What is glycogen?
branched polymer of glucose
storage form of glucose in cytoplasm
synthesis and degradation largely in liver and skeltal muscle
--cardiac muscle and kidney store in smaller quantities
How can glycogen be stored?
single granules: skeletal muscle
--stored as energy for muscle contraction
fast twitch: glucose converted primarily to lactate
slow twitch: glucose is completely oxidized
clusters of granules: liver
--stored to be mobilized during hypoglycemia
What is the structure of the granule?
central protein core (glycogenin) with polyglucose chains radiaing outward
--only linear chains: highest density of glucose near core
--branched: highest density of glucose at periphery; allow more rapid release of glucose
How is glycogen synthesized?
core protein glycogenin
--begins with glucose 6 phosphate
converted to glucose 1 phosphate and activated UDP-glucose for addition to glycogen chain by glycogen synthase
--glycogen synthase is rate limiting enzyme
What is the function of glycogen synthase? What activates and inhibits it?
forms alpha 1,4 glycosidic bonds in linear glucose chains of granule
--activated by: insulin in the liver and skeletal muscle
--inhibited by glucagon and epinephrine in the liver and epinephrine in skeletal muscle
What is the function of branching enzyme (alpha 1,4:alpha 1,6 transferase)?
introduces alpha 1,6 linked branches
--hydrolyzes one of the alpha 1,4 bonds to release a block of oligoglucose, which is moved and added in different location
--forms an alpha 1,6 bond to create a branch
What is the rate limiting enzyme of glycogenolysis?
--breaks alpha 1,4 glycosidic bonds using Pi
--glucose 1 phosphate formed is converted to glucose 6 phosphate by same mutase used in glucose synthase
--cannot break alpha 1,6 bonds; stops when it nears outermost branch points
What activates and inhibits glycogen phosphorylase?
activated: epinephrine, glucagon
inhibited by: insulin
activated by: epinephrine, AMP, Ca2+ (through calmodulin)
inhibited by: inulin and ATP
What is the function of debranching enzyme (glucosyl alpha 1,4: alpha 1,4 transferase and alpha 1,6 glucosidase)?
deconstructs branches in glycogen
--breaks an alpha 1,4 bond adjacent to branch point and moves it to small oligoglucose chain released to the exposed end of the other chain
--forms new alpha 1,4 bond
--hydrolyzes alpha 1,6 bond, releasing the single reisdue at the branch point as free glucose (only free glucose produced directly in glycogenolysis)
What is von Gierke disease?
glucose 6 phosphatase deficiency
fasting hypoglycemia, lactic acidosis, hepatomegaly
--glycogen deposits in the liver (G6P stimulates glycogen sythesis and glycogenolysis in inhibited)
--hyperuricemia predisposing to gout; decreased Pi causes increased AMP, which is degraded to uric acid--lactate slows uric acid excretion in the kidney
--hyperlipidemia with skin xanthomas; elevation of triglycerides (VLDL)
--ingestion of galactose or fructose and adminstration of glucagon and epinephrine causes no increase in blood glucose
What is myophosphorylase deficiency?
muscle glycogen phosphorylase deficiency
unable to properly break down glycogen to G6P in muscles
--exercise intolerance during initial phase of high intensity exercise
--recovery or second wind after 10-15 minutes of exercise
ameliorated by drinking sucrose rich soft drinks--provides dietary glucose for muscles to use
What is hepatic glycogen phosphorylase deficiency?
relatively mild becuase gluconeogensis compensates for lack of glycogenolysis
symptoms: hypoglycemia, hyperlipidemia, hyperketosis are mild
hepatomegaly, growth retardation in early childhood
What is lysosomal alpha 1,4 glucosidase deficiency?
deficient enzyme normally reisdes in lysosome
responsible for digseting glycogen-like material accumulating in endosomes (inclusion bodies)
tissues most severely affected arethose that normally have glycogen stores
infantile onset: massive cardiomegaly--cause of death by 2 years of age
symptoms: slowly progressing muscle weakness involving arms and legs, difficulty breathing, enlarged liver
What is Andersen disease?
