Flashcards in Chapter 9: Carbohydrate Metabolism I: Glycolysis, Glycogen, Gluconeogenesis and the Pentose Phosphate Pathway Deck (141):
What is the regular level of blood glucose?
- 100 mg/dL or
- 5.6 mM (4-6 mM)
A) Damage to the retina, kidney, blood vessels, and nerves are results of high or low blood sugar?
B) Autonomic disturbances, seizures, and comas are results of high or low blood sugar?
What is glucose entry into most cells driven by? What is it independent of?
- Driven by concentration
- Independent of sodium
What are the four glucose transporters? Which are the most significant? Why?
- GLUT 1 through GLUT 4
- GLUT 2 and GLUT 4 because they are located only in specific cells and are highly regulated
In which tissues are GLUT 2 found?
- Liver (hepatocytes)
- Pancreas (pancreatic cells)
In which tissues are GLUT 4 found?
- Adipose tissue
What is the Km of GLUT 2?
High (15 mM) - low affinity
What is the Km of GLUT 4?
Low (5 mM) - high affinity
Is GLUT 2 saturated at normal glucose levels? If so, when?
No, it cannot be saturated under normal physiological conditions
Is GLUT 4 saturated at normal glucose levels? If so, when?
Yes, saturated when glucose levels are only slightly above 5 mM
Is GLUT 2 responsive to insulin? If not, how does it relate to insulin?
No, but serves as glucose sensor to cause release of insulin in pancreatic B-cells
Is GLUT 4 responsive to insulin? If not, how does it relate to insulin?
Given that GLUT 2 has a high Km, the liver will pick up excess glucose and store it only after a meal, when blood glucose levels are low or high?
What happens when the glucose concentration drops below the Km of GLUT 2?
Much of the remainder leaves the liver and enters peripheral circulation
What does the saturation of the GLUT 4 transporter due to high blood sugar concentrations cause?
Transporters will only permit a constant rate of glucose influx because they will be saturated (zero-order kinetics)
Given that GLUT 4 transporters can be saturated, how can cells with GLUT 4 transporters increase their intake of glucose?
By increasing the number of GLUT 4 transporters on their surface
What does a decrease in insulin cause in terms of GLUT 4 transporters? Does it result in endocytosis or exocytosis?
- Decreases the number of plasma membrane GLUT 4 transporters
What does an increase in insulin cause in terms of GLUT 4 transporters? Does it result in endocytosis or exocytosis?
- Increases the number of plasma membrane GLUT 4 transporters
Diabetes mellitus is caused by a disruption of which mechanism?
Insulin/GLUT 4 mechanism
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 performed GLUT 4 with the cell membrane
Why does adipose tissue require glucose?
- To form DHAP
- Which is converted to glycerol phosphate to store incoming fatty acids such as triacylglycerols
Glycolysis represents the only energy-yield pathway for which type of cells? Why?
- Red blood cells
- Because they lack mitochondria, which are required for the TCA cycle, ETC chain, oxidative phosphorylation and B-oxidation
In glycolysis, how many molecules of pyruvate does one molecule of glucose generate?
1 Glucose = 2 Pyruvate
Where is glycolysis carried out in the cell?
In the liver, glycolysis is part of the process by which excess glucose is converted to ______ for storage.
In glycolysis, which enzymes require ATP in the preparatory stage?
- Hexokinase or Glucokinase (liver)
In glycolysis, which enzymes cause substrate level phosphorylation?
- Phosphoglycerate kinase
- Pyruvate kinase
In glycolysis, where can the energy carriers produced feed into to generate energy for a cell that has mitochondria and oxygen? What is the energy carrier produced?
- Can be oxidized (indirectly) by the mitochondrial electron transport chain, providing energy for ATP synthesis by oxidative phosphorylation
What is the rate-limiting enzyme for glycolysis?
What is the rate-limiting enzyme for fermentation?
What is the rate-limiting enzyme for glycogenesis?
What is the rate-limiting enzyme for glycogenolysis?
What is the rate-limiting enzyme for gluconeogenesis?
What is the rate-limiting enzyme for the Pentose Phosphate Pathway?
Why most glucose be phosphorylated in the first step of glycolysis?
