Chapter 9: Carbohydrate Metabolism I: Glycolysis, Glycogen, Gluconeogenesis, Pentose Phosphate Pathway Flashcards
What level should blood glucose concentrations be?
What is the long term damage of high and low blood sugar?
Blood glucose concentrations are tightly maintained around 100mg/dL (5.6 mM).
High blood glucose concentrations over time can cause damage to the retina, kidney, blood vessels, and nerves.
Low blood sugar can cause autonomic disturbances, seizures, and even coma.
What are the four glucose transporters?
What are the more significant glucose transporters?
GLUT 1, 2, 3, and 4.
GLUT stands for glucose transporter.
GLUT 2 and 4 are the more significant glucose transporters.
GLUT 2 is a low affinity transporter found in the liver and pancreas.
GLUT 4 is an insulin dependent transporter primarily expressed in muscle and adipose tissue.
What is GLUT 2?
What happens when glucose concentrations drop below Km for the transporter?
What is the Km of GLUT 2?
GLUT 2 is a low affinity transporter in hepatocytes (liver cells) and pancreatic cells.
After a meal, blood flowing through the hepatic portal system from the intestines is rich with glucose.
GLUT 2 capture that excess for storage.
When glucose concentrations fall below Km for the transporter, much of the remaining glucose bypasses the liver and enters the peripheral circulation.
The Km value of GLUT 2 is about 15mM. (Km is the concentration of substrate when an enzyme is active at half of its maximum velocity, Vmax)
What is the Km of GLUT 2? What does this implicate?
The Km of GLUT 2 is about 15mM.
This means that the liver will pick up glucose in proportion to its concentration in the blood (first order kinetics).
In other words, the liver will pick up excess glucose and store it preferentially after a meal, when blood glucose levels are high.
In the beta islets of the pancreas, GLUT 2 and the glycolytic enzyme glucokinase serve as the glucose sensor for insulin release.
GLUT 2 and what glycolytic enzyme serve as glucose sensors in the beta islets of the pancreas?
GLUT 2 and the glycolytic enzyme glucokinase serve as glucose sensors in the beta islets of the pancreas.
GLUT 2 has a low affinity for glucose. What does that mean?
GLUT2 has a low affinity for glucose, meaning it requires higher concentrations of glucose to transport it efficiently.
What is GLUT 4?
Where is it found?
What is the Km of GLUT 4? What does that mean?
GLUT 4 is an insulin dependent glucose transporter found in muscle and adipose tissue.
The Km of GLUT 4 is close to the normal blood glucose levels (around 5mM).
This means that the transporter is saturated when blood glucose levels are just a bit higher than normal.
When a person has high blood glucose concentrations, these transporters will still permit only a constant rate of glucose influx because they will be saturated (zero order kinetics).
The intake is increased by increasing the number of GLUT 4 transporters on their surface.
When a person has high blood glucose concentrations, GLUT 4 transporters will still permit only a constant rate of glucose influx because they will be saturated (zero order kinetics). How then can cells with GLUT 4 transmitters increase their intake of glucose?
The cells can increase their intake of glucose by increasing the number of GLUT 4 transporters on their cell surfaces.
Although basal levels of glucose transport occur in all cells independently of insulin, does the transport level increase in tissue when insulin levels rise?
Transport rate of glucose does increase above basal levels when glucose levels increase.
The increased levels of glucose uptake happens in adipose and muscle tissue when insulin levels rise.
How do muscle and adipose tissue store glucose?
Muscle cells store excess glucose as glycogen.
Adipose tissue requires glucose to form dihydroxyacetone phosphate (DHAP), which is converted to glycerol phosphate to store incoming fatty acids as triacylglycerols.
What is dihydroxyacetone phosphate (DHAP)?
Adipose tissue requires glucose to form dihydroxyacetone phosphate (DHAP), which is converted to glycerol phosphate to store fatty acids as triacylglycerols.
MCAT concept check glucose transport 9.1 page 333 question 1
MCAT concept check glucose transport 9.1 page 333 question 2
How does insulin promote glucose entry into cells?
GLUT 4 is saturated when glucose levels are only slightly above 5mM, so glucose entry can only be increased by increasing the number of transporters.
Insulin promotes the fusion of vesicles containing preformed GLUT 4 with the cell membrane.
Fun image of molecules involved in glycolysis.
What’s the best way to conceptualize redox reactions in biomolecules?
Oxidation: more bonds to oxygen and other heteroatoms (other than C and H).
Reduction: more bonds to hydrogen.
Hand drawn glycolysis.
ADP, ATP, and P are in yellow.
Molecule and pathway in green
Enzymes and electron carriers in orange
Irreversible or rate limiting in red
Notice insulin area (blue)
Notice presence of O2 (blue)
Notice important intermediates with black outlines:
DHAP (triacylglyceride precursor)
High energy intermediates
Important enzymes:
***Hexokinase/Glucokinase (IRREVERSIBLE)
Phosphofructokinase (PFK) I and II (***PFK-I is IRREVERSIBLE)
Glyceraldehyde 3 phosphate
dehydrogenase
3 phosphoglycerate kinase
***Pyruvate kinase (IRREVERSIBLE)
Lactate dehydrogenase
Important intermediates:
Dihydroxyacetone phosphate
What is glycolysis?
