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71 Cards in this Set

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  • Back
What are the effects of insulin (2)?
- promotes uptake of glucose into muscle and adipose tissue
- promotes storage: glucose to glycogen and fatty acids, fatty acids to triglycerides
What are the effects of glucagon (4)?
- promote the conversion of glycogen to glucose
- promote biosynthesis of glucose
- promote release of fatty acids from adipose
- promote fatty acid oxidation
What cell types produce insulin?
Beta cells of the pancreas, located in the Islets of Langerhans
What cell types produce glucagon?
alpha cells of the pancreas, located in the Islets of Langerhans
How are blood levels of insulin and glucagon regulated?
Decrease in blood glucose leads to release of glucagon and epinephrine (from adrenal gland).
Increase in blood glucose leads to secretion of insulin.
Insulin inhibits secretion of glucagon and inhibits glucagon gene transcription.
What is the mechanism of action of glucagon on metabolism?
- triggers the synthesis of cAMP
- only liver and adipose react to glucagon, not muscle
What does cAMP activate?
protein kinase A (PKA)
What enzyme breaks down cAMP to AMP?
cAMP phosphodiesterase
What holds PKA in place?
Kinase anchoring proteins - anchor regulatory subunit to microtubules, actin filaments, mitochondria, plasma membranes
Which enzyme participates in the synthesis of cAMP? What is the precursor molecule for cAMP?
anenylyl cyclase, ATP
What tissues do glucagon and epinephrine work on?
Glucagon - liver and adipose
Epinephrine - muscle, liver, and adipose
How are levels of cAMP regulated?
PKA and Insulin activated kinase stimulate the phosphorylation of phosphodiesterase, activating it to convert cAMP to AMP.
What are the structural features of phosphoprotein phosphatase?
family of enzymes containing a constant catalytic subunit and a variable regulatory subunit
How is phosphoprotein phosphatase activity regulated?
regulated by phosphorylation of the regulatory subunit
What is the purpose of phosphoprotein phosphatase?
turn off proteins that are activated by PKA
What stimulates the production of phosphoprotein phosphatase inhibitor? Why?
cAMP, so that the proteins phosphorylated by PKA stay turned on
What are the dietary sources of glucose, fructose, and galactose?
Starch -> Glucose
Sucrose -> Glucose and Fructose
Glycogen -> Glucose
Lactose -> Galactose and Glucose
What are the structural features of glucose, fructose, and galactose?
Galactose and glucose are different on Carbon 4. Glucose and fructose are different on carbons 1 and 2.
How is glucose transported into hepatocytes? Does insulin stimulate transport?
GLUT 2, Km = 15mM
not stimulated by insulin
What is glucokinase?
a hexokinase enzyme specific to liver and beta cells in pancreas
converts glucose to glucose-6-phosphate, using ATP
What are the kinetic properties of glucokinase?
High Km = 8mM, so has low rate at resting blood glucose levels (5mM)
is not inhibited by glucose-6-phosphate
What is the effect of insulin on glucokinase?
- causes rapid increase in glucokinase mRNA
- leads to increase in amount of glucokinase
- cAMP turns off the transcription
- in diabetic lacking insulin, glucokinase is absent
How does glucokinase regulatory protein control levels of glucokinase?
- at low blood glucose, GRP is bound to glucokinase so it is inactive
- fructose-6-phosphate promotes binding
- glucose promotes reversal of binding
- fructose-1-phosphate inhibits binding
What enzyme is specific to fructose metabolism in the liver?
Aldolase B
What are the products of Aldolase B reaction?
fructose-1-phosphate -> glyceraldehyde + dihydroxyacetone phosphate
What is fructose intolerance?
hereditary deficiency in Aldolase B - depletes liver of phosphate and leads to lower ATP
What are the key enzymes in the conversion of galactose to glucose-1-phosphate?
galactokinase = galactose -> galactose-1-phosphate
galactose-1-phosphate uridylyl transferase = galactose-1-phosphate -> glucose-1-phosphate
What is the role of UDP-glucose in galactose metabolism?
exchanges a glucose for a galactose
What enzyme is deficient in galactosemia?
galactose-1-P uridylyl transferase, results in increased blood galactose, leading to failure to thrive, mental retardation, cataract formation
What reactions are involved in cataract formation?
aldose reductase - converts galactose and glucose to insoluble alcohols. Has a high Km (200mM), so only a problem if there is hgh blood galactose or glucose, like in galactosemia or diabetes.
