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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
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