Carbohydrate

Metabolism

Dietary carbohydrates (starch, glycogen,

sucrose, lactose

Oligosaccharides and disaccharides

Mouth salivary amylase

Stomach, non-enzymatic hydrolysis

Monosaccharides

Small intestine, pancreatic amylase

Monosaccharides in bloodstream

Small intestinal lining

Storage (glycogenesis)

Conversion to other carbohydrates

Utilization for energy (glycolysis)

Excretion

Undesired biochemical

processes

Summary of Carbohydrate

Utilization

Glycolysis

Glycolysis is a nine step biochemical pathway that oxidizes glucose into two molecules of pyruvic acid (pyruvate).

During this process, energy is released and some of it is captured

in the form of ATP.

The electrons removed from glucose are captured in the form of NADH.

O

CH2OH

OH

OH

HO OH

+ 2 NAD+ + 2 ADP + 2 Pi

2 + 2 ATP + 2 NADH + 2 H+ + 2 H2OC6H12O6

C3H3O3-

glucose

pyruvate

H3CC

CO

O

O

Glycolysis

The pyruvate formed may be

oxidized to carbon dioxide and water in the citric acid cycle

may be reduced to L-lactic acid

or

Lactate Dehydrogenase Reaction

C

C

CH3

O

O

O

C

C

CH3

O

OH

O

H

NADH,H+ NAD+

Glycolysis Proceeds in Two Stages

Stage 1 of Glycolysis:

Glucose and other hexoses are converted into glyceraldehyde-3-phosphate.

Stage 1 of Glycolysis:glucose

glucose-6-phosphate

fructose-6-phosphate

fructose-1,6-bisphosphate

glyceraldehyde -3-phosphate

dihydroxyacetone phosphate

ATP

ADP

ATP

ADPhexokinase

phosphohexose isomerase

phosphofructo kinase

aldolase

triosephosphate isomerase

6 C

6 C - P

6 C - P

P - 6 C - P

3 C - P 3 C - P

Stage 2 of Glycolysis:

2 molecules of glyceraldehyde-3-phosphate are oxidized and converted into two molecules of pyruvate.

The NADH generated during stage 2 may be used to reduce the pyruvate molecules to lactate molecules.

Stage 2 of Glycolysis:glyceraldehyde-3-phosphate

1,3-bisphosphoglycerate

3-phosphoglycerate

2-phosphoglycerate

phosphoenolpyruvate

pyruvate

ATP

ADP

NAD+, Pi

NADH, H+

ADP

ATP

3 C - P

P - 3 C - P*

3 C - P

3 C - P

3 C - P

P - 3 C - P*

glyceraldehyde-3-phosphate dehydrogenase

phosphoglcerate kinase

phosphoglycerate mutase

enolase

pyruvate kinase

G3P

BPG

3PG

2PG

PYR

PEP

GLU

G6P

F6P

FBP

G3P DHAP

Stage 1 Stage 2

Energy consumed Energy produced

The Individual Chemical Transformations of

Glycolysis

Distinguish Between the Two Stages Count the Carbons

Identify High Energy Compounds Understand the Overall Transformation

Chemical Transformations of GlycolysisThe overall reaction of steps 1-10 is:

In cells where a high rate of ATP production is not needed, the pyruvate formed by glycolysis is not reduced to lactate, but instead is oxidized to

carbon dioxide and water in the mitochondria.

This allows the cell to capture a greater amount of energy from the original glucose molecule.

Note:In some microorganisms, such as yeast, pyruvate is first decarboxylated and the resulting acetaldehyde is reduced to ethanol, regenerating NAD+.

Glucose + 2 ADP + 2 Pi 2 lactate + 2 ATP

C

C

CH3

O

O

OH

C

CH3

O

CO2

H

HC

CH3

OH

NADH,H+ NAD+pyruvate

decarboxylase

alcohol dehydrogenase

6C 3C

The Pentose Phosphate Pathway

The pentose phosphate pathway utilizes glucose to produce pentoses (for DNA, RNA) and NADPH (for reductive biosynthesis).

This pathway includes additional enzymes that allow the interconversion of pentoses and hexoses.

This allows the cell four alternatives:

Produce both pentoses and NADPH.

Produce only NADPH when pentoses are not required.