- GLUT transporters are specific for glucose (not phosphorylated glucose)
- Prevents glucose from leaving via the transporter
How does glucose enter the cell?
Facilitated diffusion or active transport
Where is hexokinase found? What is it inhibited by?
- Widely distributed in tissues
- Inhibited by its product: glucose-6-phosphate
What two molecules act as the glucose sensor in pancreatic B-islet cells?
- GLUT 2
Where is glucokinase found? What is it induced by?
- Liver cells (hepatocytes)
- Pancreatic B-islet cells
- Induced by insulin in hepatocytes
Does hexokinase have a low or high Km? What about glucokinase?
Hexokinase: low - reaches maximum velocity at low (glucose)
Glucokinase: high Km - acts on glucose proportionally to its concentration
What is the function of hexokinase and glucokinase? Are they reversible?
- Phosphorylates glucose (Glucose -> Glucose-6-Phosphate) and "traps" it in the cell
What is the function of PFK-1? Is it reversible?
- Catalyzes the rate-limiting step of glycolysis
- Phosphorylating fructose-6-phosphate to fructose 1,6-biphosphate using ATP
What is PFK-1 inhibited by?
ATP, citrate, glucagon
What is PFK-1 activated by?
AMP, fructose 2,6-biphosphate, and insulin
How does insulin activate PFK-1? Which cells does it mostly affect? Why?
- Insulin activates PFK-2
- Which converts a tiny amount of fructose-6-phosphate to fructose-2,6-biphosphate
- F-2,6-BP activates PFK-1
- Hepatocytes (liver) since PFK-2 is mostly found in the liver
- Glucagon does the opposite of insulin
What is the function of glyceraldehyde-3-phosphate dehydrogenase? Is it reversible?
- Generates NADH from NAD+ and Pi while phosphorylating glyceraldehyde-3-phosphate to 1,3-biphosphoglycerate
What is the function of 3-phosphoglycerate kinase? Is it reversible?
- Performs a substrate-level phosphorylation, transferring a phosphate from 1,3-biphosphoglycerate to ADP
- Forms ATP and 3-phosphoglycerate
What is the function of pyruvate kinase? Is it reversible?
- Performs another substrate-level phosphorylation, transferring a phosphate from phosphoenolpyruvate to ATP
- Forms ATP and pyruvate
What is pyruvate kinase activated by?
What is the only means of ATP generation in an anaerobic tissue?
What is feed-forward activation? How does it relate to glycolysis?
The product of an earlier reaction in glycolysis (fructose 1,6-biphosphate) stimulates, or prepares, a later reaction in glycolysis (by activating pyruvate kinase)
How is the NADH produced in glycolysis oxidized if oxygen or mitochondria are absent?
Cytoplasmic lactate dehydrogenase (fermentation)
What does lactate dehydrogenase do? What does it replenish?
- Oxidizes NADH to NAD+
- Replenishing the oxidized coenzyme for glyceraldehyde-3-phosphate dehydrogenase
Without mitochondria and oxygen, when would glycolysis stop? What prevents this from happening?
- When all the available NAD+ has been reduced to NADH
- Lactate dehydrogenase
Lactate is not present in significant amounts in aerobic tissues. In what situations would it be more present?
When oxygenation is poor (stenuous exercise in skeletal muscle, heart attack, stroke), most cellular ATP is generated by anaerobic glycolysis, and lactate production increases
What is fermentation in yeast cells?
Conversion of pyruvate (three carbons) to ethanol (two carbons) and carbon dioxide (one carbon)
How do yeast and mammalian fermentation differ? How are they similar?
Similarity: result replenishes NAD+
Difference: end products are different
What are the three important intermediates of glycolysis?
What is the function of DHAP as an intermediate of glycolysis?
- Used in hepatic and adipose tissue for triacylglycerol synthesis
- DHAP can be isomerized to glycerol-3-phosphate, which can be converted to glycerol, the backbone of triacylglycerols
What is the function of 1,3-biphosphoglycerate and phosphoenolpyruvate as intermediates of glycolysis?
High-energy intermediates used to generate ATP by substrate-level phosphorylation
Which intermediate of glycolysis is involved in triacylglycerol synthesis in hepatic and adipose tissue?