What cells carry out glycolysis (which cells into metabolize via glycolysis? Which cells often use glycolysis?)
What monosaccharides ex an undergo glycolysis?
Glycolysis is a cytoplasmic pathway that converts glucose into two pyruvate molecules. Glycolysis releases a modest amount of energy captured in two substrate level phosphorylations and an oxidation reaction.
All cells carry out glycolysis.
Erythrocytes only used glycolysis for metabolism.
Skeletal muscle cells under demand use glycolysis.
Glucose is the major monosaccharide that enters the glycolysis pathway, galactose and fructose can also feed into the glycolysis pathway.
What are three important intermediates of glycolysis? What do they do?
Dihydroxyacetone phosphate (DHAP) is used in hepatic and adipose tissue for triacylglycerol synthesis. DHAP is formed from fructose 1,6 bisP (then isomerized to glycerol 3-P, which is converted to glycerol for triglyceride synthesis)
1,3 Bisphosphoglycerate (1,3 BPG) and phosphoenolpyruvate (PEP) our high energy, intermediate used to generate ATP by substrate level phosphorylation. This is the only ATP gained in anaerobic respiration (glycolysis).
What are the important enzymes of glycolysis?
Hexokinase and glucokinase (convert glucose to glucose 6-P, IRREVERSIBLE)
Phosphofructokinase I and II:
PFK-I is rate limiting step and main control of glycolysis. Phosphorylates glucose 6-P to fructose 1,6-bisP. Uses ATP.
PFK-II is activated by insulin and found mostly in the liver. The product of PFK-II, fructose 2,6-bisP activates PFK-I.
Glyceraldehyde 3-P dehydrogenase: catalyzes oxidation and addition of inorganic phosphate to glyceraldehyde 3-P, making a high energy intermediate called 1,3 bisphosphoglyerate and the reduction of NAD+ to NADH.
3-phosphoglycerate kinase: transfers the high energy phosphate from 1,3 bisphosphoglycerate to ADP to form ATP and 3-phosphoglycerate. SUBSTRATE LEVEL PHOSPHORYLATION.
Pyruvate kinase: last enzyme in aerobic glycolysis. Catalyzes a substrate level phosphorylation of ADP using the high energy substrate phosphoenolpyruvate (PEP), making pyruvate.
What is fermentation?
What is the key fermentation enzyme and what does it do?
Fermentation is metabolism in the absence of oxygen.
The main enzyme in fermentation is lactate dehydrogenase, which oxidizes NADH to NAD+, replenishing the oxidized coenzyme for glyceraldehyde 3 hydrogenase.
Again, just list them, what are the important enzymes and intermediates of glycolysis?
Hexokinase and glucokinase.
Phosphofructokinase I and II
Glyceraldehyde 3-P dehydrogenase
3 phosphoglycerate kinase
Pyruvate kinase
What is the important enzyme in fermentation?
Lactate dehydrogenase
What are the three irreversible enzymes of glycolysis? Rate limiting?
Hexokinase and glucokinase are irreversible.
PFK-I is irreversible and rate limiting.
Pyruvate kinase is irreversible.
What is hexokinase? Glucokinase?
How does glucose get trapped in the cell?
What’s the difference and where are they found?
The first step in glucose metabolism is to get glucose into the cell (which is what GLUT does) and phosphorylate it by kinase enzymes.
Glucose enters the cell by facilitate diffusion or active transport, and get phosphorylated by hexokinase or glucokinase.
Because GLUT transporters are specific to glucose, the phosphorylated glucose gets “stuck” in the cell and cannot leak out.
Hexokinase is widely distributed in tissues and inhibited by its product.
Glucokinase is found only in liver and beta islet pancreatic cells.
The differences in hexokinase and glucokinase coincides with the differences between the glucose transporters in these tissues (glut 2 in liver and pancreatic, glut 4 in adipose and muscle)
What is Phosphofructokinase I?
What is special about it?
What is it inhibited by (3 things) and activated by?
PFK-I is the rate limiting enzyme of glycolysis. The process is also irreversible.
PFK-1 is the main control point in glycolysis.
PFK-1 phosphorylates fructose 6-P to fructose 1,6 bisP, using ATP.
PFK-1 is inhibited by ATP, citrate, glucagon. and activated by AMP: turns off glycolysis when it has sufficient energy in ATP, and turn on glycolysis when it needs energy (high AMP). (High levels of citrate indicate that the cell is producing sufficient energy as citrate is an intermediate of the citric acid cycle).
What is PFK II?
What stimulates PFK II?
Where is PFK II found?
What inhibits PFK I, and then what happens?
PFK II is an enzyme in the glycolytic pathway which coverts a small amount of fructose 6-P to fructose 2,6-P, which activates PFK I.
Insulin stimulates PFK II.
PFK2 is found in the liver.
Glucagon, a hormone produced by the pancreas that plays a crucial role in regulating blood sugar levels, inhibits PFK I in hepatocytes.
What does glucagon do regarding PFK I and PFK II?
*Glucagon inhibits PFK I in liver cells by an indirect mechanism involving PFK II and fructose 2,6 bisP, as shown in the image.