Produce only pentoses when NADPH is not required.

Produce ATP (glycolysis) and NADPH when both are required.

Glucose-6-PO42- + 2 NADP+ ribose-5-PO42- + 2 NADPH + 2 H+ + CO2 5C6C

Name Derivation of Name Function

Glycolysis glyco-, glucose “sweet” glucose--->pyruvate

Pentose Phosphate Pathway

pentose-, five carbon sugar

glucose---> 5-carbon sugars

Gluconeogenesis neo-, “new” genesis-, “creation”

small molecules---> glucose

Glycogenesis glyco (gen)-glycogen genesis-, “creation” glucose--->glycogen

Glycogenolysis glyco (gen)-glycogen -lysis, “breakdown” glycogen--->glucose

Metabolic Pathways of Glucose

Gluconeogenesis

Gluconeogenesis is the biosynthesis of glucose from lactate and certain other small molecules.

Gluconeogenesis occurs in the liver and kidney.

Gluconeogenesis reverses many of the reactions in glycolysis; however, three irreversible reactions

must be bypassed using different reactions and enzymes.

glucose

glucose-6-phosphate

fructose-6-phosphate

fructose-1,6-bisphosphate

glyceraldehyde-3-phosphate

ATP

ADP

ATP

ADP

glyceraldehyde-3-phosphate

1,3-bisphosphoglycerate

3-phosphoglycerate

2-phosphoglycerate

phosphoenolpyruvate

pyruvate

ADP

ATP

ATP

ADP

NAD+, Pi

NADH, H+

Glycolysis

Glycolytic Reaction Step ΔG(kJ/mol)1 glucose + ATP → glucose-6-phosphate + ADP -332 glucose-6-phosphate ⇄ fructose-6-phosphate 0 to 2.53 fructose-6-phosphate + ATP → fructose-1,6-bisphosphate + ADP -224 fructose-1,6-bisphosphate ⇄ DHP + G3P 0 to -6

dihydroxyacetone phosphate ⇄ glyceraldehyde-3-phosphate 0 to 45 glyceraldehyde-3-phosphate ⇄ 1,3-bisphosphoglycerate -2 to 26 1,3-bisphosphoglycerate + ADP ⇄ 3-phosphoglycerate + ATP 0 to 27 3-phosphoglycerate ⇄ 2-phosphoglycerate 0 to 0.88 2-phosphoglycerate ⇄ phosphoenolpyruvate 0 to 3.39 phosphoenolpyruvate + ADP → pyruvate + ATP -17

Free Energy Changes for Glycolysis Reactions Steps*

*calculated from the actual physiological concentrations in erythrocytes

glucose

glucose-6-phosphate

fructose-6-phosphate

fructose-1,6-bisphosphate

glyceraldehyde-3-phosphate

ATP

ADP

ATP

ADP

glyceraldehyde-3-phosphate

1,3-bisphosphoglycerate

3-phosphoglycerate

2-phosphoglycerate

phosphoenolpyruvate

pyruvate

ADP

ATP

ATP

ADP

NAD+, Pi

NADH, H+

Glycolysis

Gluconeogenesis

glyceraldehyde-3-phosphate

1,3-bisphosphoglycerate

3-phosphoglycerate

2-phosphoglycerate

phosphoenolpyruvate

pyruvateglyceraldehyde-3-phosphate

1,3-bisphosphoglycerate

3-phosphoglycerate

2-phosphoglycerate

phosphoenolpyruvate

pyruvate

ADP

ATP

ATP

ADP

NAD+, Pi

NADH, H+

Glycolysis

NAD+, Pi

NADH, H+

ATP

ADP

cytosolmitochondria

pyruvate

oxaloacetate

phosphoenolpyruvate

oxaloacetate

malate

malate

Gluconeogenesis

GDP, HCO3-

GTP

ATP, HCO3-

ADP

NADH, H+

NAD+

NADH, H+

NAD+

glyceraldehyde-3-phosphate

1,3-bisphosphoglycerate

3-phosphoglycerate

2-phosphoglycerate

phosphoenolpyruvate

pyruvate

ATP

ADP

NAD+, Pi

NADH, H+

pyruvate

oxaloacetate

phosphoenolpyruvate

oxaloacetate

malate

malate

GDP, HCO3-

GTP

ATP, HCO3-

ADP

NADH, H+

NAD+

NADH, H+

NAD+

pyruvate carboxylase (requires biotin)

