GLYCOLYSIS AND GLUCONEOGENESIS

INSTRUCTOR-RCL

GROUP 4

NITI KR. SHAHANUP BIK. SHAH

REVOLUTION SHERETHA SMIRITI KHADKA

BIJAY RAJBANSHI TAKAR ABDIGANI

Glycolysis (Embden-Meyerhof pathway)

• Glycolysis is the breakdown of glucose into pyruvic acid

• Does not require oxygen

• Occurs free in the cytoplasm

• Begins with D-glucose as the substrate

The two parts of glycolysis:

glucose glucose 6-phosphate fructose 1,6- diphosphate

Part one(enery invesment phase):

ATP ATP

Part two(energy generating phase):

fructose 1,6-diphosphate

2 ATP 2 ATP2 NADH

2 pyruvic acid

Glycolysis

• Overall net equation is:Glucose + 2NAD + 2ADP + 2Pi 2 pyruvates +

2NADH + 2 ATP + 2 NADH + 2 H+ + 2 H2O

• Glycolysis is exergonic - produces net of 2ATPs and 2NADHs

Glycolysis

• Coenzyme NAD+ is a biological oxidizing agent that converts C-H bonds to C-O bonds. In the process, NAD+ is reduced to NADH + H+.

• The phosphorylation of ADP requires energy and forms ATP, a high-energy nucleoside triphosphate.

• The hydrolysis of ATP releases energy and forms ADP

Steps in glycolysis • Step 1• Substrate glucose is phosphorylated by

hexokinase• Product is glucose-6-phosphate

– Source of the phosphoryl group is ATP– Expenditure of ATP early in the pathway

works as energy “debt” necessary to get the pathway started

Step 1

Step 2• Product of step 1 is rearranged to the

structural isomer fructose-6-phosphate by enzyme phosphoglucose isomerase

- Converts and aldose to a ketose

Step 3• Substrate fructose-6-phosphate

is phosphorylated by phosphofructokinase

• Product is fructose-1,6-bisphosphate– Source of the phosphoryl group is ATP

•

Step 4• Product of step 3 is split into two 3-

carbon intermediates by the enzyme aldolase forming:– Glyceraldehyde-3-phosphate (substrate of

next reaction)– Dihydroxyacetone phosphate

Step 5• Dihydroxyacetone phosphate is

rearranged into a second glyceraldehyde-3-phosphate by the enzyme triose phosphate isomerase– Glyceraldehyde-3-phosphate is the only

substrate for the next reaction

Step 6• Substrate glyceraldehyde-3-phosphate is

oxidized to a carboxylic acid by glyceraldehyde-3-phosphate dehydrogenase– Reduces NAD+ to NADH

• Product is 1,3-Bisphosphoglycerate – New phosphate group attached with a “high-

energy” bond

Step 7• Harvest energy in the form of ATP• 1,3-Bisphosphoglycerate high energy

phosphate group is transferred to ADP by phosphoglycerate kinase:– 3-Phosphoglycerate– ATP

• This is the first substrate level phosphorylation of glycolysis

Step 8• 3-Phosphoglycerate is isomerized into 2-

phosphoglycerate by the enzyme phosphoglycerate mutase– Moves the phosphate group from carbon-3 to

carbon-2

Step 9• The enzyme enolase catalyzes

dehydration of 2-phospholgycerate– Phosphoenolpyruvate

• Energy rich – highest energy phosphorylated compound in metabolism

Step 10• Final substrate-level dehydration in the

pathway• Phosphoenolpyruvate serves as donor of

the phosphoryl group transferred to ADP by pyruvate kinase making ATP and releasing water– Pyruvate is the final product of glycolysis

Summary of glycolysis

Net result of glycolysis• The final products are:

– Two pyruvic acid molecules– Two NADH + H+ molecules

(reduced NAD+)– A net gain of two ATP molecules

• Fructose is obtained by the hydrolysis of the disaccharide sucrose, found in sugar beets and sugarcane

• Galactose is obtained by the hydrolysis of the dissacharide lactose in milk

• Mannose is obtained from polysaccharides in fruits such as cranberries and currants

Glycolysis and other hexoses

Acetyl CoA, CH₃COSCoA, is formed under aerobic conditions

Lactate, CH₃CH(OH)CO2⁻, is formed under anaerobic conditions.

