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 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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Page 1: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

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.

Page 2: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

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

Page 3: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

GluconeogenesisGluconeogenesis

6 ATP needed total

4 needed to overcome barrier of production of 2 mol of PEP

Page 4: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

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

Page 5: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

GluconeogenesisGluconeogenesis

No ATP needed sinceFru-1,6-bisP not high energy intermediate

Page 6: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

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)

Page 7: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

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

Page 8: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

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)

Page 9: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

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

Page 10: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

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

Page 11: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

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

Page 12: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

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]

Page 13: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of 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

Page 14: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

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

Page 15: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

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)

Page 16: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

The Oxidation Stage of PPP

Allosteric- NADPH

Loss of Carbon

Major reg step

Page 17: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

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

Page 18: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

The Non-Oxidation Stage of PPP

Convert 5C sugars into glycolytic intermediates

Can be used in glycolysis of Gluconeogenesis

Page 19: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

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

Page 20: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

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

Page 21: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

Glycogen MetabolismGlycogen Metabolism

Synthesis: Different enzymes for syn and degradation

Driven by PPi hydrolysis

Major regulatory step

Page 22: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

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

Page 23: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

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

Page 24: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

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

Page 25: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of 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

Page 26: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

Intracellular Regulation of Glycogen Metabolism by Interconvertible Enzymes:

Low [Glc]Simultaneouseffect

cAMP

AMP

phosphodiesterase

Low glc activate kinase and breakdown

Page 27: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of 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

Page 28: Chapter 12: Gluconeogenesis, Pentose Phosphate Pathway, & Glycogen Metabolism Glucose catabolism for the production of energy requires a source of Glc

High [Glc]