What are the major carbon sources for gluconeogenesis?
1. Amino acids from dietary proteins and from tissue proteins (starvation)
2. Lactate from muscle and erythrocytes
3. Fructose and galactose
4. Glycerol from triglyceride breakdown
How is oxaloacetate formed from pyruvate? What regulates the reaction? What is the required cofactor and what vitamin is involved?
Pyruvate carboxylase converts pyruvate to oxaloacetate in the mitochondria, incorporating CO2 and using ATP. It uses a biotin cofactor (Vitamin B8). Acetyl CoA enhances the reaction.
What are the reactions involved in the conversion of pyruvate to phosphoenolpyruvate (PEP)?
Mitochondria: pyruvate -(CO2, ATP)> oxaloacetate -(NADH)> malate
Cytosol: malate -(NAD)> oxaloacetate -(GTP, CO2 out)> PEP
What happens when lactate is a precursor to pyruvate?
Conversion of pyruvate to PEP occurs entirely in mitochondria, since lactate to pyruvate produces NADH.
How does the malate shuttle operate?
transfers reducing equivalents to cytosol along with carbons from amino acids entering the TCA cycle and pyruvate derived form those amino acids
What is the alanine cycle?
In muscle, pyruvate gains a nitrogen from glutamate, and is converted to alanine. Alanine is shuttled to the liver, where the nitrogen is removed for excretion, and the remaining pyruvate can be converted to glucose and returned to the muscle for fuel.
How is pyruvate kinase (PEP-(ADP)>Pyruvate) regulated?
1. As in muscle, inhibited allosterically by ATP and alanine, stimulated by fructose-1,6-bisP
2. In liver, also regulated by phosphorylation (important in gluconeogenesis)
3. Insulin also regulates it by increasing transcription (important in glucose storage)
What are the three points in gluconeogenesis that are regulated?
1. Pyruvate to PEP
2. Fructose-1, 6-bisphosphate to Fructose-1-phosphate
3. Glucose-6-phosphate to glucose
What is the committed step in the synthesis of glucose via the TCA cycle?
Oxaloacetate (cytosol) -(GTP, CO2 out)> PEP
What is the enzyme involved in the reaction Oxaloacetate (cytosol) -> PEP?
PEP carboxykinase
How is PEP carboxykinase regulated?
regulated by transcription:
increased in starvation
increased by glucocorticoids and thyroid hormone
decreased by insulin
What is the effect of glucagon on pyruvate kinase? What is the mechanism for this action and why is the control important?
Glucagon stimulates PKA to phosphorylate pyruvate kinase, inactivating it. It is important for pyruvate kinase to be turned off in situations that require gluconeogenesis so PEP can be used for gluconeogenesis.
How does insulin modulate the activity of pyruvate kinase and what is the significance?
Insulin stimulates phosphoprotein phosphatase, which dephosphorylates pyruvate kinase, activating it. PEP can then be recycled to pyruvate, which can proceed to the TCA cycle.
How is pyruvate carboxylase regulated?
fatty acid mobilization and oxidation leads to Acetyl CoA, which increases the activity of pyruvate carboxylase and decreases the conversion of pyruvate to Acetyl CoA
What is the alanine cycle?
In muscle, pyruvate gains a nitrogen from glutamate, and is converted to alanine. Alanine is shuttled to the liver, where the nitrogen is removed for excretion, and the remaining pyruvate can be converted to glucose and returned to the muscle for fuel.
How is pyruvate kinase (PEP-(ADP)>Pyruvate) regulated?
1. As in muscle, inhibited allosterically by ATP and alanine, stimulated by fructose-1,6-bisP
2. In liver, also regulated by phosphorylation (important in gluconeogenesis)
3. Insulin also regulates it by increasing transcription (important in glucose storage)
What are the three points in gluconeogenesis that are regulated?
1. Pyruvate to PEP
2. Fructose-1, 6-bisphosphate to Fructose-1-phosphate
3. Glucose-6-phosphate to glucose
What is the committed step in the synthesis of glucose via the TCA cycle?
Oxaloacetate (cytosol) -(GTP, CO2 out)> PEP
What is the enzyme involved in the reaction Oxaloacetate (cytosol) -> PEP?