What is Cori disease?
What is gluconeogenesis?
promoted by glucagon and epinephrine and inhibited by insulin
--gluconeogenesis when glycogen reserves drop after 12 hours
after 24 hours, it is sole source of glucose
What are important substrates for gluconeogenesis?
glycerol 3 phosphate (from triacylglycerol in adipose)
lactate (from anaerobic glycolysis)
gluconeogenic amino acids (protein from muscle)
What are the ketogenic and glucogenic amino acids?
What are the steps of gluconeogenesis?
What can and cannot be converted to glucose in the liver?
can be converted:
*dietary fructose and galactose in liver
*odd number cabon fatty acids yield small amount of propionyl CoA that is gluconeogenic
cannot be converted:
*acetyl CoA to glucose
*FA converted to acetl CoA so not major source of glucose
What enzyme coonverts lactate to pyruvate in gluconeogenesis?
lactate dehydrogenase oxidizes lactate --> pyruvate
What is the function of alanine in gluconeogenesis?
important gluconeogenic amino acid
converted to pyruvate via alanine aminotransferase (ALT or GPT)
What converts glycerol 3 phopsphate to dihydroxyacetone phosphate (DHAP)?
glycerol 3 phosphate dehydrogenase: oxidizes
What is the function of pyruvate carboxylase?
mitochondrial enzyme requiring biotin
--activated by acetyl CoA from beta oxidation
--product oxaloacetate (TCA intermediate) can't leave mitochondria
--reduced to malate that can leave via malate chuttle
--in cytoplasm: malate reoxidized to OAA
What is the function of phosphoenolpyrvuate carboxykinase (PEPCK)?
induced by glycagon and coritsol
converts OAA to phosphoenolpyrvuate (PEP)
PEP then converted F1,6bisphosphate
What is the function of fructose 1,6 bisphosphate?
key control point in gluconeogenesis
hydrolyzes phosphate from F1,6 bisphosphate
phosphatases oppose kinases
activated by: ATP
inhibited by: AMP, fructose 2,6 bisphosphate
F26bisphosphate: produced by PFK2 controls gluconeogensis and glycolysis (in liver)
--PFK2 is activated by insulin and inhibited by glucagon
--glucagon will lower F26BP and stimulate gluconeogenesis
--insulin will increase F26BP and inhibit gluconeogenesis
What is the function of glucose 6 phosphatase?
lumen of ER
G6P is transported into ER
free glucose transported back into cytoplasm where it leaves cell
only in liver
absense in skeletal muscle: why muscle glycogen can't serve as source of blood glucose
What are the gluconeogenic amino acids
18 of 20 (all except leucine and lysine) are gluconeogenesis
most are converted to TCA intermediates then to malate
How is gluconeogenesis and beta oxidation related?
glucose produced by hepatic gluconeogenesis goesn't represent energy source for liver
gluconeogenesis requires expenditure of ATP that is provided by beta-oxidation of FA
--during hypoglycemia, adipose tissue releases fatty acids by breaking down triglyceride
What occurs with biotin deficiency?
symptoms: alopecia, scaly dermatitis, waxy pallow, acidosis (mild)
causes: raw egg whites (avidin)
long term home TPN
How is acetyl CoA from FA utilized?
can't be converted to glucose but can be converted to ketone bodies as alternative fuel for cells, including brain
--chronic hypoglycemia: accompanied by increase in ketone bodies
How does acetyl CoA regulate mitochondrial enzymes that use pyruvate?
pyruvate carboxylase & pyruvate dehydrogenase
--between meals, when FA oxidized in liver for energy, accumulating acetyl CoA activates pyruvate carboxylase and gluconeogensis and inhibits PDH,thus preventing conversion of lactate and alanine to acetyl CoA
--in well fed, absorptive state (insulin), accumulating acetyl CoA is shuttle into cytoplasm for FA synthesis; OAA in necessary for transport and acetyl CoA can stimulate its formation from pyruvate
What is the Cori cycle?
during fasting, lactate from RBC (and exercising skeletal muscle( is converted to glucose in the liver that can be returned to the RBC or muscle
What is the alanine cycle?
