Glycolysis: The Three-Stage Process of Glucose Metabolism - Prof. Yogarajah Joseph, Study notes of Biochemistry

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Biochemistry: A Short Course

First Edition

Biochemistry: A Short Course

First Edition

Tymoczko • Berg • Stryer

© 2010 W. H. Freeman and Company

CHAPTER 15

Glycolysis

Glycolysis Is an Energy-Conversion Pathway in Many Organisms

common to virtually all cells, both prokaryotic and eukaryotic.

common to virtually all cells, both prokaryotic and eukaryotic.

This pathway can be thought of as comprising

This pathway can be thought of as comprising

three stages

three stages

Stage 1

Stage 1

, which is the conversion of glucose into fructose 1,6-

, which is the conversion of glucose into fructose 1,6-

bisphosphate,

bisphosphate,

consists of three steps: a phosphorylation, an isomerization,

consists of three steps: a phosphorylation, an isomerization,

and a second phosphorylation reaction.

and a second phosphorylation reaction.

Stage 2

Stage 2

is the cleavage of the fructose 1,6-bisphosphate into

is the cleavage of the fructose 1,6-bisphosphate into

two three-carbon fragments.

two three-carbon fragments.

In stage 3

In stage 3

, ATP is harvested when the three-carbon fragments

, ATP is harvested when the three-carbon fragments

are oxidized to pyruvate

are oxidized to pyruvate

ATP

ATP

is generated.

is generated.

Hexokinase

Hexokinase Traps Glucose in the Cell and Begins Glycolysis

Traps Glucose in the Cell and Begins Glycolysis

Glucose -

Glucose - it is phosphorylated by ATP to form glucose 6-phosphate

it is phosphorylated by ATP to form glucose 6-phosphate .

This step is notable for

This step is notable for two reasons

two reasons : (1) glucose 6-phosphate

: (1) glucose 6-phosphate

cannot diffuse through the membrane, because of its negative

cannot diffuse through the membrane, because of its negative

charges, and

charges, and

(2) the addition of the

(2) the addition of the phosphoryl group

phosphoryl group begins to

begins to destabilize

destabilize

glucose, thus

glucose, thus facilitating its further metabolism

facilitating its further metabolism .

The transfer of the phosphoryl group from

The transfer of the phosphoryl group from ATP

ATP to the

to the

hydroxyl group on carbon 6 of glucose is catalyzed by hydroxyl group on carbon 6 of glucose is catalyzed by

hexokinase

hexokinase .

.

Induced Fit

Induced Fit in

in Hexokinase

Hexokinase

. As shown in . As shown in

blue, the two lobes of hexokinase are

blue, the two lobes of hexokinase are

separated in the absence of glucose. The

separated in the absence of glucose. The

conformation of hexokinase changes

conformation of hexokinase changes

markedly on binding glucose, as shown in

markedly on binding glucose, as shown in

red. The

red. The two lobes

two lobes of the enzyme come

of the enzyme come

together and surround.

together and surround.

The Formation of Fructose 1,6-bisphosphate from Glucose 6-

The Formation of Fructose 1,6-bisphosphate from Glucose 6-

phosphate

phosphate

The next step in glycolysis is the

The next step in glycolysis is the isomerization of glucose 6-phosphate

isomerization of glucose 6-phosphate

to fructose 6-phosphate

to fructose 6-phosphate .

Recall that the open-chain form of glucose has an aldehyde group at

Recall that the open-chain form of glucose has an aldehyde group at

carbon 1, whereas the open-chain form of fructose has a keto group at

carbon 1, whereas the open-chain form of fructose has a keto group at

carbon 2. Thus, the

carbon 2. Thus, the isomerization of glucose 6-phosphate to fructose 6-

isomerization of glucose 6-phosphate to fructose 6-

phosphate is a

phosphate is a conversion of an aldose into a ketose

conversion of an aldose into a ketose .