So. Insulin activates PFK2. PFK2 converts F6P to F26BP, F26BP activates PFK1.
*Glucagon inhibits PFK2, lowers F26BP and thereby inhibiting PFK1.
Activating PFK1 allows cells to override ATP inhibition of PFK1 so that glycolysis can continue even when cells have plenty of energy.
THE REASON THIS HAPPENS IS BECAUSE THE METABOLITES OF GLYCOLYSIS CAN BE FED INTO PRODUCTION OF GLYCOGEN, FATTY ACIDS, AND OTHER STORAGE MOLECUKES RATHER THAN BEING BURNED TO PRODUCE ATP.
What are the products of glycolysis?
Glycolysis, the breakdown of glucose, produces two molecules of pyruvate, two molecules of ATP (with a net gain of 2 ATP), and two molecules of NADH.
What is glyceraldehyde 3 phosphate dehydrogenase?
What happens if glycolysis is aerobic?
Glyceraldehyde 3P dehydrogenase catalyzes and oxidation and addition of an organic P to glyceraldehyde 3P.
This is important because it creates a high energy intermediate, 1,3 bisPglycerate and the reduction of NAD+ to NADH.
If glycolysis is aerobic, NADH can be utilized in the mitochondrial ETC to provide energy to synthesize ATP via oxidative phosphorylation.
What is 3 phosphoglycerate kinase?
3Pglycerate kinase forms ATP and 3phosphoglycerate by transferring highE P from 1,3bPglycerate to ADP.
What is pyruvate kinase?
What activates pyruvate kinase?
The last enzyme in glycolysis.
Catalyzes a substrate level phosphorylation of ADP. It produces ATP and pyruvate.
It transfers a high every P from phosphenolpyruvate (PEP) to ADP.
F1,6bP (from PFK1) activates pyruvate kinase. This is interesting because it is a FEED FORWARD ACTIVATION.
Which enzymes in glycolysis work on feed forward activation?
Pyruvate kinase is activated by F1,6bP, feed forward activation.
At a minimum, which metabolic enzymes need to be memorized?
PFK1: glycolysis, the rate limiting enzyme and is also irreversible.
Lactate dehydrogenase: fermentation enzyme, oxidizes NADH to NAD+.
What is fermentation? Enzyme?
Is there a loss of carbon in this reaction?
In the absence of oxygen, lactate dehydrogenase will oxidize NADH to NAD+.
This replenishes NAD+ in the absence of oxygen. This is then used to allow glycolysis to continue.
There is no net loss of carbon because pyruvate and lactate are both 3 carbon molecules.
A little more: Without the mitochondria and oxygen, glycolysis would stop when all of the available NAD+ has been reduced to NADH. By reducing pyruvate to lactate, and oxidizing NADH to NAD+ (using lactate dehydrogenase), the problem of not having NAD+ in the absence of oxygen is temporarily solved.
What are the important intermediates of glycolysis?
DHAP, dihydroxyacetone phosphate, a precursor to tracylglycerol synthesis. Used in hepatic and adipose tissue.
1,3bPglycerate and phosphoenolpyruvate (PEP) are high E intermediates used to generate ATP by substrate level phosphorylation.
What are the three irreversible enzymes of glycolysis?
Glucokinase and hexokinase
PFK1
Pyruvate Kinase
What are the physiological changes that promote a shift to the right in the oxygen dissociation curve?
High 2,3 BPG
Low pH
High [H+]
High pCO2
These all occur during exercise. Exercise is the Right thing to do; the oxygen dissociation curve shifts to the Right during exercise.
What are the adaptations involved for high altitude (low pCO2)?
Increased respiration
Increase oxygen affinity for hemoglobin (initial)
Increase rate of glycolysis
Increased 2,3 BPG in RBC (over 12-24 hour period)
Normalized oxygen affinity for hemoglobin restored by increase levels of 2,3 BPG
Increase hemoglobin (over days to weeks)
What is the only pathway for ATP production in RBC?
How many ATP does it produce?
Anaerobic glycolysis is the only pathway for ATP production in RBC.
2 ATP per glucose.
4 ATP gross but 2 are used in the process.
What is the enzyme in RBC used for anaerobic glycolysis?
What are the reactants and products?
Bisphosphoglycerate mutate is the enzyme in RBC used for anaerobic glycolysis.
Bisphosphoglycerate produces 2,3 BPG from 1,3 BPG.
Recall that MUTASES are enzymes that move functional groups from one place on a molecule to another place on a molecule.
In this case, the phosphate is moved from the 1 position to the 2 position.
What is a mutase?
A mutase is an enzyme that moves a functional group on a molecule.
What does 2,3 BPG do to hemoglobin?
2,3 BPG binds allosterically to the beta chains of hemoglobin A and decreases its affinity for oxygen.
This is seen in the oxygen dissociation curve of hemoglobin (HbA). The right shift is sufficient to allow unloading of oxygen at tissues, but still allows 100 saturation in the lungs.
What happens when too much erythrocyte 2,3 BPG accumulates?
An abnormal increase in erythrocyte 2,3 BPG might shift the oxygen dissociation curve far enough to the right that HbA is not fully saturated in the lungs.
What are the function and key regulators for hexokinase? Is it reversible?
