Gluconeogenesis

1
Gluconeogenesis

• Lecturer Rick Kahn, Ph.D.
• RRC G-217
• PH. 7-3561
• rkahn_at_emory.edu

Objectives To know how cells/tissues reverse
glycolysis to generate glucose To understand
where and when gluconeogenesis occurs To learn
how gluconeogenesis is regulated and coordinated
with glycolysis
2
Why gluconeogenesis?The Cori Cycle
During times of high work load the muscles
generate high levels of lactate as they are
operating under anaerobic conditions. The liver
is the main organ capable of gluconeogenesis,
thus setting up the cycle shown at left.
3
Gluconeogenesis is simply the reversal of
glycolysis
Glucose 6- phosphatase
Hexokinase
Fructose 1,6 bisphosphatase
PFK1

• Three exceptions
• Hexokinase?Gluc. 6 Pase
• PFK1?Fruct. 1,6-bisPase
• PK?Pyruv. Carboxylase
• PEP carboxykinase

PEP CK
Pyruvate kinase
Pyruv. Carblase
4
Glucose is formed (from gluconeogenesis) only in
the liver (90) and kidney (10)
Glucose
GlucoseBLOOD 5 mM
Glucose 6-phosphatase (only found in the liver)
Glucokinase
KM10mM
KM3mM
Glucose 6-phosphate
Only liver (and kidney) make G6Pase
enzyme!!! The liver is a huge reservoir or
buffer for glucose Glucokinase rate never
achieves equilibrium/satn As G6P inside liver
increases, due to glucokinase and
gluconeogenesis, G6Pase increases
5
Fructose 1,6-bisphosphatase is the mirror image
of PFK1
Fructose 6-phosphate
Phosphofructokinase 1 (PFK1)
Fructose 1,6 bisphosphatase
Fructose 1,6-bisphosphate
Like PFK1, fructose 1,6-bisphosphatase is highly
regulated Fortunately (for you and your cells)
regulation is exactly opposite of each other
6
Coordinate Regulation of Glycolysis and
Gluconeogenesis Note dashed lines are
gluconeogenesis
7
Pyruvate Kinase (PK) is the third step that
cannot be reversed directly
Pyruvate must transit in and out of mitochondria
during conversion to PEP Oxaloacetate cannot
cross mito memb. Pyr Carbase only in liver and
kidney Malate can cross mito memb. Malate
dehydrogenase in both places PEP CK in cytosol
completes the detour NET Pyruvate ATP GTP
? Phosphoenolpyruvate GDP ADP P Note
Double above to make glucosei
8
Cost (ATPNADH) of Gluconeogenesis
Note ATP and GTP are equivalent in terms of cost
so while glycolysis generates 2 ATP per glucose
it costs 6 ATPs to reverse.
9
Glucagon is the main endocrine regulator of
gluconeogenesis
also
PK ? phosphoPK (active) ?
(inactive) Shuts off pyruvate prod. i.e. exit
from glycolysis