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Biochemistry Lecture 11
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Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

Mar 26, 2015

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Page 1: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

Biochemistry

Lecture 11

Page 2: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

Gluconeogenesis

Page 3: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &
Page 4: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

Gluconeogenesis

Metab1

A B

Metab2

XY

-Metabolic Pathways are Irreversible∆G between the 1st & last metabolite is large & neg.

- If 2 metabolites are interconvertible (metab 1 metab 2), the path from Metab 1 Metab 2 must be different from that of Metab 2 Metab 1

Page 5: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &
Page 6: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &
Page 7: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

1. Carboxylation of pyruvate to oxaloacetate √

2. Transport of oxaloacetate out of mitochondriamitocyto Oxaloacetate

Malate

NADH + H+

NAD+

Malate

Oxaloacetate

NADH + H+

NAD+

Inner mito. Memb.

A. Circumventing Pyruvate Kinase - Conversion of Pyruvate to Phosphoenolpyruvate

3. PEP Carboxykinase: decarboxylates and adds phosphate

Page 8: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &
Page 9: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &
Page 10: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &
Page 11: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

• Dephosphorylation is not phosphorylation in reverse!• Reverse Phosphorylation of ADP by F1,6 BP to

generate F6P (and ATP) would be steeply uphill:

F1,6 BP + ADP F6P + ATP ∆G° = +3.4 kcal/mol

• Instead, dephosphorylation is carried out:

F1,6 BP + H2O F6P + PO4 ∆G° = -3.9 kcal/mol

• Reverse Phosphorylation would be mediated by PFK

• Dephosphorylation is mediated by F1,6BPase

B. Circumventing PFK – dephosphorylation of F1,6BP

Page 12: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

C. Circumventing Hexokinase – dephosphorylation

of G6P

• Mediated by G6Pase• G6Pase is present only in liver and

kidney• Hence, these are the only tissues that

can synthesize and secrete glucose into the blood

Page 13: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

The Gluconeogenic Response is Activated Largely by the State of

Feeding/Fasting

Glycogen

Glucose

Pyruvate

Acetyl CoA

Blood Glucose

Alanine

FA’s

Blood Glucose

Blood Glucose

Page 14: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &
Page 15: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

The Cory Cycle

Page 16: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

Gluconeogenesis & Glycolysis can Occur at the Same Time in Different

OrgansIN LIVER

Glucose Glucose

IN MUSCLE

B L OO D

PyruvatePyruvate

LactateLactate

Alanine

GlycolysisGluconeogen.

RED BLOOD CELLS

Glucose

Pyruvate

Lactate

Alanine

*** The main substrate here is LACTATE***

Page 17: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

Regulation of Metabolism

Page 18: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

Overview of Energy Metabolism

FATS POLYSACCHARIDES PROTEINS

Fatty Acids, Glucose and Amino Acids

Glycerol other sugars

Stage I Digestion

Acetyl CoA

Stage II Anaerobic

TCA cycle CO2

CoA

e-

ADPATP

O2Oxidative

Phosphorylation

Stage III Aerobic

Page 19: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &
Page 20: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

Principles of Regulation• The flow of metabolites through the

pathways is regulated to maintain homeostasis

• Sometimes, the levels of required metabolites must be altered very rapidly– Need to increase the capacity of glycolysis

during the action

– Need to reduce the capacity of glycolysis after the action

– Need to increases the capacity of gluconeogenesis after successful action

Page 21: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

Rates of a Biochemical Reaction

• Rates of a biochemical reaction depend on many factors• Concentration of reactants

• Activity of the catalyst– Concentration of the enzyme

– Intrinsic activity of the enzyme

• Concentrations of effectors– Allosteric regulators

– Competing substrates

– pH, ionic environment

• Temperature

Page 22: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &
Page 23: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

Reactions Far From Equilibrium are Common Points of Regulation

Page 24: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &
Page 25: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

Hexokinase

• Isozymes are different enzymes that catalyze the same reaction

• They typically share similar sequences

• Their regulation is often different

Page 26: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

P

eg. G6P is structurally similar to glucose, and competes with glucose for active site of hexokinase

Page 27: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &
Page 28: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &
Page 29: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

AMP

ATP

F6P

Active site

Allosteric site

PFK

Page 30: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

Fructose-2,6-bisphosphate

Page 31: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &
Page 32: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &
Page 33: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &
Page 34: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &
Page 35: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

Two Alternative Fates for Pyruvate

• Pyruvate can be a source of new glucose– Store energy as glycogen– Generate NADPH via pentose phosphate

pathway• Pyruvate can be a source of acetyl-CoA

– Store energy as body fat– Make ATP via citric acid cycle

• Acetyl-CoA stimulates glucose synthesis by activating pyruvate carboxylase

Page 36: Biochemistry Lecture 11. Gluconeogenesis Metab 1 AB Metab 2 XY -Metabolic Pathways are Irreversible G between the 1st & last metabolite is large &

Pancreas

Glucagon

Liver

Glycogen

Glucose

F6P

F1,6BP

Pyruvate

PK

F2,6BP

PFK

Glucose(Blood)

Brain

Epinephrine

Adrenal Medulla

Glucose

Muscle

Glycogen

F6P F2,6BP

PFK

F1,6BP

Pyruvate

PK

+

+

+

+++

+

+