8 gluconeogenesis, ppp, glycogen

7/24/2019 8 Gluconeogenesis, PPP, Glycogen

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(PEP)

- Synthesis of glucose from non-carbohydrateprecursors

- Overall conversion: 2 pyruvateglucose- Hydrolysis of 6 ATPs- Not a simple reversal of glycolysis

Gluconeogenesis

In glycolysis, three reactions are irreversible:(1) Hexokinase(2) Phosphofructokinase(3) Pyruvate kinase


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Gluconeogenesis begins with pyruvate

Pyruvate carboxylase- Carboxylates pyruvate to oxaloacetate (OAA)- Requires ATP

CO2+ H2O


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Phosphoenolpyruvate carboxykinase- Decarboxylation of oxaloacetate (OAA)

Fructose 1,6-bisphosphate

5 stepsReversal of

glycolysis


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Fructose bisphosphatase- Hydrolyzes the phosphoester at C-1

Glucose 6-phosphate

Reversal of

glycolysis


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Glucose 6-phosphatase- Hydrolyzes the phosphoester at C-6

-Most mammalian tissues use glucose 6-phosphate to make storagecarbohydrate-Liver is one exception: it maintains blood glucose levels and releasesfree glucose into the blood-Other tissues that make glucose: kidney and small intestine


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Precursors for gluconeogenesis

Lactate Pyruvate Glucose

lactatedehydrogenase gluconeogenesis

NAD+ NADH + H+

1. Lactate

In liver:


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2. Amino acids


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3. Glycerol


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Regulation of gluconeogenesis

-Glucose synthesis is expensive: 6ATPs-Reciprocal regulation with glycolysis


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Role of fructose 2,6-bisphosphate in regulating glycolysisand gluconeogenesis:

FBPase/PFK-2- a bifunctional enzyme


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Effect of glucagon on gluconeogenesis

PKA = protein kinase

FBPase/PFK-2- a bifunctional enzyme


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Pentose Phosphate Pathway (PPP)

-An alternative oxidation pathway for glucose 6-P-Generation of NADPH as reducing power-Active in rapidly dividing cells, tissues with active biosynthesis

-Generation of ribose 5-phosphates-Protection against oxidative damages

+

+

G6PD


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Oxidative Phase

Production of pentose phosphates and NADPH Irreversible with large and negative standard free-energy changes Overall reaction:

Glucose-6-P + 2NADP+ + H2O ribose-5-phosphate + CO2+ 2NADPH + 2H+

6-Phosphogluconolactone6-Phosphogluconate


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Non-oxidative Phase

Operating when pentose phosphates are not used for nucleotide biosynthesis Recycling of pentose phosphates to glucose-6-P

1. Isomerization of ribulose 5-phosphate


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Reversible reactions Six 5-C sugar-P are converted to five 6-C sugar-P Allows continued oxidation of glucose-6-P with NADPHproduction Involves transketolase and transaldolase reactions

2. Rearrangement of carbon skeletons


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Summary of carbon flow in the pentose phosphate pathway

(a) (b) (c)

Fructose 6-P

Glucose 6-P

Glyceraldehyde 3-P x 2

Gluconeogenesis

6 G-6-P 6 R-5-P4 F-6-P

+2 Gly-3-P

5 G-6-P


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Regulation of Pentose Phosphate Pathway (PPP)

Glucose-6-P is partitioned between glycolysis and PPP

PPP activities depend on [NADP+] and [NADPH]

Glucose 6-phosphate

dehydrogenase

(G6PD)


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Glycogen Metabolism

Glycogen- readily mobilized storage form of glucose

- branched polymer of glucose residues- liver and muscle: major storage sites- in liver: serving as a buffer to maintain blood glucose levels- in muscles: meeting energy needs

(branch point)

Amylose: linear chain with -1,4 linkage


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Glycogen degradation

- Glycogen can be broken down into large amounts of glucosein a short period of time

- Glucose is released by 2 enzymes

(1) Glycogen phosphorylase

- Releases the terminal glucose as G-1-P

- Cannot cleave beyond a point 4 glucoseresidues upstream of an -1, 6 branchpoint

- Four residues are left on each branch


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(2) Debranching enzyme

Two enzyme activities

a. 4--Glucotransferase activity- Transfers 3 terminal -1, 4-linkedresidues from a branch to the end ofthe parent chain

b. Amylo-1, 6-glucosidase activity- Cleaves the remaining -1, 6-linkedglucose.


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Fates of glucose released from glycogen breakdown


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Glycogen synthesis begins with Glucose-6-P:

1. Phosphoglucomutase

Glucose-6-P Glucose-1-P

-Glycogen is synthesized by reactions separate from glycogen degradation

Glycogen synthesis


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UDP-glucose pyrophosphorylase

Glucose-1-P + UTP UDP-glucose + PPi

UDP l i h dd h l h i b h i


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UDP-glucose can either add to the amylose chain or start a new branch point:

1. Glycogen synthase - creation of -1,4 linkage

UDP + ATP UTP + ADP


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- solubility of glycogen is increased by branching

- branching increase the rate of both glycogen synthesis and degradation(due to more terminal residues)

2. Amylo-(1,4 1,6)-transglycosylase- Branching enzyme- Generation of -1,6 branch


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Initiation of glycogen synthesis

Glycogenin: both a primer and an enzyme

Chain

extension

Glycogensynthase


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Structure of the glycogen molecule

Mature glycogen molecule:12 tiers, ~55 K glucose residuesMW ~ 107, 21 mm diameter


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Regulation of glycogen metabolism

- Reciprocal regulation of glycogen synthase and glycogen phosphorylase

Phosphorylation and dephosphorylation of interconvertible forms

H l ti ti f l b kd


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Hormonal activation of glycogen breakdown


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Hormonal activation of glycogen synthesis


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Five phases of glucose homeostasis

- A 70 kg man who consumed 100 g glucose and thenfasted for 40 days

8 gluconeogenesis, ppp, glycogen

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