PEP carboxykinase
How is PEP carboxykinase regulated?
regulated by transcription:
increased in starvation
increased by glucocorticoids and thyroid hormone
decreased by insulin
What is the effect of glucagon on pyruvate kinase? What is the mechanism for this action and why is the control important?
Glucagon stimulates PKA to phosphorylate pyruvate kinase, inactivating it. It is important for pyruvate kinase to be turned off in situations that require gluconeogenesis so PEP can be used for gluconeogenesis.
How does insulin modulate the activity of pyruvate kinase and what is the significance?
Insulin stimulates phosphoprotein phosphatase, which dephosphorylates pyruvate kinase, activating it. PEP can then be recycled to pyruvate, which can proceed to the TCA cycle.
How is pyruvate carboxylase regulated?
fatty acid mobilization and oxidation leads to Acetyl CoA, which increases the activity of pyruvate carboxylase and decreases the conversion of pyruvate to Acetyl CoA
How is the fructose-6-phosphate ->fructose 1,6-bisP reaction regulated?
6-phosphofructo-1-kinase is stimulated by AMP, reversed by ATP
inhibited by citrate
stimulated by fructose-2,6-bisphosphate
What controls the synthesis of fructose-2,6-bisP?
Glucagon stimulates protein kinase A to phosphorylate (activate) the enzyme that converts f-2,6-bisP to f-6-P and phosphorylate (inactivate) the enzyme that catalyzes the reverse reaction.
What is the mechanism for the regulation by glucagons and insulin of the fructose-6-phosphate ->fructose 1,6-bisP reaction?
Glucagon stimulates PKA to decrease f-2,6-bisP production, which leads toa a decrease in f-1,6-bisP production, which leads to an increase in gluconeogenesis b/c of actions on glucokinase regulation. Insulin has the opposite effect.
How does the regulation of the fructose-6-phosphate ->fructose 1,6-bisP reaction in liver, cardiac muscle, and skeletal muscle differ?
Cardiac muscle - active PKA form epinephrine leads to increased glycolysis.
Skeletal muscle - not regulated by phosphorylation, but by an increase in fructose-6-phosphate, which leads to increased glycolysis
How is glucose produced from glucose-6-phosphate?
glucose-6-phosphatase, which is bound in the ER membrane, catalyzes the reaction in the ER lumen
How are glucokinase and glucose-6-phosphatase regulated by insulin and glucagon?
transcription
Insulin - increase glucokinase transcription, repress transcription of glucose-6-phosphatase
Glucagon - decrease transcription of glucokinase
How is glycerol converted to glucose?
glycerol -(ATP)> glycerol-3-phosphate -(NAD)> dihydroxyacetone-phosphate -> fructose-1,6-bisP -> fructose-6-P -> glucose-6-P -> glucose
What are the structural features of glycogen?
branched, with a reducing end and nonreducing ends
straight chains have alpha-1,4 linkages
branches have alpha-1,6 linkages
glycogenin bound at reducing end
How is glucose-1-phosphate formed from glycogen?
glycogen phosphorylase removes glucose-1-phosphate from the non-reducing end
reacts only at alpha-1,4 bonds
requires pyridoxal phosphate
How is glycogen synthesized?
glucose-6-phosphate -> glucose-1-phosphate -> UDP-glucose
glucose is then transferred to chain by glycogen synthase
What is the role of glycogenin?
primer - glycogen synthase will only add to an existing glycogen chain
What is the role of branching and debranching enzymes and how to they operate?
debranching enzyme breaks alpha-1,4 bond and forms a new one at the nonreducing end of the long chain, then releases free glucose from branch by hydrolyzing alpha-1,6 bond
How is glycogen phosphorylase regulated?
by phosphorylation (phosphorylase kinase), AMP, and glucose
How is glycogen synthase regulated?
phosphorylation inactivates the enzyme
How does glucose function as a sensor?
the active form of phosphorylase a senses glucose, causing a conformation change to the inactive form
How is calcium connected to the regulation of glycogen metabolism?
pushes phosphorylase to active form and increases activity of active form
What is the function of UDP-glucouronate and how is it synthesized?
important in drug metabolism
synthesized by oxidation of UDP-glucose
What are the various functions of UDP-glucose?
synthesis of glycogen
synthesis of glycolipids
synthesis of oligosaccharides and glycoproteins
breakdown of galactose