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GLYCOGEN METABOLISM
GLUCONEOGENESIS
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 + CO2 + ATP + HOH ------------ oxaloacetate + ADP + Pi + 2H+
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-bisphosphate + HOH -------------- fructose-6-phosphate + Pi
Glucose is formed by hydrolysis of G-6-P
Glucose-6-phosphate + HOH ------------- glucose + Pi
Pyruvate carboxylase
PEP carboxykinase
Fructose-1,6-bisphosphatase
Glucose-6-phosphatase
RECIPROCAL REGULATION OF GLYCOLYSIS & GLUCONEOGENESIS
Glucose
Fructose-6-phosphate
Fructose-1,6-bisphosphate
PEP
Pyruvate
Oxaloacetate
PFK F-1,6-BPase
Several steps
PK
PEP carboxykinase
Pyruvate carboxylase
GLUCONEOGENESIS
F-2,6-BP +
AMP +
ATP -
Citrate -
H+ -
F-2,6-BP -
AMP -Citrate +
F-1,6-BP +
ATP -
Alanine - AcetylCoA +
ADP -
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
GlycogenGlycogen n-1
Glucose-1-phosphate
Glucose-6-phosphate
Glycolysis PPP
Pyruvate Glucose Ribose + NADPH
Lactate CO2 + HOHBlood for use by
other tissues
Muscle,Brain
Liver
Glycogen phosphorylase
Glucose-6-phosphatase
Phosphoglucomutase
GLYCOGENESIS Regulated by a complex system and requires a
primer, glycogenin
Requires an activated form of glucose, theUridine 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 synthesisEpinephrine
Adenylate cyclase Adenylate cyclase
ATP cAMP
Protein kinase A Protein kinase A
Phosphorylase kinase Phosphorylase kinase
Phosphorylase b Phosphorylase a
Glycogen synthase a Glycogen synthase b
PINK – inactive GREEN - active
GLYCOGEN STORAGE DISEASETYPE DEFECTIVE
ENZYMEORGAN AFFECTED GLYCOGEN IN
AFFECTED ORGANCLINICAL FEATURES
I (Von Gierke) Glucose-6-phosphatase
Liver & kidney Increased amount; normal structure
Hepatomegaly, failure to thrive, hypoglycemia, ketosis, hyperuricemia, hyperlipidemia
II (Pompe dse) α-1,4 glucosidase All organs Massive increase in amount; normal structure
Cardiorespiratory failure causes death usually before age 2
III (Cori dse) Amylo-1,6-glucosidase (debranching)
Muscle & liver Increased amount; short outer branches
Like type 1 but milder
IV (Andersen dse)
Branching enzyme (α-1,4 & 1,6)
Liver & spleen Normal amount; very long outer branches
Progressive cirrhosis of the liver; liver failure causes death before age 2
V (McArdle dse) Phosphorylase muscle Moderately increased amount; normal structure
Limited ability to perform strenuous exercise because of painful muscle cramps. Otherwise patient is normal or well-developed.
VI (Hers dse) Phosphorylase liver Increased amount Like type 1 but milder
VII Phosphofructokinase
muscle Increased amount; normal structure
Like type V
VIII Phosphorylase kinase
liver Increased amount; normal structure
Mild liver enlargement. Mild hypoglycemia
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