Hexokinase phosphorylates glucose to G6P, trapping glucose in the cell.
It is inhibited by G6P and is irreversible.
What are the function and key regulators for glucokinase? Is it reversible?
Glucokinase phosphorylates glucose to G6P and traps glucose in the LIVER and PANCREAS cells.
Glucokinase works with GLUT2 as part of the glucose sensor in beta islets cells.
In liver cells, it is induced by insulin.
It is irreversible.
What are the function and key regulators for PFK1? Is it reversible?
PFK1 catalyzes the rate limiting step of glycolysis and is irreversible.
PFK1 phosphorylates F6P to F16bP using ATP.
PFK1 is inhibited ATP, citrate, and glucagon.
PFK1 is activated by AMP, F2,6bP, and insulin.
What are the function and key regulators for glyceraldehyde 3P dehydrogenase? Is it reversible?
Glyceraldehyde 3P dehydrogenase generates NADH while phosphorylating glyceraldehyde 3P to glyceraldehyde 1,3 bPglycerate.
Glyceraldehyde 3P is reversible.
What are the function and key regulators for 3Pglycerate kinase? Is it reversible?
3P glycerate kinase performs a substrate level phosphorylation.
3P glycerate kinase transfers a P from 1,3bPglycerate to ADP, forming ATP and 3Pglycerate.
It is reversible.
What are the function and key regulators for pyruvate kinase? Is it reversible?
Pyruvate kinase performs a substrate level phosphorylation.
Pyruvate kinase transfers a P from phosphoenolpyruvate (PEP) to ADP, forming ATP and Pyruvate.
Pyruvate kinase is activated by F1,6bP.
Pyruvate kinase is irreversible.
MCAT concept check glycolysis 9.2 page 342 question 2
Why must pyruvate undergo fermentation for glycolysis to continue?
Fermentation must occur to oxidize NADH to NAD+, which is in limited supply in cells.
Fermentation generates no ATP or energy carriers, it merely regenerates the coenzymes needed for glycolysis.
MCAT concept check glycolysis 9.2 page 342 question 3
Why is it necessary that fetal hemoglobin does not bind to 2,3BPG?
The binding of 2,3BPG decreases oxygen affinity for oxygen.
Fetal hemoglobin must be able to take oxygen from maternal hemoglobin at the placental interface. Therefor it would be disadvantageous to lower fetal hemoglobins affinity for oxygen.
Hand written glycolysis again.
Glucose represents the primary monosaccharide used by cells. What other two sugars can contribute to ATP production by feeding into glycolysis or other metabolic processes?
Galactose and fructose can contribute to ATP production by feeding into glycolysis or other metabolic processes.
Describe galactose metabolism.
A big source of galactose in the diet is the disaccharide lactose, present in milk.
Lactose is hydrolyzed to galactose and glucose by lactase (a brush border enzyme of the duodenum).
Galactose reaches the liver through the hepatic portal vein.
Galactose is phosphorated by galactokinase, trapping it in the cell similar to what happens to glucose when it is phosphorylated.
Galactose one phosphate is converted to glucose one phosphate by galactose one phosphate uridyltranferase, an epimerase.
What is lactose?
What enzyme hydrolyzes lactose?
Where is that enzyme found?
Lactose is a disaccharide of galactose and glucose.
Lactase hydrolyzes lactose to galactose and glucose.
Lactase is a brush border enzyme found in the duodenum.
What are two enzymes to remember regarding the galactose metabolism?
Galactokinase: phosphorylates galactose, trapping it in the cell.
Galactose 1P uridyltranserase: an epimerase that converts galactose1P to glucose1P.
Describe fructose metabolism.
Fructose is found in honey and fruit.
Sucrose is a disaccharide, composed of fructose and glucose, that is found in honey and fruit.
Sucrose is hydrolyzed by the duodenal brush border enzyme sucrase, resulting in glucose and fructose.
Glucose and fructose are absorbed into the hepatic portal vein.
The liver phosphorylates fructose using fructokinase, trapping it in the cell.
The resulting fructose1P is cleaved into glyceraldehyde and dihydroxyacetoneP (DHAP) by aldolase B.
MCAT concept check other monosaccharide metabolism 9.3 page 345 question 1
Which enzyme is responsible for trapping galactose in the cell? When enzyme galactose metabolism results in a product that can feed directly into glycolysis, linking the two pathways.
Glactokinase phosphorylates galactose and traps it in the cell.
Galactose 1 phosphate uridyltransferase produces glucose1P, a glycolic intermediate, linking the metabolic pathways.
MCAT concept check other monosaccharide metabolism 9.3 page 345 question 2
Which enzyme is responsible for trapping fructose in the cell?
What enzyme in fructose metabolism results in a product that can feed directly into glycolysis, linking the two pathways?
Frictokinase phosphorylates fructose to fructose 1P, trapping it in the cell.
Aldolase B cleaves fructose 1P into glyceraldehyde (can be phosphorylated to glyceraldehyde 3P) and DHAP (dihydroxyacetone phosphate). Both products are glycolytic intermediates.
What is acetyl coA?
Acetyl coA is a coenzyme made from pyruvate (product of aerobic glycolysis) which is a precursor for the citric acid cycle and fatty acid synthesis.