What are the four irreversible enzymes in glycolysis? What is the mnemonic?
- How Glycolysis Pushes Forward the Process: Kinases
- Pyruvate Kinase
How many ATP molecules does anaerobic glycolysis yield per glucose molecule?
2 ATP = 1 Glucose
What enzyme do erythrocytes (red blood cells) possess that impact glycolysis? How?
Biphosphoglycerate mutase, which produces 2,3-biphosphoglycerate from 1,3-biphosphoglycerate
What does 2,3-biphosphoglycerate do? What are its physiological effects? What are the effects of an abnormal increase of 2,3-BPG? How does the oxygen dissociation curve shift?
- Binds allosterically to the B-chains of hemoglobin A and decreases its affinity for oxygen
- Abnormal increase might shift the curve far enough so that HbA is not fully saturated in the lungs
- Right shift of the oxygen dissociation curve
Where do monosaccharides go once they have been absorbed into the bloodstream?
They travel to the liver through the hepatic portal vein
Is glucose the only monosaccharide that contributes to ATP production?
No, galactose and fructose can contribute as well
What happens to galactose once it has been transported to tissues. Hint: there are three enzymes involved.
1) Galactokinase phosphorylates galactose, trapping it into the cell
2) Galactose-1-phosphate uridyltransferase and an Epimerase convert galactose-1-phosphate to glucose-1-phosphate
What are epimerases?
Enzymes that catalyze the conversion of one sugar epimer to another
What are the two important enzymes of galactose metabolism?
2) Galactose-1-phosphate uridyltransferase and epimerase
How is galactose metabolism linked to glucose metabolism?
Galactose-1-phosphate uridyltransferase produces glucose-1-phosphate, a glycolytic intermediate
How is fructose metabolism linked to glucose metabolism?
Aldolase B produces DHAP and glyceraldehyde (which can be phosphorylated to form glyceraldehyde-3-phosphate), which are glycolytic intermediates
Which enzyme is responsible for trapping fructose in the cell?
Fructokinase (with a small contribution from hexokinase)
Following aerobic glycolysis, what are the two possible fates of pyruvate once it has entered the mitochondria and has been converted to acetyl-CoA?
1) If ATP is needed: converted to acetyl-CoA for entry into the citric acid cycle
2) If sufficient ATP is present: fatty acid synthesis
Is the pyruvate dehydrogenase complex reaction reversible?
- Cannot be used to convert acetyl-CoA to pyruvate or to glucose
Can Acetyl-CoA be converted to pyruvate or to glucose? Why not?
No, since the pyruvate dehydrogenase complex reaction is irreversible
What is pyruvate dehydrogenase activated by in the liver? What about in the nervous system?
- Liver: activated by insulin
- Nervous system: enzyme is not responsive to hormones
What are the three possible fates of pyruvate?
1) Conversion to acetyl-CoA by pyruvate dehydrogenase complex
2) Conversion to lactate by lactate dehydrogenase
3) Conversion to oxaloacetate by pyruvate carboxylase
Name some cofactors and coenzymes of the pyruvate dehydrogenase complex.
Thiamine, pyrophosphate, lipoic acid, CoA, FAD, NAD+
What is pyruvate dehydrogenase inhibited by? How? What is pyruvate converted to?
- By its product acetyl-CoA
- Buildup of acetyl-CoA causes a shift in metabolism
- Pyruvate is no longer converted into acetyl-CoA, but rather into oxaloacetate (to enter gluconeogenesis)
What are the reactants in the PDH complex?
Pyruvate, NAD+, CoA
What are the products in the PDH complex?
Acetyl-CoA, NADH, CO2
Where does glycogen synthesis and degradation occur primarily?
Liver and skeletal muslces
How do the roles of glycogen in the liver and skeletal muscles differ?
Liver: broken down to maintain a constant level of glucose in the blood
Skeletal muscles: muscle glycogen is broken down to provide glucose to the muscle during vigorous exercise
Where is glycogen stored in the cell? Under what form?
- In the cytoplasm
- As granules
Describe the structure of glycogen granules.