msucles releases alanine delivering a gluconeogenic substrate (pyruvate) and an amino group for urea synthesis
Why are alcoholics suscpetible to hypoglycemia?
alcohol is metabolized to acetate (acetyl Coa)
high amounts fo cytoplasmic NADH formed by alcohol dehydrogenase and acetaldehyde dehydrogenase interfere with gluconeogensis
high NADH favors formation of:
--lactate from pyruvate
--malate from OAA in cytoplasm
--glycerol 3 phosphate from DHAP
diverts important gluconeogenic substrates from entering the pathway
accumulation of cytoplasmic NADH and glycerol 3P-->lipid accumulation in alcoholic liver disease
--free FA released form adipose in part enter the liver where beta oxidation is very slow (high NADH)
in presence of high glycerol 3 phosphate, fatty acids are inappropriately sotred in liver as triglyceride
What occurs with extreme exercise and alcohol consumption?
excessive alcohol consumption --> hypoglycermia after running marathon
--exercising muscle, lactic acid builds up in muscle due to anaerobic glycolysis ,causing muscle cramping and pain
lactate spills into blood and converted to glucose in liver (Cori cycle)
to carry out gluconeogensis NAD is required by lactate dehydrogenase to oxidize lactate to pyruvate
but much of NAD is being used for ethanol metabolism and is unavailable for lactate oxidation
result=metabolic acidosis and hypoglycemia
What is the hexose monophosphate shunt? (pentose phosphate pathway)
cytoplasm of all cells
functions=NADPH production and source of ribose 5P for nucleotide synthesis
What is the rate limiting enzyme of the HMS?
Glucose 5 phosphate dehydrogenase (G6PDH)
--induced by insulin and NADP
--inhibited by NADPH
What are the importance of the frcutose 6P and glyceraldehyde 3P intermediates in the HMS?
can feed back into glycolysis
can make pentoses without going through G6PDH reaction via transketolase (thiamine requiring enzyme)
--transketolase is only thiamine enzyme in RBC
What are the functions of NADPH?
maintenance of a supply of reduced glutathione to protect against reactive oxygen species (ROS)
bactericidal activity in polymorphonuclear leukocytes (PMN)
What is favism?
ingestion of Fava beans may cause severe hemolysis in G6PDH individuals
symptoms: pallor, hemoglobinuria, jaundice, severe anemia 24-48 hours after ingestion of beans
common in: Greece, Italy, Spain, Portugal, Turkey
What is chronic granulomatous disease (CGD)?
deficiency of NADPH oxidase in PMN
susceptible to infection by catalase positive organsms (Staph. aureus, Klebsiella, Escherichia coli, Candida, Aspergillus)
negative nitroblue tetrazolium test: positive diagnosis
What is a benefit of G6PDH deficiency?
many parasites (plasmodium) are deficient in antioxidant mechanisms--making them susceptible to oxygen radicals
--G6PDH deficiency: ability of erythrocytes to detoxify oxygen radicals is impaired
accumulation of radicals in erythrocytes in G6PDH deficiency gives protection against malaria
What is G6PDH deficiency?
hemolytic anemia, symptoms resemble CGD (insufficient activity of G6PDH in PMN to generate NADPH from the NADPH oxidase bactericidal system)
X linked recessive
acute episodic or rarely chornic hemolysis
female carrier: increased resistance to malaria
most likely cause of hemolytic episode is overwhelming infection, often pneumonia (viral and bacterial) or infectious hepatitis
mutation may decrease the activity od G6PDH sufficiently to cause chronic nonspherocytic hemolytic anemia
What is the function of ROS in RBC?
RBC contain a large amount of oxygen
prone to spntaneously generate ROS that dmage protein and lipid in cell
in presence of ROS, hemoglobin may precipitate (heinz bodies) and membrane lipids may undergo peroxidation, weakening the membrane and causing hemolysis
as peroxides form, they are rapidly destroyed by the glutathione peroxidase/glutatione reductase system in the red bloo cell
--NADPH required by glutathione reductase is supplied by teh HMP shutn in the erythrocyte