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7
Gluconeogenesis
[BIOCHEM] 2.7 Gluconeogenesis
Dr.
Magat
Dr. M. Magat
August 8, 2013
OUTLINE
I.
I. Overview of Gluconeogenesis
II. Important cycles between tissues that involve
Gluconeogenesis
A. Cori cycle (Glucose Lactate cycle)
B. Alanine cycle (Glucose Alanine cycle)
III. Pathways of Glucose Synthesis
A. Gluconeogenesis from Amino Acids
B. Gluconeogenesis from Triacylglycerol
C. Gluconeogenesis from Other Sugars
IV. Metabolic Steps of Gluconeogenesis
V. Gluconeogenic Enzymes
VI. Regulation
A. Expenditure of ATP
B. Regulation of gluconeogenesis
C. Hormonal control
D. Fates of lactate formed during muscle
contraction
E. PEPCK regulation in promoter region
VII. Summary
VIII. Appendix
IX. Study Guide
OBJECTIVES
At the end of the lecture, the student should be able to:
1. Appreciate that glucose can be synthesized from lactate,
pyruvate, amino acids, triacylglycerides, and fructose
2. Understand that gluconeogenesis is mostly the reverse of
glycolysis with a few bypassed reactions
3 Discuss the metabolic steps of gluconeogenesis
4. Discuss the regulation of gluconeogenesis
References:
Devlin, Thomas M. Textbook of Biochemistry with Clinical
Correlations. 7th ed.: Wiley, 2010.
Murray, Robert K. Harper's Illustrated Biochemistry. 29th
ed.: McGraw-Hill, 2012. Print.
Nelson, David L. Lehninger's Principles of Biochemistry. 5th
ed. 2009.
Stryer, Lubert. Biochemistry. 6th ed. 2006.
Marks, Allan D. Mark's Basic Medical Biochemistry a Clinical
Approach. 2nd ed., 2005.
Grisham, Charles M. Biochemistry. 4th ed. 2010.
Voet, Donald J. Principles of Biochemistry.: Wiley, 2008.
Harvey, Richard A. Biochemistry (Lippincott's Illustrated
Reviews). 5th ed., 2010.
Boyer, Rodney F. Concepts in Biochemistry. 3rd ed., 2005.
2016A. Gluconeogenesis Trans
Madarcos Notes
th
[Devlin, 7 Ed]
th
[Harper, 29 Ed]
II.
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OVERVIEW OF GLUCONEOGENESIS
A.
Glucogenic
Glycine
Serine
Valine
Histidine
Arginine
Cysteine
Proline
Hydroxyproline
Alanine
Glutamate
Glutamine
Aspartate
Asparginine
Methionine
B.
Ketogenic
Leucine
Lysine
Both
Threonine
Isoleucine
Phenylalanine
Tyrosine
Tryptophan
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b.
GALACTOSE
FRUCTOSE
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Reaction
Pyruvate + CO2 + ATP Oxaloacetate + ADP + Pi
2-phosphoglycerate 3-phosphoglycerate
Glyceraldehyde-3-PO4 Dihydroxyactone-PO4
9
10
Fructose-6-PO4 Glucose-6-PO4
11
Mitochondrial enzyme
Requires biotin as coenzyme
First regulatory enzyme in the gluconeogenic
pathway
Requires acetyl-CoA as a positive effector
Note: Acetyl-CoA is produced by fatty acid
oxidation and its accumulation signals the
availability of fatty acids as fuel
It is a Mg dependent reaction
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Enzyme: Enolase
Step 4: Conversion
phosphoglycerate
3-
Enzyme: Aldolase A
of
2-phosphoglycerate
to
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Enzyme: Fructose-1,6-bisphosphatase
V.
1.
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GLUCONEOGENIC ENZYMES
Pyruvate Carboxylase
OxaloacetatePhosphoenolpyruvate Step2 of 2
Cytosolic/mitochondrial enzyme
2.
