3. GLUCONEOGENESIS
synthesis of glucose from noncarbohydrate
precursors during longer periods of
starvation
a very important pathway since the brain
depends on glucose as its primary fuel
(120g of the 160g daily need for glucose)
and RBCs use only glucose as fuel
amount of glucose in body fluids is 20g and
the amount that can be derived from
glycogen is 190g
major noncarbohydrate sources are lactate,
amino acids, and glycerol
4. noncarbohydrate sources need to be first
converted to either
pyruvate,
oxaloacetate or
dihydroxyacetone phosphate (DHAP)
to be converted to glucose
major site is the liver with small amount taking
place in the kidneys
gluconeogenesis in the liver and kidneys helps
maintain the glucose demands of the brain and
muscles by increasing blood glucose levels
little occurs in the brain, skeletal muscle or
heart muscle
not a reversal of glycolysis
5. NONCARBOHYDRATE SOURCES
Pyruvate is converted to glucose in the
gluconeogenetic pathway
Lactate is formed by active skeletal muscle when
glycolytic rate exceeds oxidative rate; becomes
glucose by first converting it to pyruvate
Amino acids are derived from dietary proteins and
internal protein breakdown during starvation;
becomes glucose by converting them first to either
pyruvate or oxaloacetate
Glycerol is derived from the hydrolysis of
triacylglycerols (TAG) or triglycerides; becomes
glucose by conversion first to dihydroxyacetone
phosphate (DHAP)
6. IRREVERSIBLE STEPS of GLYCOLYSIS
Causes of most of the decrease in free energy
in glycolysis
Bypassed steps during gluconeogenesis
Steps catalyzed by the enzymes
Hexokinase
(glucose + ATP G-6-P + ADP)
Phosphofructokinase
(F-6-P + ATP F-1,6-BP + ADP)
Pyruvate kinase
(PEP + ADP Pyruvate + ATP)
7. NEW STEPS in GLUCOSE FORMATION from PYRUVATE via
GLUCONEOGENESIS
PEP is formed from pyruvate by way of
oxaloacetate Pyruvate carboxylase
Pyruvate + CO2 + ATP + HOH ------------ oxaloacetate + ADP + Pi + 2H+
PEP carboxykinase
Oxaloacetate + GTP ------------- PEP + GDP + CO2
F-6-P is formed from F-1,6-BP by hydrolysis of
the phosphate ester at carbon 1, an
exergonic hydrolysis
Fructose-1,6-bisphosphatase
Fructose-1,6-bisphosphate + HOH -------------- fructose-6-phosphate + Pi
Glucose is formed by hydrolysis of G-6-P
Glucose-6-phosphatase
Glucose-6-phosphate + HOH ------------- glucose + Pi
8. RECIPROCAL REGULATION OF GLYCOLYSIS
& GLUCONEOGENESIS
Glucose GLUCONEOGENESIS
F-2,6-BP + F-2,6-BP -
Fructose-6-phosphate
AMP +
PFK F-1,6-BPase
AMP -
ATP - Citrate +
Fructose-1,6-bisphosphate
Citrate -
Several steps ADP -
H+ -
PEP
PEP
F-1,6-BP + carboxykinase
PK Oxaloacetate
ATP -
Pyruvate Pyruvate AcetylCoA +
Alanine -
carboxylase
ADP -
9. GLYCOGEN
Readily mobilized storage form of glucose
very large, branched polymer of glucose
residues linked via α-1,4 (straight) and α-
1,6 glycosidic bonds
branching occurs for every 10th glucose
residue of the open helical polymer
not as reduced as fatty acids are and
consequently not as energy-rich
serves as buffer to maintain blood sugar
levels
Released glucose from glycogen can provide
energy anaerobically unlike fatty acids
10. Two major sites of glycogen storage are the
liver (10% by weight) and skeletal muscles (2%
by weight)
In the liver, its synthesis and degradation are
regulated to maintain normal blood glucose
in the muscles, its synthesis and degradation is
intended to meet the energy needs of the
muscle itself
present in the cytosol as granules (10-40nm)
11. GLYCOGENOLYSIS
Consists of three steps
1. release of glucose-1-phosphate from
from the nonreducing ends of
glycogen (phosphorolysis)
2. remodeling of glycogen substrate to
permit further degradation with a transferase
and α-1,6 glucosidase
3. conversion of glucose-1-phosphate
to glucose-6-phosphate for further
metabolism
12. Fates of Glucose-6-Phosphate
Initial substrate for glycolysis
Can be processed by the pentose
phosphate pathway to NADPH and
ribose derivatives
Can be converted to free glucose in the
liver, intestine and kidneys for release into
the blood stream
13. Glycogen
Glycogen n-1 Glycogen phosphorylase
Glucose-1-phosphate
Phosphoglucomutase
Glucose-6-phosphate
Muscle,Brain
Glycolysis Glucose-6-phosphatase PPP
Liver
Pyruvate Glucose Ribose +
NADPH
Lactate CO2 + HOH
Blood for use by
other tissues
14. GLYCOGENESIS
Regulated by a complex system and requires a
primer, glycogenin
Requires an activated form of glucose, the
Uridine diphosphate glucose (UDP-
glucose) formed from UTP and glucose-1-
phosphate
UDP-glucose is added to the nonreducing end of
glycogen using glycogen synthase, the key
regulatory enzyme in glycogen synthesis
Glycogen is then remodeled for continued
synthesis
15. GLYCOGEN BREAKDOWN & SYNTHESIS ARE
RECIPROCALLY REGULATED
Glycogen breakdown Glycogen synthesis
Epinephrine
Adenylate cyclase Adenylate cyclase
ATP cAMP
Protein kinase A Protein kinase A
Phosphorylase kinase Phosphorylase kinase Glycogen synthase a Glycogen synthase b
Phosphorylase b Phosphorylase a
PINK – inactive GREEN - active
16. GLYCOGEN STORAGE DISEASE
TYPE DEFECTIVE ORGAN AFFECTED GLYCOGEN IN CLINICAL FEATURES
ENZYME AFFECTED ORGAN
I (Von Gierke) Glucose-6- Liver & kidney Increased amount; Hepatomegaly, failure to thrive,
phosphatase normal structure hypoglycemia, ketosis,
hyperuricemia, hyperlipidemia
II (Pompe dse) α-1,4 glucosidase All organs Massive increase in Cardiorespiratory failure causes
amount; normal death usually before age 2
structure
III (Cori dse) Amylo-1,6- Muscle & liver Increased amount; Like type 1 but milder
glucosidase short outer branches
(debranching)
IV (Andersen Branching enzyme Liver & spleen Normal amount; very Progressive cirrhosis of the liver;
dse) (α-1,4 & 1,6) long outer branches liver failure causes death before
age 2
V (McArdle dse) Phosphorylase muscle Moderately Limited ability to perform
increased amount; strenuous exercise because of
normal structure painful muscle cramps.
Otherwise patient is normal or
well-developed.
VI (Hers dse) Phosphorylase liver Increased amount Like type 1 but milder
VII Phosphofructokina muscle Increased amount; Like type V
se normal structure
VIII Phosphorylase liver Increased amount; Mild liver enlargement. Mild
kinase normal structure hypoglycemia