Ethanol CH₃CH2OH, is formed in fermentation

Fate of pyruvate

Gluconeogenesis: The Synthesis of Glucose

• Gluconeogenesis makes glucose from noncarbohydrate starting materials – Lactate– Glycerol– Most amino acids (not leucine,

lysine)– Glycerol and amino acids are used

only in starvation conditions• Process occurs primarily in the

liver

The gluconeogenic pathway converts pyruvate into glucose.

pyruvate glucose→→ → → →

gluconeogenesis

glycolysis

Gluconeogenesis is not a reversal of glycolysis

Comparison of Glycolysis

and Gluconeogenesis• While basically opposite processes

glycolysis and gluconeogenesis are not a simple reversal of each other

• The three nonreversible steps of glycolysis must be bypassed with new routes– Pyruvate Phosphoenolpyruvate – Fructose-1,6-bisphosphate Fructose-6-

phosphate– Glucose-6-phosphate Glucose

Comparison of Glycolysis and Gluconeogenesis

Pyruvate Phosphoenolpyruvate

• The two enzymes that catalyze the reactions for bypass of the Pyruvate Kinase reaction are the

following:

• Pyruvate Carboxylase (Gluconeogenesis) catalyzes:pyruvate + HCO3

- + ATP oxaloacetate + ADP + Pi

• PEP Carboxykinase (Gluconeogenesis) catalyzes:oxaloacetate + GTP PEP + GDP + CO2

C

C

CH 2

O O

O PO 32

C

C

CH 3

O O

O

A T P A D P + P i C

CH 2

C

C

O

O O

O O

HC O 3

G T P G D P

CO 2

p y r u v a te o x a lo a c e ta te P E P

P y ru v a te C a rb o x y la s e P E P C a rb o x y k in a s e

Fructose-1,6-bisphosphate Fructose-6-phosphate

• Fructose 6-phosphate is formed from 1,6-bisphosphate by hydrolysis of the phosphate ester at carbon1.Fructose 1,6-bisphosphatase catalyzes this exergonic hydrolysisFructose 1,6-bisphosphate + H2O

fructose 6-phosphate + Pi

Glucose-6-phosphate Glucose• Glucose is formed by the hydrolysis

of gulcose 6-phosphate in a reaction catalyzed by gulcose 6-phosphate

Gulose 6-phosphate + H2O gulcose + Pi

Glyceraldehyde-3-phosphate Dehydrogenase

Phosphoglycerate Kinase

Enolase

PEP Carboxykinase

glyceraldehyde-3-phosphate

NAD+ + Pi

NADH + H+

1,3-bisphosphoglycerate

ADP

ATP

3-phosphoglycerate

Phosphoglycerate Mutase

2-phosphoglycerate H2O

phosphoenolpyruvate

CO2 + GDP

GTP oxaloacetate

Pi + ADP

HCO3 + ATP

pyruvate

Pyruvate Carboxylase

Gluconeogenesis

Summary of Gluconeogenesis

Pathway:

Gluconeogenesis enzyme names in

red.

Glycolysis enzyme names in blue.

Glucose-6-phosphatase

Fructose-1,6-bisphosphatase

glucose Gluconeogenesis

Pi

H2O glucose-6-phosphate

Phosphoglucose Isomerase

fructose-6-phosphate

Pi

H2O fructose-1,6-bisphosphate

Aldolase

glyceraldehyde-3-phosphate + dihydroxyacetone-phosphate

Triosephosphate Isomerase (continued)

Gluconeogenesis Regulation• Step 3 of glycolysis:

– Catalyzed by phosphofructokinase

– Stimulated by: high AMP, ADP, Pi

– Inhibited by: high ATP• Reverse occurs in gluconeogenesis:

– Fructose-1,6-bisphosphatase stimulated by high ATP

– At times of excess energy (high ATP) gluconeogenesis is favored

Reciprocal regulation of gluconeogenesis and glycolysis in

the liver.

The interconversion of fructose 6-phosphate

and fructose 1,6-bisphosphate

is stringently controlled

The interconversion of phosphoenolpyruvate and pyruvate also is

preciselyregulated.

Cori Cycle

• In the Cori cycle,– Lactate from skeletal muscle is

transferred to the liver – Converted to pyruvate then glucose – This glucose can be returned to the

muscle

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