The Six-Carbon Sugar Is Cleaved into Two Three-

The Six-Carbon Sugar Is Cleaved into Two Three-

Carbon Fragments by Aldolase

Carbon Fragments by Aldolase

The second stage of glycolysis begins with the splitting of

The second stage of glycolysis begins with the splitting of

fructose 1,6-bisphosphate into

fructose 1,6-bisphosphate into

glyceraldehyde 3-phosphate

glyceraldehyde 3-phosphate

GA

GA

P

P

) and

) and

dihydroxyacetone phosphate

dihydroxyacetone phosphate

DHAP

DHAP

Triose phosphate isomerase Salvages a Three-Carbon

Triose phosphate isomerase Salvages a Three-Carbon

Fragmen

Fragmen

t

t

Glyceraldehyde 3-phosphate

Glyceraldehyde 3-phosphate

is on the

is on the

direct pathway of

direct pathway of

glycolysi

glycolysi

s, whereas

s, whereas

dihydroxyacetone phosphate is not

dihydroxyacetone phosphate is not

These compounds are isomers that can be readily

These compounds are isomers that can be readily

interconverted: The

interconverted: The

isomerization

isomerization

of these three-carbon

of these three-carbon

phosphorylated sugars is catalyzed by

phosphorylated sugars is catalyzed by

triose phosphate

triose phosphate

isomerase

isomerase

This reaction is rapid and reversible.

This reaction is rapid and reversible.

The Formation of ATP from 1,3-Bisphosphoglycerate

The Formation of ATP from 1,3-Bisphosphoglycerate

The final stage in glycolysis is the generation of ATP from the

The final stage in glycolysis is the generation of ATP from the

phosphorylated three-carbon metabolites of glucose.

phosphorylated three-carbon metabolites of glucose. Phosphoglycerate

Phosphoglycerate

kinase

kinase catalyzes the

catalyzes the transfer of the phosphoryl group

transfer of the phosphoryl group from the acyl

from the acyl

phosphate of 1,3-bisphosphoglycerate to ADP. ATP and 3-

phosphate of 1,3-bisphosphoglycerate to ADP. ATP and 3-

phosphoglycerate are the products. The formation of ATP in this

phosphoglycerate are the products. The formation of ATP in this

manner is referred to as

manner is referred to as substrate-level phosphorylation

substrate-level phosphorylation because the

because the

phosphate donor,

phosphate donor, 1,3-BPG, is a substrate

1,3-BPG, is a substrate with

with high phosphoryl-transfer

high phosphoryl-transfer

potenti

potenti al.

al.

The Generation of Additional ATP and the Formation of Pyruvate

The Generation of Additional ATP and the Formation of Pyruvate

In the remaining steps of glycolysis,

In the remaining steps of glycolysis, 3-phosphoglycerate is converted

3-phosphoglycerate is converted

into pyruvate

into pyruvate with the concomitant conversion of ADP into ATP. The

with the concomitant conversion of ADP into ATP. The

first reaction is a rearrangement

first reaction is a rearrangement

. The position of the phosphoryl group . The position of the phosphoryl group

shifts in the conversion of

shifts in the conversion of 3-phosphoglycerate into 2-

3-phosphoglycerate into 2-

phosphoglycerate,

phosphoglycerate, a reaction catalyzed by

a reaction catalyzed by phosphoglycerate mutase

phosphoglycerate mutase .

Diverse Fates

Diverse Fates of Pyruvate

of Pyruvate

. Ethanol and lactate can be formed by . Ethanol and lactate can be formed by

reactions involving NADH. Alternatively, a two-carbon unit from

reactions involving NADH. Alternatively, a two-carbon unit from

pyruvate can be coupled to coenzyme A to form

pyruvate can be coupled to coenzyme A to form acetyl CoA.

acetyl CoA.

Location of redox balance steps. The

Location of redox balance steps. The

generation and consumption of

generation and consumption of

NADH,

NADH,

located within the glycolytic

located within the glycolytic

pathway.

pathway.

Active Site of

Active Site of Alcohol Dehydrogenase

Alcohol Dehydrogenase

. The active site contains a . The active site contains a zinc

zinc

ion

ion bound to two cysteine residues and one histidine residue.

bound to two cysteine residues and one histidine residue. The zinc

The zinc

ion binds the

ion binds the acetaldehyde substrate through its oxygen atom

acetaldehyde substrate through its oxygen atom ,

polarizing it so that it more easily accepts a hydride

polarizing it so that it more easily accepts a hydride

The conversion of glucose into ethanol is an example of

The conversion of glucose into ethanol is an example of alcoholic

alcoholic

fermentation

fermentation

. The net result of this anaerobic process is: . The net result of this anaerobic process is:

NADH generated by the oxidation of glyceraldehyde 3-phosphate

NADH generated by the oxidation of glyceraldehyde 3-phosphate

is consumed in the reduction of acetaldehyde to ethanol.

is consumed in the reduction of acetaldehyde to ethanol. Thus,

Thus,

there is no net oxidation-reduction in the conversion of glucose

there is no net oxidation-reduction in the conversion of glucose

into ethanol

into ethanol .