Acetyl coA will go to the citric acid cycle if ATP is needed.
Acetyl coA will go synthesize fatty acids if there is sufficient ATP.
What does pyruvate dehydrogenase do?
Where is it found?
Is it reversible?
Pyruvate dehydrogenase is found in mitochondrial matrix.
Pyruvate dehydrogenase in the liver is activated by insulin. This makes sense because high insulin means well fed and the liver should not only burn glucose, but it could shift the fatty acid equilibrium toward production and storage.
The pyruvate dehydrogenase complex is not reversible. It cannot be used to convert acetyl coA back to pyruvate or glucose.
Is the pyruvate dehydrogenase complex reversible?
The pyruvate dehydrogenase complex is not reversible. It cannot be used to convert acetyl coA back to pyruvate or glucose.
What are the three possible fates of pyruvate?
Conversion to acetyl CoA by PDH (pyruvate dehydrogenase complex)
Conversion to lactate by lactate dehydrogenase (NAD+ and NADH)
Conversion to oxaloacetate by pyruvate carboxylase.
What are the cofactor and coenzymes involved in the pyruvate dehydrogenase complex?
Thiamine pyrophosphate
Lipoid acid
CoA
FAD
NAD+
What is pyruvate dehydrogenase inhibited by?
Why?
Pyruvate dehydrogenase is inhibited by its product: acetyl CoA.
The buildup of acetyl CoA causes a shift in metabolism: pyruvate is no longer converted to acetyl CoA but rather into oxaloacetate (to enter gluconeogenesis).
What causes Beriberi and Wernicke-Korsakoff syndrome?
MCAT concept check pyruvate dehydrogenase 9.4 page 347 question 1
What are the reactants and products of the pyruvate dehydrogenase complex?
Reactants: pyruvate, NAD+, CoA
Products: Acetyl CoA, NADH, and CO2
MCAT concept check pyruvate dehydrogenase 9.4 page 347 question 2
How does acetyl CoA affect PDH complex activity? Why?
Acetyl CoA inhibits the PDH complex.
As a product of the enzyme complex, a buildup of acetyl CoA from either the citric acid cycle or fatty acid oxidation signals that the cell is energetically satisfied and that the production of acetyl CoA should be slowed or stopped.
Pyruvate can then be used to form other products, such as oxaloacetate for use in gluconeogenesis.
What is glycogen?
Glycogen is a branched polymer of glucose and is used to store glucose.
How is glycogen in the liver used? In skeletal muscle cells?
Glycogen in the liver is broken down to maintain constant levels of glucose in the blood.
Glycogen in muscles is broken down to provide glucose during exercise.
Where does synthesis and degradation glycogen primarily occur?
In the cytoplasm of liver and skeletal muscle cells. Stored as granules.
Describe a glycogen granule.
Glycogen is stored in the cytoplasm as granules.
Each granule has a central protein core with polyglucose chains radiating outward to form a sphere.
Speak about the density of glycogen with branches chains and linear chains.
Branched chains: density is highest at the periphery of the granule allowing more rapid release of glucose on demand.
Linear chains: higher density of glucose near the core of the granule.
What is glycogenesis?
What is the core protein of a glycogen granule?
Glycogenesis is the synthesis of glycogen granules.
The core protein of a glycogen granule is called glycogenin.
Glucose 6P to glucose 1P to UDP glucose to glycogen.
What is glycogen synthase?
What is it stimulated by?
What is it inhibited by (think hormones)?
Glycogen synthase is the rate limiting enzyme of glycogen synthesis.
Glycogen synthase forms the alpha 1,4 glycosidic bonds found in linear chains of glucose of the granule.
Glycogen synthase is stimulated by glucose 6P and insulin.
Glycogen synthase is inhibited by epinephrine and glucagon.
What is branching enzyme?
Branching enzyme introduces branching of a glycogen molecule by introducing alpha 1,6 linked branches into the granule as it grows.
Mnemonic for remembering alpha glycosyl 1,4 and alpha 1,6 tranferase
What is glycogenolysis?
What is the main enzyme?
Glycogenolysis is breaking down glycogen.
The main enzyme of glycogenolysis is glycogen phosphorylase.
Glycogen phosphorylase breaks alpha 1,4 glucosidic bonds, releasing glucose 1P from the periphery of a granule.
What is a phosphorylase? How does it contrast to a hydrolase?
Phosphorylase breaks binds using inorganic phosphate.
Hydrolase breaks binds using water.
Why are there two debranching enzymes for glycogenolysis?
What is glycogen phosphorylase?
What is it activated by?
Glycogen phosphorylase breaks alpha 1,4 glucosidic bonds, releasing glucose 1P from the periphery of a granule.
Glycogen phosphorylase is activated by glucagon in the liver.
Glycogen phosphorylase is activated by AMP and epinephrine in the muscle, which signals that the muscle needs more glucose. Inhibited by ATP.
What is debranching enzyme?
Debranching enzyme is a complex of two enzymes thus deconstructs the branches of glycogen.
The linear binds are alpha 1-4, the branching are alpha 1,6. These areas require different enzymes to phosohrylase and hydrolyze.
What is the most common glycogen storage disease?
What is an isoform?
Relate isoforms to glycogen storage diseases.