phosphoenolpyruvate carboxykinase

ATP

GDP

ADP

mitochondria

cytosol

only occurs when there is an

abundance of ATP

Glycolysisglucose

glucose-6-phosphate

fructose-6-phosphate

fructose-1,6-bisphosphate

glyceraldehyde-3-phosphate

ATP

ADP

ATP

ADP

Gluconeogenesisglyceraldehyde

-3-phosphatedihydroxyacetone

-3-phosphate

fructose-1,6-bisphosphate

fructose-6-phosphate

glucose-6-phosphate

glucose

H2O

Pi

glucose- 6-phosphatase

H2O

Pi

fructose-1,6- bisphosphatase

Dietary carbohydrates (starch, glycogen,

sucrose, lactose

Oligosaccharides and disaccharides

Mouth salivary amylase

Stomach, non-enzymatic hydrolysis

Monosaccharides

Small intestine, pancreatic amylase

Monosaccharides in bloodstream

Small intestinal lining

Storage (glycogenesis)

Conversion to other carbohydrates

Utilization for energy (glycolysis)

Excretion

Undesired biochemical

processes

Summary of Carbohydrate

Utilization

Glycogenesis and

Glycogenolysis

Glucose-1-phosphate

(Glucose)n glycogen

UTP

Glucose-UDP

2 Pi

UDP (Glucose)n-1

glycogenesis

Glucose

Glucose-6-phosphate glycolysis

gluconeogenesis

HPO32-

(Glucose)n-1

glycogenolysis

GlycogenesisWhen the concentration of ATP is high, glycogen is synthesized and stored in liver and muscle cells as

glycogen granules.

The addition of a molecule of glucose to a growing α 1→4 glycogen strand involves these reactions:

1) Glucose-6-phosphate → Glucose-1-phosphate

2) Glucose-1-phosphate + UTP → UDP-glucose + PP,

PPi + H2O → 2 Pi

3) UDP-glucose + (glucose)n-1 → UDP + (glucose)n

O

CH2

OH

OH

O

HO

O

CH2

OH

OH

HO O

HO

O

OCH2

OHOH

PO

O

P

O

O O

ON

NH

O

O

O

CH2

OH

OH

HO O

HO

OCH2

OHOH

PO

O

P

O

O O

ON

NH

O

OUDP-Glucose

non-reducing end of glycogen

elongated glycogenUDP

Glycogen Synthase Reaction

O

CH2

OH

OH

O

HO

O

CH2

OH

OH

O

HO

O

CH2

OH

OH

HO O

HO

Glycogenesis

When a growing α 1→4 glycogen strand reaches a certain length, a branching enzyme breaks the α 1→4 chain and

remakes an α 1→6 linkage. this results in branches, each of which can be extended by further α 1→4 linkages

glycogenin

glycogenin

OCH

2

OH

OH

O

HOOCH

2

OH

OH

O

HOOCH

2

OH O

HO

OCH

2

OH

OH

O

HOOCH

2

OH

OH

O

HOOCH

2

OH

OH

O

HO

OCH

2

OH

OH

O

HOOCH

2

OH

OH

O

HOOCH

2

OH

OH

O

HO

OCH

2

OH

OH

O

HO

HO

OCH

2

OH

OH

O

HOOCH

2

OH

OH

O

HOOCH

2

OH

OH

O

HO

OH

autocatalysis

O

CH2

OH

OH

O

HO

HO

O

CH2

OH

OH

O

HOO

CH2

OH

OH

O

HOO

CH2

OH

OH

O

HO

glycogenin

glycogen synthase

glycogenin

OCH2

OH

OH

O

HO

HO

OCH2

OH

OH

O

HOOCH2

OH

OH

O

HOOCH2

OH

OH

O

HO

OCH2

OH

OH

O

HOOCH2

OH

OH

O

HOOCH2

OH

OHHOO

HO

OCH2

OH

OH

O

HOOCH2

OH

OH

O

HOOCH

OH

OH

O

H

OCH2

OH

OH

O

HOOCH2

OH

OH

O

HOOCH2

OH

OH

O

HO

glycogen branching enzyme

Further elongation and branching

Glycogenesis

Glycogen synthesis is stimulated by insulin through a covalent modification of the glycogen synthase kinase

enzyme.

