Gluconeogenesis

Key knowledge base & conceptual questions

• In what sense can gluconeogenesis be considered a reversal of the glycolytic pathway? Why can it be said that glycolysis gives energy which gluconeogenesis takes energy? Why is it important to prevent gluconeogenesis when the cell is low on ATP? • Know the three steps of glycolysis which are bypassed by enzymes of gluconeogenesis. Know which of the glycolysis steps requires ATP, GTP, and/or NADH. • Know the 4 reactions that ‘reverse’ the three steps above. Know which of these steps requires ATP, GTP, and/or NADH. • Why can oxaloacetate be said to be ‘starting material’ for gluconeogenesis? How is oxaloacetate derived from lactate, amino acids, and glycerol? • For pyruvate carboxylase, know the general features of its (a) location, (b) mechanism, and (3) regulation. Why is this enzyme the key to understanding regulation of gluconeogenesis? Know does this enzyme connect intermediates in glycolysis and in the CAC?

© Sunyoung Kim 2008 Gluconeogenesis • anabolic process by which glucose is Overview: synthesized from smaller molecules such as lactate and pyruvate Introduction • important for maintenance of blood glucose levels within critical limits G

Glucose lu c o is s n e ly +

NADH + H o o c + g e ly ATP n G e s

Pyruvate is

Ribose Disaccharides 5-phosphate Glucose Glucose + NADH + H • major energy source + for most tissues ATP • brain alone uses more than 100 g/day Pyruvate • can be stored as glycogen or used for biosynthesis.

i m H i P K

D g n 6 A u

o y + N n

u S 2

O G 2 P

Gluconeogenesis + T 2 H

D G + 2

2 + P N

+ + D e e 2

e s H A t a P

o + v a 2 t c

T 4 u c

u r l + A a y +

G L

P 4 e

s +

o r c y lu p

g 2 + + D + A H N 2

2 +

e e + e e t t H

t i s a a a t o D v t P c c

c u A a u r l 2 a L y

N L G O

P + 2

D 2 G is s ly o c ly P A

T 2

e + s

r o y c p

lu 2 g Gluconeogenesis

• Key intermediate oxaloacetate, i.e. starting material for pathway COO C O

CH2 COO-

• Substrates are lactate, amino acids, or glycerol.

is NOT a reversal of glycolysis

involves reversal of some glycolytic steps and some unique steps

Three steps in glycolysis are NOT reversible: Glu + ATP G-6-P + ADP F-6-P + ATP F-1,6-BP + ADP PEP + ADP pyr + ATP

Four unique gluconeogenesis reactions are catalyzed by:

1. Pyruvate carboxylase 2. PEP carboxykinase 3. fructose 1,6-bisphosphatase 4. glucose 6-phosphatase

The second unique enzyme of gluconeogenesis, phosphoenolpyruvate (PEP) carboxykinase, converts oxaloacetate to PEP. © Sunyoung Kim 2008 Pathway: Review

Fructose-1,6-bis-P

Gluconeogenesis steps up to generation of fructose-1,6-bisphosphate uses same enzymes as glycolysis.

Phosphoenolpyruvate

Reversal of the phosphofructokinase step is provided by fructose 1,6-bisphosphatase.

Recognize enzymes that use up 4 ATP and 2 GTP in this pathway

1. Pyruvate carboxylase 2. PEP carboxykinase 3. Phosphoglycerate kinase