluconeogenesis
6 Glc-6-P + 12 NADP+ 5 Glc-6-P + 12 NADPH + 6 CO2 + Pi
Thru PPP
Allow sub regenerationvia PPP and glyconeogenesis
3 Glc-6-P + 6 NADP+ + 3 H2O 2 Fru-6-P + G3P + 6 NADPH + 3 CO2
Pentose Phosphate PathwayPentose Phosphate Pathway
6 ribulose 5-P 5 Glc 5-P
Can be metabolized in Glycolysis or Glcneogenesis
Recycle 6C sugar
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
Dec F-2,6-bisPPFK-1 less active…..dec glycolysis
Increased glycolysisFruc-6P inc….inc F-2,6-bisPStim PFK-1
Activate Protein Kinase A
Dec glycolysis Inc glc syn
Stimulate glycogen breakdown Figure 11-17
PFK-1 and pyruvate kinase
High [Glc]