Isoforms are slightly different versions of the same protein.
In the case of glycogen enzymes, there are ten different isoforms of the enzymes in the liver and muscle.
Deficiencies are termed glycogen storage diseases because all are characterized by accumulation or lack of glycogen in one or more tissues.
MCAT concept check glycogenesis and glycogenolysis 9.5 page 352 question 1
What is the structure of glycogen?
What types of glycosidic links exist in a glycogen granule?
Glycogen is made up of a core protein of glycogenin with linear chains of glucose emanating out from the center connected by alpha 1,4 glucosidic linkage.
Branched chains require alpha 1,6 glucosidic linkage.
MCAT concept check glycogenesis and glycogenolysis 9.5 page 352 question 2
What are the two main enzymes of glycogenesis and what does each accomplish?
Glycogen synthase attached the glucose molecule from UDP-glucose to the growing glycogen chain, forming an alpha 1,4 link.
Branching enzyme creates a branch by breaking an alpha 1,4 link in the growing chain and moving a block of oligoglucose to another location in the glycogen granule.
The oligoglucose is then attached with an alpha 1,6 link.
MCAT concept check glycogenesis and glycogenolysis 9.5 page 352 question 3
What are the two main enzymes of glycogenolysis and what does each accomplish?
Glycogen phosphorylase removes a glucose molecule from glycogen using a phosphate, breaking the alpha 1,4 link and creating a glucose 1P.
Debranching enzyme moves all of the glucose from a branch to a longer glycogen chain by breaking an alpha 1,4 link and forming a new alpha 1,4 link to the longer chain.
The branch point is left behind, which is removed by breaking the alpha 1,6 link to form a free molecule of glucose.
Where does glycolysis happen?
Pyruvate oxidation?
Citric acid cycle?
Oxidative phosphorylation?
What are the products of each?
What is gluconeogenesis?
Where does it happen?
What promotes gluconeogenesis? Inhibits?
What are the importantly substrates for gluconeogenesis?
The liver in the blood during fasting through either glycogenolysis or gluconeogenesis. The kidney also does this to a lesser extent.
Gluconeogenesis is promoted by glucagon and epinephrine, which act to raise blood sugar levels.
Gluconeogenesis is inhibited by insulin, which acts to lower blood sugar level levels.
Glycerol 3P (from stored fats, or triglycerides, in adipose tissues)
Lactate (from anaerobic glycolysis)
Glucogenic amino acids (from muscle proteins).
Speak about fasting and glycogenolysis and gluconeogenesis.
During fasting, glycogen reserves dropped dramatically in the first 12 hours. During which time gluconeogenesis increases. After 24 hours, gluconeogenesis represents the sole source of glucose.
What are glucogenic amino acids?
What’s the other one?
All AA expect luecine and lysine (which are ketogenic) can be converted into intermediates that feed into gluconeogenesis.
The other one lol are ketogenic (leucine and lysine) and can be converted into ketone bodies which can be used as alternate fuel during periods of prolonged starvation.
What are ketogenic AA? Which ones are?
What’s the other one. Which ones are?
Ketogenic AA (leucine and lysine) and can be converted into ketone bodies which can be used as alternate fuel during periods of prolonged starvation.
The other ones are glucogenic AA (all except leucine and lysine) which can be converted to intermediates that feed into gluconeogenesis.
What processes produce acetyl CoA in humans?
Is this reversible?
Can fatty acids be converted to glucose?
Glucose is converted into acetyl CoA through glycolysis and pyruvate dehydrogenase.
It is not possible to convert acetyl CoA back into glucose.
Most fatty acids are metabolize solely to acetyl CoA and therefore not a major source of glucose.
Pathway of gluconeogenesis in MCAT book.
What are the important gluconeogenic intermediates?
Why does this matter?
Which enzymes do the thing?
The important intermediates of gluconeogenesis are:
Lactate
Alanine
Glycerol 3P
This is important because there are enzymes that convert these intermediate into glycolytic intermediate.
Lactate is converted to pyruvate by lactate dehydrogenase.
Alanine is converted to pyruvate by alanine aminotransferase.
Glycerol 3P is converted to dihydroxyacetone phosphate by glycerol 3P dehydrogenase.
What are the four important enzymes of gluconeogenesis?
Pyruvate carboxylase: mitochindral enzyme: produces oxaloacetate OAA, a citric acid cycle intermediate.
Phosphoenolpyruvate carboxykinase (PEPCK): in cytoplasm: raise blood sugar levels by converting OAA to phosphoenolpyruvate (PEP).
Fructose 1,6bphosphatase: in cytoplasm: RATE LIMITING point of gluconeogenesis, reverses PFK1 to make fructose 6P from fructose 1,6bP.
Glucose 6 phosphatase: lumen of ER in liver cells: convert glucose 6P to free glucose to be transported back to cytoplasm (diffuses out of cell using GLUT transporters remember???)
What phosphatases do?
Phosphatases oppose kinases.
Kinases deliver p to molecules, phosphatases remove P from molecules.
Think of them as “on/off” switches sort of kind of a little bit.
What is pyruvate carboxylase?
Where find?
Products?
What activates it?
Pyruvate carboxylase is a mitochondrial enzyme that is activated by acetyl CoA and produces oxaloacetate (OAA).
