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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
F-2,6-BP +
GLUCONEOGENESIS F-2,6-BP
Fructose-6-phosphate
AMP +
-
ATP
Citrate H+
PFK
AMP
F-1,6-BPase
-
-
Citrate + Fructose-1,6-bisphosphate
-
Several steps
PEP F-1,6-BP + ATP
PK
-
Alanine
-
ADP
-
PEP carboxykinase Oxaloacetate
Pyruvate
AcetylCoA + Pyruvate carboxylase ADP -
GLYCOGEN Readily mobilized storage form of glucose very large, branched polymer of glucose residues linked via α-1,4 (straight) and α1,6 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 ď Ź
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 Îą-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 phosphorylase Glycogen n-1 Glucose-1-phosphate Phosphoglucomutase
Glucose-6-phosphate Muscle,Brain
Glycolysis
Glucose-6-phosphatase
PPP
Liver
Pyruvate Lactate
Glucose
CO2 + HOH
Blood for use by other tissues
Ribose + NADPH
GLYCOGENESIS
Regulated by a complex system and requires a primer, glycogenin
Requires an activated form of glucose, the Uridine diphosphate glucose (UDPglucose) formed from UTP and glucose-1phosphate
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
Protein kinase A
Phosphorylase kinase
Phosphorylase kinase
Phosphorylase b
cAMP
Protein kinase A
Glycogen synthase a
Glycogen synthase b
Phosphorylase a
PINK – inactive
GREEN - active
GLYCOGEN STORAGE DISEASE TYPE
DEFECTIVE ENZYME
ORGAN AFFECTED
GLYCOGEN IN AFFECTED ORGAN
CLINICAL FEATURES
I (Von Gierke)
Glucose-6phosphatase
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-1,6glucosidase (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
Phosphofructokina se
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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