Glycogen synthesis is inhibited by glucagon and epinephrine through a covalent modification of the

glycogen synthase phosphatase enzyme.

Glycogenolysis

When the blood glucose concentration drops below about 5 mM, glycogen in the liver is degraded to free glucose

which is released into the bloodstream.

Glycogenolysis proceeds by a different route from glycogen biosynthesis.

Glucose, as glucose-1-phosphate, is released from glycogen by the active form of the enzyme: glycogen phosphorylase.

O

CH2

OH

OH

O

HO

O

CH2

OH

OH

HO O

HO

non-reducing end of glycogen

shortened glycogen

Glycogen Phosphorylase

O

CH2

OH

OH

O

HO

O

CH2

OH

OH

O

HO

O

CH2

OH

OH

HO O

HO

Glycogenolysis

HOPO

OO

O

CH2

OH

OH

HO O

HO

PO

OO

Called a “phosphorolysis” reaction

Glycogenolysis

When a shrinking α 1→4 glycogen strand approaches a branching point, a debranching enzyme transfers a

portion of the α 1→6 branching chain and remakes an α 1→4 linkage. A second enzyme (an α 1→6 glucosidase)

removes the remaining glucose residue from the branching point, and degradation continues by the

phosphorylase.

glycogenin

OCH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

HO

OCH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

HO

OCH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

OCH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

HO

HO

OCH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

HO

OCH2

OH

OHO

HO

HO

OCH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

HO

glycogenin

OCH2

OH

OHO

HO

HO

OCH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

HO

OCH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

OCH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

HO

HO

OCH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

HO

phosphorylase

transferase

glucosidase

phosphorylase

OCH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

HO

OCH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

HO

OCH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

OCH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

HO

HO

HO

glycogenin

O

CH2

OH

OH

HO O

HO

PO

OO

HOPO

OO

O

CH2

OH

OH

HO O

HO

PO

OO

glycogenin

OCH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

HO

OCH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

OCH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

HO

HO

OCH2

OH

OHO

HOO

CH2

OH

OHO

HOO

CH2

OH

OHO

HO HO

HOPO

OO

O

CH2

OH

OH

HO O

HO

PO

OO Further chain cleavage

HOPO

OO

Glycogenolysis

Glycogenolysis is stimulated by glucagon and epinephrine through covalent modification of a

phosphorylase kinase enzyme.

Insulin

Hormonal Regulation of Blood Glucose

Glucagon, epinephrine

ACTIVE Phosphorylase

kinase

INACTIVE Glycogen Synthase

kinase

ACTIVE Glycogen Synthase

phosphorylase

ACTIVE Glycogen Synthase a

Storageof

glucose

ACTIVE Glycogen Phosphorylase a

Releaseof

glucose

P

Active phosphorylase

kinase

Inactive phosphorylase

kinase

Active phosphorylase

Inactive phosphorylase

(Glucose)n (Glucose)n-1 + Glucose-1-PO42-

Glucose-6-PO42-

Glucose

Liver and Muscle

Liver

Glycolysis

Bloodstream

Glucagon, epinephrine

Active adenyl cyclase

Inactive adenyl cyclase

Active G-protein

Inactive G-protein

cAMPATP

Active protein kinase

Inactive protein kinase

Active phosporylase

kinase

Inactive phosphorylase

kinase

Active phosphorylase

Inactive phosphorylase

Primary messenger (glucagon, epinephrine)

binds to cell surface.

*

(Glucose)n (Glucose)n-1

+ Glucose-1-PO42-

Secondary messenger

1x

40x

10x

100x

1000x

10,000x

Glucagon, epinephrine

Amplification Mechanisms

The glycogen cascade is one example of a general biochemical scheme for the use of relatively small

numbers of secondary messenger molecules to produce general cellular and physiological responses.

Active protein kinase

Inactive protein kinase

Active protein kinase

Inactive protein kinase

Active protein kinase

Inactive protein kinase

Active protein

Inactive protein

primary messenger

General Cellular Response

active relay molecule (second messenger)

receptor proteins