Interesting thing: OAA cannot leave the mitochondrion. It is reduced to malate through the malate-aspartate shuttle to the cytoplasm where it is oxidized to OAA.
Acetyl CoA activates pyruvate carboxylase.
Acetyl CoA activates pyruvate carboxlyase.
What is pyruvate carboxylase and why is this an important point?
Pyruvate carboxylase produces oxaloacetate by carboxylation of pyruvate.
Acetyl CoA inhibits pyruvate dehydrogenase because high levels of acetyl CoA implies that the cell is energetically satisfied and need not run the citric acid cycle forward (the cell should stop burning glucose)
Pyruvate will be shunted through pyruvate carboxylase to help generate additional glucose through gluconeogenesis.
Where is the source of acetyl CoA for gluconeogenesis?
The source of acetyl CoA for glucogenesis is not from glycolysis and pyruvate dehydrogenase.
The source of acetyl CoA for gluconeogenesis is fatty acids.
Thus, to produce glucose in the liver during gluconeogenesis, fatty acids must be burned to provide this energy, stop the flow of the citric acid cycle, and produce massive amounts of OAA that can eventually lead to glucose production for the rest of the body.
What is phosphenolpyruvate carboxykinase (PEPCK)?
What is it induced by?
Does it require energy?
PEPCK is an enzyme in the cytoplasm that is important for gluconeogenesis.
PEPCK is induced by glucagon and cortisol, which act to raise blood sugar level levels.
PEPCK converts OAA to phosphenolpyruvate (PEP), requires GTP.
PEP then continues in the pathway to fructose 1,6bP.
Pyruvate carboxylase and PEPCK circumvent the action of pyruvate kinase by converting pyruvate back into PEP.
Remember that this process is all about producing glucose.
What is fructose 1,6 bisphosphatase?
Where?
Is it rate limiting?
What activates it?
What is a phosphatase?
Fructose 1,6 bphosphatase in the cytoplasm is the rate limiting enzyme of gluconeogenesis.
Frustose 1,6 bisphosphatase reverses PFK1, making fructose 6P from fructose 1,6bP.
Fructose 1,6 bphosphatase is activated by ATP and inhibited by AMP and fructose 2,6 bP.
Phosphatases do the opposite of kinases.
Why is fructose 2,6 bisphophate thought of as a marker for satisfactory energy levels in liver cells?
F2,6BP helps these cells override the inhibition of PFK1 that occurs when high levels of acetyl CoA are formed, signaling to the liver cell that it should shift its function from burning to storing fuel.
Fructose-2,6-bisphosphate (F2,6BP) is a crucial metabolite that plays a key role in regulating glycolysis and gluconeogenesis by allosterically activating phosphofructokinase-1 (PFK-1) and inhibiting fructose-1,6-bisphosphatase.
Does glucagon lower F2,6BP?
What does glucagon do for gluconeogenesis?
How about insulin?
Glucagon will lower F2,6BP and stimulate gluconeogenesis, whereas insulin will increase F2,6BP an inhibit glucogenesis.
High levels of ATP imply that a cell is energetically satisfied enough to produce glucose for the rest of the body. High levels of AMP imply that a cell needs energy and cannot afford to produce energy for the rest of the body before satisfying its own requirements.
F2,6BP is thought of as a marker for satisfactory energy levels in liver cells. It helps these cells override the inhibition of PFK1 that occurs when high levels of acetylCoA are formed, signaling to the liver cell that it should shift its function from burning to storing fuel.
F2,6BP, produced by PFK2 controls, both gluconeogenesis and glycolysis (in the liver). PFK2 is activated by insulin and inhibited by glucagon. Thus, top of answer card. Read it again.
What is glucose 6 phosphatase?
Where?
What does the absence of this enzyme mean?
Enzyme in the lumen of the ER in liver cells that makes glucose from glucose 6P.
Glucose 6 phosphatase is the last enzyme in gluconeogenesis.
Glucose comes out of the cell using GLUT transporters.
The absence of glucose six phosphatase in skeletal muscle means that muscle glycogen cannot serve as a source of blood glucose and rather is for use only within the muscle.
Glucose six phosphatase circumvents glucokinase and hexokinase.
How is gluconeogenesis inextricably linked to fatty acid oxidation?
What is the Cori cycle (red blood cell and liver)?
Alanine, glucose produced by the liver, acetyl CoA sources. Read and understand this.
Glucose 6 phosphatase is found in the liver cells and is the final enzyme in gluconeogenesis. It dephosphorylates glucose 6P to glucose, which is then transported out of the cell into the bloodstream using GLUT for other tissues to use for metabolism.
Muscle cells do not contain glucose 6 phosphatase as they do not send glucose into the bloodstream for other tissues to use for metabolism. They use the glucose 6P for their own metabolism.
Alanine is the main glucogenic AA, but most of the others are glucogenic as well. Recalling that leucine and lysine are ketogenic AA.
Glucose formed through gluconeogenesis does not serve as a metabolite for liver cells.
Acetyl CoA from fatty acids cannot be converted back into glucose, but it can be converted to ketone bodies for alternative fuel for cells, including the brain. Think of ketones as a transportable form of acetyl CoA that is primarily utilized in periods of extended starvation.
