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GLUCONEOGENESIS

GLYCOGEN METABOLISM
 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
 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
 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)
 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)
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
 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 -
 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
 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)

 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
 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
 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
 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
 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

 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
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