4.
Cytosolic PEPCK
Glucose 6-Phosphatase
Glucose 6 phosphate Glucose
Induced during fasting
In luminal side of the ER
Present in liver and kidney
Absent in muscle, adipose and brain tissue,
therefore cannot export glucose into the
bloodstream
2+
Mg enzyme found on the luminal side of the
endoplasmic reticulum of hepatocytes and renal
cells
Enzyme
Positive
effectors
Negative
effectors
PC/PEPCK
Acetyl CoA
F 1,6-BP
F 1,6-BPase
F 2,6-BPase,
AMP
G6Pase
F6P
VI. REGULATION
A.
EXPENDITURE OF ATP
Induced
by
glucagon,
epinephrine
and
glucocorticoids
Repressed by insulin
B.
3.
Fructose 1,6-bisphosphatase
REGULATION OF GLUCONEOGENESIS
Phosphorylates
and
inactivates
pyruvate
dehydrogenase complex
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Favors gluconeogenesis
Activation of F1,6-BPase
C.
HORMONAL REGULATION
CATECHOLAMINES
Gluconeogenesis is stimulated:
o By blocking conversion of PEP to pyruvate
o Decreased concentration of fructose 2,6bisphosphate (allosteric effector of 6phosphofructo-1-kinase; allosteric inhibitor of
Fructose 1,6-BPase)
ACTIVATION
OF
GLYCOLYSIS
(LIVER:
FROM
GLUCONEOGENESIS TO GLYCOLYSIS)
Inhibition
or
uncoupling
of
oxidative
phosphorylation
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Bifunctional enzyme
Phosphorylation of this enzyme is stimulated by
cAMP
When phosphorylated
o Kinase activity: INACTIVE
o Phosphatase activity: ACTIVE
Fructose-2,-6-Bisphosphate
o Potent stimulator of phosphofructokinase
o Powerful
inhibitor
of
fructose-1,6bisphosphatase
INSULIN
Inhibits gluconeogenesis
LACTATE
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2.
3.
4.
Enzyme
Pyruvate
carboxylase and
PEP
carboxykinase
(PEPCK)
Fructose-1,6Bisphosphatase
Glucose-6phosphatase
5.
6.
7.
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Step # in
Glycolysis
Pyruvate kinase
10
Phosphofructokinase
(PFK)
Hexokinase/Glucokinase
8.
9.
Parent Compound
Product
DNA
DNA
RNA
DNA
DNA
Protein
Conditions
Activation
Inhibition
Pathway active
High AMP
concentration
Phosphofructokinase
Glycolysis
Phophofructokinase
Gluconeogenesis
Pyruvate Kinase
Gluconeogenesis
ADP
Pyruvate
Carboxylase
PEP Carboxykinase
Glycolysis
Acetyl CoA
Pyruvate
Carboxylase
Gluconeogenesis
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Intracellular
Location
Nucleus
Nucleus
Cytoplasm
Additional
Information
Citrate is an indicator
of the status of TCA
which means energy
charge
is
high,
biosynthetic
intermediates
are
abundant
(for
gluconeogenesis)
Energy charge is
high,
Biosynthetic
intermediates
are
abundant.
Like
Citrate
(indicates status of
TCA)
2.
B.
C.
D.
3.
The uncontrolled production of NADH from NAD during ethanol metabolism blocks gluconeogenesis from all of the
following EXCEPT:
A. galactose
B. glycerol
C. -ketoglutarate
D. oxaloacetate
4.
5.
Elevated levels of circulating glucagon are associated with which one of the following:
A. Increased activity of phosphofructokinase-2
B. Decreased level of fructose-2,6-bisphosphatase
C. Decreased fructose-1,6-bisphosphatase activity
D. Fasting
E. Ingestion of a carbohydrate-rich meal
6.
Answers: D, B, A, D, D, C
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