MCAT concept check gluconeogenesis 9.6 page 356 question 1
Under what physiological conditions should the body carry out gluconeogenesis?
Gluconeogenesis occur occurs when an individual has been fasting for more than 12 hours.
To carry out gluconeogenesis, hepatic and renal cells must have enough energy to drive the process of glucose creation, which requires sufficient fats to undergo beta oxidation.
MCAT concept check gluconeogenesis 9.6 page 356 question 2
MCAT concept check gluconeogenesis 9.6 page 356 question 3
How does acetyl CoA shift the metabolism of pyruvate?
Acetyl CoA inhibits pyruvate dehydrogenase complex while activating pyruvate carboxylase.
The net effect is to shift from burning pyruvate in the citric acid cycle to creating new glucose molecules for the rest of the body.
The acetyl CoA for this regulation comes predominantly from beta oxidation, not glycolysis.
MCAT concept check gluconeogenesis 9.6 page 356 question 4
Given that the glycogen storage disorder von Gierke’s disease affects the last enzyme of gluconeogenesis, predict the associated metabolic derangement that occurs.
The last enzyme in gluconeogenesis is glucose 6 phosphatase.
Patient with von Gierke’s disease are unable to perform gluconeogenesis in addition to glycogenolysis.
This means that patients will be unable to produce glucose during periods of fasting (resulting from hypoglycemia). Furthermore, given a blocker in the glucogenic pathway, a buildup of intermediates (including lactate resulting in lactic acidosis) would also be expected.
What is the pentose phosphate pathway?
What is the rate limiting enzyme?
The pentose phosphate pathway occurs in the cytoplasm of all cells which produces:
NADPH
ribose 5P for nucleotide synthesis and nucleic acid production (particularly DNA and RNA)
Glucose 6 dehydrogenase is the rate limiting enzyme.
Also known as the hexose monophosphate shunt (HMP shunt).
What is glucose 6 dehydrogenase?
What is it induced by? Inhibited by?
Rate limiting enzyme in pentose phosphate pathway.
Start with glucose 6P and end with ribulose 5P. Irreversible.
This enzyme produces NADPH and 6phosphogluconate.
Induced by insulin and inhibited by NADPH (activated by NADP+).
What is the point of the pentose phosphate pathway?
Making a pool of sugars for biosynthesis, including ribulose 5P for nucleotide synthesis and nucleic acid production (DNA and RNA).
Fructose 6P and glyceraldehyde 3P are among the sugars produced, which are intermediates of glycolysis and can go that way. Conversely, those intermediates can be made into pentoses for biosynthesis with transketolase and transaldolase.
What is NADPH?
NADPH and NADH are not the same thing.
NAD+ is high energy electron acceptor (- potent oxidizing agent because it oxidizes other biomolecules while itself gets reduced).
NADPH is an electron donor and this is a potent reducing agent as it helps other molecules be reduced while itself gets oxidized.
Things it does include:
Biosynthesis of fatty acids and cholesterol.
Cellular bleach production in white blood cells, contributing to bactericidal activity.
Maintenance of a supply of reduced glutathione to protect against reactive oxygen species (acting as an antioxidant).
Compare and contrast NADH and NADPH.
Bridge from pentose phosphate pathway to biosynthesis.
Describe the antioxidant quality of NADPH, and therefor the pentose phosphate pathway.
MCAT concept check pentose phosphate pathway 9.7 page 358 question 1
What are the two major metabolic products of the pentose phosphate pathway?
NADPH and ribose 5P
MCAT concept check pentose phosphate pathway 9.7 page 358 question 2
What are three primary functions of NADPH?
Lipid biosynthesis
Bactericidal bleach formation
Maintenance of glutathione stores to protect against reactive oxygen species.
MCAT mastery chapter 9 carbohydrate metabolism 1 page 328 question 1
MCAT mastery chapter 9 carbohydrate metabolism 1 page 328 question 2
MCAT mastery chapter 9 carbohydrate metabolism 1 page 328 question 3
MCAT mastery chapter 9 carbohydrate metabolism 1 page 328 question 4
MCAT mastery chapter 9 carbohydrate metabolism 1 page 328 question 5
MCAT mastery chapter 9 carbohydrate metabolism 1 page 328 question 6
MCAT mastery chapter 9 carbohydrate metabolism 1 page 328 question 7
MCAT mastery chapter 9 carbohydrate metabolism 1 page 328 question 8
MCAT mastery chapter 9 carbohydrate metabolism 1 page 328 question 9
MCAT mastery chapter 9 carbohydrate metabolism 1 page 328 question 10
MCAT mastery chapter 9 carbohydrate metabolism 1 page 328 question 11
MCAT mastery chapter 9 carbohydrate metabolism 1 page 328 question 12
What do carboxylases do?
Enzymes that catalyze the incorporation of CO2 into organic substrates.
For example. Pyruvate carboxylase adds a CO2 molecule to pyruvate to make oxaloacetate (OAA).
MCAT mastery chapter 9 carbohydrate metabolism 1 page 328 question 13
MCAT mastery chapter 9 carbohydrate metabolism 1 page 328 question 14
MCAT mastery chapter 9 carbohydrate metabolism 1 page 328 question 15
