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

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#10

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**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]

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