Download The importance of gluconeogenesis as an important

Glucose Metabolism: Gluconeogenesis
By
Reem M. Sallam, MD, PhD
Assistant Prof. , Clinical Chemistry Unit,
Pathology Dept., College of Medicine, KSU
[email protected]
Objectives
The importance of gluconeogenesis as an
important pathway for glucose production
 The main reactions of gluconeogenesis
 The rate-limiting enzymes of gluconeogenesis
 Gluconeogensis is an energy-consuming,
anabolic pathway
Gluconeogenesis: An Overview
• In the absence of dietary intake of carbohydrate, liver
glycogen is an important source of glucose (through
glycogenolysis) to meet the tissue needs for 10-18 hours.
• During prolonged fasting, liver glycogen stores are depleted,
and glucose is formed by gluconeogenesis.
• During Overnight fast:
• 90% of gluconeogenesis occurs in liver
• 10% of gluconeogenesis occurs in Kidneys
• During Prolonged fast:
• 60% of gluconeogenesis occurs in liver
• 40% of gluconeogenesis occurs in Kidneys
• Gluconeogenesis requires both mitochondrial & cytosolic
enzymes (exception: if gluconeogenesis starts by Glycerol, it
will need only the cytosol)
Gluconeogenic Pathway

Seven glycolytic reactions are reversible & are used in gluconeogenesis from lactate or pyruvate.

Three glycolytic reactions are irreversible & must be reversed (by 4 alternate reactions) in gluconeogenesis.
These reactions are:
Glyolysis
Gluconeogenesis
Pyruvate Kinase:
(PEP 
Pyruvate)
1- Pyruvate Caroxylase: Carboxylation reaction, requires Biotin and ATP,
occurs in the mitochondria, allosterically activated by acetyl CoA. OAA has to be
transported from mitochondria to cytosol.
(PyruvateOxaloacetate “OAA”)
2- PEPCK: Decarboxylation & phosphorylation reaction, requires energy (GTP),
occurs in cytosol, the enzyme’s gene is induced by glucagon & repressed by insulin
(Oxaloacetate  PEP)
PFK-1:
(Fructose 6-P 
Fructose 1,6
Bisphosphate)
3- Fructose 1,6 Bisphosphatase: Dephosphorylation reaction. It is inhibited by
high levels of AMP, and activated by high levels of ATP & low levels of AMP. It is
allosterically inhibited by Fructose 2,6-bisphosphate (reciprocal regulation with
glycolysis)
(Fructose 1,6 BisphosphateFructose 6-P )
Hexokinase:
(Glucose 
Glucose 6-P)
4- Glucose 6-Phosphatase: Dephosphorylation reaction, enzyme is found only
in liver and kidney
(Glucose 6-P  Glucose)
Gluconeogenic Substrates
 They are molecules that can be used to produce glucose
through gluconeogenesis pathway.
 They include:
 Intermediates of glycolysis and of TCA cycle
 Glycerol
 Lactate & Pyruvate
 Glucogenic amino acids
The most important
gluconeogenic
precursors
Gluconeogenic Substrates: Glycerol
 Glycerol is released during the hydrolysis of Triacylglycerol
(TAG) in adipose tissue.
 In liver and kidney, glycerol will be phosphorylated by
glycerol kinase to glycerol-P.
 Glycerol-P will be oxidized by glycerol-P dehydrogenase to
dihydroxyacetone phosphate(DHAP: an intermediate of
glycolysis).
Gluconeogenic Substrates: Glucogenic
Amino Acids (AAs)
 AAs can be derived from hydrolysis of tissue proteins.
 Example of Glucogenic AA are:
Amino Acids
Sites of entrance to the Krebs
Cycle
Glutamate and Glutamine
Alpha keto Glutarate (KG)
Methionine & Valine
Succinyl CoA
Phenylalanine & Tyrosine
Fumarate
Aspartate & Asparagine
OAA
Alanine & Glycine amino acids are gluconeogenic substrates
through conversion to Pyruvate
Gluconeogenic Substrates: Lactate
(Cori Cycle)
 Lactate is released into the blood by exercising skeletal
muscle & by cells lacking mitochondria (Anaerobic glycolysis
of glucose).
 Lactate is taken up by the liver and reconverted to glucose
(gluconeogenesis)
 Glucose will then be released to the circulation to be used by
skeletal muscles.
Gluconeogensis:
Energy Consumed
With the formation of each molecule of glucose
from pyruvate:

six high-energy phosphate bonds are cleaved

& two NADH are oxidized
Regulation of Gluconeogenesis:
by AMP
 Elevated AMP  stimulates glycolysis (at the PFK-1
step) & inhibits gluconeogenesis (at the Fructose
1,6-bisphosphatase step)
Regulation of Gluconeogenesis:
Pruvate Carboxylase regulation by Acetyl CoA
 Fasting  ↑lipolysis in adipose tissue  ↑ Free
Fatty Acid (FFA) to liver  The capacity of the liver
for FA oxidation is exceeded  accumulation of
Acetyl CoA  allosteric activation of pyruvate
carboxylase to increase the Gluconeogensis rate
Gluconeogenesis: Regulation by
Glucagon
↑Glucagon (or ↓ Insulin/Glucagon
ratio): stimulates gluconeogenesis by the
following mechanisms:
1.
Allosteric (glucagon lowers the level of
Fructose 2,6-Bisphosphate activation of
Fructose 1,6-Bisphosphatase & inhibition of
PFK-1 (Reciprocal regulation of
gluconeogenesis & glycolysis)
2. Induction (glucagon  induction of PEP-CK
gene)
Gluconeogenesis: Summary for
Regulation
• Reciprocal control
Gluconeogenesis & Glycolysis
• Allosteric:
↑Acetyl CoA  stimulates Pyruvate carboxylase
↓ AMP or ↑ ATP
(i.e. energy-rich state in cells)
↓ F 2,6-Bisphosphate
 Stimulate F 1,6-bisphosphatase
• ↑Glucagon (or ↓ I/G ratio): stimulates gluconeogenesis by:
Allosteric regulation (glucagon  ↓ F 2,6-Bisphosphate)
Induction (glucagon  induction of PEP-CK gene)
Take Home Message
• Gluconeogenesis:
•Synthesis of glucose from noncarbohydrates
•Anabolic
•Energy-consuming
• 4 Unique enzymes are required for
reversal of the 3 irreversible reactions
of glycolysis
• Both gluconeogenesis & glycolysis are
reciprocally-regulated