CARBOHYDRATE METABOLISM

METABOLISM? WHY?

A 59-year-old man with a history of diabetes and alcohol abuse is brought to the emergency room in a semiconscious and minimally responsive state

How are glucose, triacylglycerols, and amino acids normally metabolized and what happens in diabetes?

Major Pathways

1. Glycolysis2. Citric acid cycle3. Gluconeogenesis4. Glycogen metabolism (a) Glycogenesis (b) Glycogenolysis

Glucose is the most important carbohydrate Glucose is the major metabolic fuel of

mammals. Monosaccharide from diet : - Glucose - Fructose - Galactose Fructose and Galactose glucose at the

liver

Glucose

Acetyl-CoALactate

G6P

Glucose

Glycolysis

Pyruvate

Krebscycle

ElectronTransport

Chain

Glycogen

Glycogenolysis

Fatty acids(TGA)β-Oxidation

Ketone

bodies

Glycogenesis

Gluconeogenesis

Lipogenesis

Amino acids

(Protein)

Lipolysis

Glucose at the center of metabolism

Major organ of metabolismGlycogenesis

GlycogenolysisLipogenesis

Lipolysisβ-Oxidation

GlycogenesisGlycogenolysisGluconeogene

sisLipogenesis

Lipolysisβ-OxidationKetogenesis

GlycogenesisGlycogenolysis

Glycolysisβ-Oxidation

GlycogenesisGlycogenolysis

Glycolysisβ-Oxidation

Blood GlucoseSerum Triglycerides

The origine of glucose

GLUCOSE

Fats

Amino acidsmonosacchar

ide

GlycogenExogenous

Glucose Homeostasis

The fate of glucose

Glycolysis

Krebs Cycle

Integration of metabolism

Common intermediates Common organs

The metabolic intermediates. Metabolic integration

Major organ of metabolism, metabolic integration

GlycogenesisGlycogenolysis

LipogenesisLipolysis

β-Oxidation

GlycogenesisGlycogenolysisGluconeogene

sisLipogenesis

Lipolysisβ-OxidationKetogenesis

GlycogenesisGlycogenolysis

Glycolysisβ-Oxidation

GlycogenesisGlycogenolysis

Glycolysisβ-Oxidation

Blood GlucoseSerum Triglycerides

Glucose, in between organ currency

Regulation of Blood Glucose: Insulin Insulin

Produced by beta cells of the pancreas Helps transport glucose from the blood into

cells Stimulates the liver to take up glucose and

convert it to glycogen

Regulation of Blood Glucose: Insulin

Insulin

Glucagon Produced by alpha cells of the pancreas Stimulates the breakdown of glycogen to

glucose to make glucose available to cells of the body

Stimulates gluconeogenesis—the production of “new” glucose from amino acids

Regulation of Blood Glucose: Glucagon

Regulation of Blood Glucose: Glucagon

Glucangon

Insulin, Glucagon, and blood glucose

High Blood glucose 1. Glycolysis 2. Glycogenesis 3. HMP Shunt 4. Oxidation of Pyruvate 5. Kreb’s Cycle 6. Change to lipids Low blood glucose 1. Glycogenolysis 2. Gluconeogenesis

Blood glocose

GLUCONEOGENESIS

Overview of Glucose Metabolism

gluco neo genesis

sugar (re)new create

glycolysis

glucose

pyruvatelactate

gluconeogenesis

Topics: Gluconeogenesis

1. Principles, substrates & relationship to glycolysis

2. Bypass of irreversible steps in glycolysis

3. Link between liver gluconeogenesis and muscle/RBC/brain glycolysis; the Cori and Alanine cycles

Gluconeogenesis

Occurs in all animals, plants, fungi and microbes

Occurs largely in the liver; some in renal cortex

Of 10 enzymatic steps, 7 are reversals of glycolytic reactions

Metabolites feed into

gluconeogenesis at various points

mainpath

AA can feed into gluconeogenesis

TCA intermediates are gluconeogenic;funnel through oxaloacetate

Bypass of irreversible steps in glycolysis

Irreversible glycolytic stepsbypassed

1. Hexokinase (hexK)

2. Phosphofructokinase-1 (PFK-1)

3. Pyruvate kinase (PyrK)

by Glucose-6-phosphatase

by Fructose 1,6-bisphosphatase (FBP-1)

by Pyruvate Carboxylase & Phosphoenolpyruvate carboxykinase (PEPCK)

These 3 key enzymes

glycolysis gluconeogenesis

Pyruvate can go “up” or “down” depending upon energy needs

First bypass step is generation of PEP from pyruvate via oxaloacetate

*Note:In order to cross the

mito membrane, oxaloacetate must:

1. Be reduced to malate

2. Go through the malate shuttle

3. Be reoxidized to oxaloacetate

Addition of CO2 to pyruvate to form oxaloacetate

• Hydrolysis of ATP

Decarboxylation and phosphorylation to PEP

2nd & 3rd bypass steps are near the end of gluconeogenesis(“top” of glycolysis)

Regulation of FBP-1 by AMP and F2,6P

Dephosphorylation of G6P,3rd bypass reaction

Glucose 6-phosphatase removes the phosphate to liberate free glucose

• This is primarily a function of the liver to buffer blood glucose levels

• G6Pase is NOT present in brain and muscle! (Gluconeogenesis does not occur in these tissues)

glucose-6-P + H2O glucose + Pi

G6Pase

Gluconeogenesis is energetically expensive to cells (hepatocytes)

cost

Note that both Glycolysis and Gluconeogenesis are energetically favorable under physiological conditions and therefore both ~ irreversible processes

Glycolysis DG[phys] = -63 kJ/mol

Gluconeogenesis DG[phys] = -16 kJ/mol

Liver is the major source of blood glucose from GN

Is the primary gluconeogenic organ

Produces glucose for export to brain, muscle, RBC’s

Uses many small metabolites and fatty acids to feed GN

Liver function is highly sensitive to insulin & glucagon

The Cori Cycle

2 ATP

6 ATP2

Lactate and glucose shuttle between active muscle/RBC and liver (glucagon/insulin reg.)

Liver gluconeogenesis buffers the blood glucose for use by muscle, RBC’s and brain (120 g/day)

*Note: the brain fully oxidizes glucose, so it does not funnel back lactate

GN

GL

RBCs

The Alanine CycleThe liver can also use the amino acid Alanine similarly to Lactate

Following transamination to pyruvate, gluconeogenesis allows the liver to convert it to glucose for secretion into the blood

REGULATION OF GLUCONEOGENESIS

First Coordinated Control Point

(1)

(2)

(3)

1. high energy charge or abundance of biosynthetic intermediates turn off glycolysis.. Glycolytic pathway intermediate turns it on

2. when energy charge of the cell is low, the biosynthetic pathway is turned off.

3. when excess acetyl CoA builds up glucose formation is stimulated. When the energy charge in the cell is low, biosynthesis is turned off.

Second Coordinated Control Point

Recall that F-2,6-BP is a signal molecule that is present at low concentration during starvation and high concentration in the fed state due to the antagonistic effects of glucagon and insulin on its production.

Glucagon

Fructose-2,6-bisphosphate is a powerful inhibitor of fructose-1,6-bisphosphatase

Inhibition of fructose-1,6-bisphosphatase by fructose-2,6-bisphosphate.