Gluconeogenesis

Formation of glucose from non-carbohydrate source

• occurs mainly in liver and

• to a limited extent in kidney & small intestine

• Synthesis of glucose from pyruvate utilizes many of the same enzymes as Glycolysis

• Three Glycolysis reactions have such a large negative G that they are essentially irreversible Hexokinase (or Glucokinase) Phosphofructokinase Pyruvate Kinase

These steps must be bypassed in Gluconeogenesis.

The first two of the bypass reactions involve simple hydrolysis reactions

Glucose-6-Phosphatase (Gluconeogenesis) catalyzes:

glucose-6-phosphate + H2O glucose + Pi

This enzyme is embedded in the endoplasmic reticulum (ER) membrane in liver cells

H O

OH

H

OHH

OH

CH2OH

H

OH

HH O

OH

H

OHH

OH

CH2OPO32

H

OH

HH2O

1

6

5

4

3 2

+ Pi

glucose-6-phosphate glucose

Glucose-6-phosphatase

Fructose-1,6-bisphosphatase (Gluconeogenesis) catalyzes:

fructose-1,6-bisP + H2O fructose-6-P + Pi

fructose-6-phosphate fructose-1,6-bisphosphate

Phosphofructokinase CH2OPO3

2

OH

CH2OH

H

OH H

H HO

O6

5

4 3

2

1 CH2OPO32

OH

CH2OPO32

H

OH H

H HO

O6

5

4 3

2

1ATP ADP

Pi H2O

Fructose-1,6-biosphosphatase Fructose-1,6-bisphosphatase

Bypass of Pyruvate Kinase:

Pyruvate Kinase (last step of Glycolysis) catalyzes: phosphoenolpyruvate + ADP pyruvate + ATP

For bypass of the Pyruvate Kinase reaction, 2 ~P bonds is required.

Bypass of Pyruvate Kinase (2 enzymes):

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