BiochemistryLecture 11

Gluconeogenesis

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

1. Carboxylation of pyruvate to oxaloacetate √

2. Transport of oxaloacetate out of mitochondriamitocyto Oxaloacetate

Malate

NADH + H+

NAD+

Malate

OxaloacetateNADH + H+

NAD+

Inner mito. Memb.

A. Circumventing Pyruvate Kinase - Conversion of Pyruvate to Phosphoenolpyruvate

3. PEP Carboxykinase: decarboxylates and adds phosphate

• 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

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

The Gluconeogenic Response is Activated Largely by the State of

Feeding/FastingGlycogen

Glucose

Pyruvate

Acetyl CoA

Blood Glucose

Alanine

FA’s

Blood Glucose

Blood Glucose

The Cory Cycle

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 CELLSGlucose

Pyruvate

Lactate

Alanine

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

Regulation of Metabolism

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

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

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

Reactions Far From Equilibrium are Common Points of Regulation

Hexokinase• Isozymes are

different enzymes that catalyze the same reaction

• They typically share similar sequences

• Their regulation is often different

P

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

AMP

ATP

F6P

Active site

Allosteric site

PFK

Fructose-2,6-bisphosphate

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

Pancreas

Glucagon

Liver

Glycogen

Glucose

F6P

F1,6BP

Pyruvate

PK

F2,6BPPFK

Glucose(Blood)

Brain

Epinephrine

Adrenal Medulla

Glucose

MuscleGlycogen

F6P F2,6BPPFK

F1,6BP

PyruvatePK

+

+

+

+++

+

+