Each granule has a central protein core with polyglucose chains radiating outward to form a sphere
What kind of glycogen granules have the highest density of glucose near the core? Does this allow slow or rapid release of glucose on demand?
- Composed entirely of linear chains
- Slow release
What kind of glycogen granules have the highest density of glucose at the peripheral of the granule Does this allow slow or rapid release of glucose on demand?
- Composed of branched chains
- Fast release
How do plants store excess glucose?
In long a-linked chains of glucose called starch
What is glycogenesis?
- Glycogen synthesis
- Production of glycogen
What are the two main enzymes in glycogenesis?
- Glycogen synthase
- Branching enzyme
In glycogenesis, what does glycogen synthase do? What kind of link does it form in the process?
Attaches the glucose molecule from UDP-glucose to the growing glycogen chain, forming an a-1,4 glycosidic link found in the linear glucose chains of the granule in the process
In glycogenesis, what does the branching enzyme do? What linkages are broken and formed during this process?
- Creates a branch by breaking an a-1,4 link in the growing chain and moving a block of oligoglucose to another location in the glycogen granule.
- Oligoglucose is then attached with an a-1,6 link
Where is glycogen synthase activated?
In liver and muscle
Glycogenesis begins with a core protein called ______. What happens afterwards?
- glucose-6-phosphate is converted to glucose-1-phosphate
- Activated by coupling to UDP, which permits its integration into the glycogen chain by glycogen synthase
What is the rate-limiting enzyme in glycogenesis?
What is glycogen synthase stimulated by? What is it inhibited by?
Stimulate: glucose-6-phosphate and insulin
Inhibited: epinephrine and glucagon
What is glycogenolysis?
The process of breaking down glycogen
What is the rate-limiting enzyme of glycogenolysis?
What does a phosphorylase enzyme do?
Breaks bonds by using an inorganic phosphate instead of water
What are the two main enzymes used in glycogenolysis?
1) Glycogen phosphorylase
2) Debranching enzyme
In glycogenolysis, what does glycogen phosphorylase do?
Removes a glucose molecule from glycogen using a phosphate, breaking the a-1,4 link and creating glucose-1-phosphate
In glycogenolysis, what does debranching enzyme do?
- Moves all of the glucose from a branch to a longer glycogen chain by breaking an a-1,4 link and forming a new a-1,4 link to a longer chain
- The branchpoint is left behind; this is removed by breaking the a-1,6 link to form a free molecule of glucose
Can glycogen phosphorylase break a-1,6 bonds?
What is glycogen phosphorylase activated by in the liver? What is it activated by in skeletal muscle? What is it inhibited by?
Skeletal muscle: AMP and epinephrine
How many enzymes does the debranching enzyme complex contain?
What kind of glycosidic links exist in a glycogen granule?
- Linear chains of glucose connected by a-1,4 glycosidic links
- Branched chains connected by a-1,6 glycosidic links
What happens if there are different isoforms of enzymes related to glycogen metabolism?
If it is excessive or severe, it will lead to glycogen storage diseases --> characterized by accumulation of glycogen in one or more tissues
The liver maintains glucose levels in blood during fasting through either __________ or ___________
glycogenolysis or gluconeogenesis
What organs can carry out gluconeogenesis? Where is it carried out in the cell?
- Liver (mainly)
- Kidney (smaller amounts)
- In both the cytoplasm and mitochondria
What is glucogeneogensis activated by? What is it inhibited by?
Activated: glucagon + epinephrine (act to raise blood sugar)
Inhibited: insulin (acts to lower blood sugar)
When is glucogoneogenesis needed?
- During fasting, glycogen reserves drop dramatically in the first 12 hours, gluconeogenesis increases
- After 24 hours, it represents the sole source of glucose
What are the three important substrates for gluconeogenesis?
- Glucogenic amino acids
In terms of gluconeogenesis, where does the glycerol-3-phosphate come from?
From stored fats or triacylglycerols, in adipose tissue
In terms of gluconeogenesis, where does the lactate come from?
From anaerobic glycolysis
In terms of gluconeogenesis, where do the glucogenic amino acids come from?
From muscle protein
What are glucogenic amino acids? What are the two exceptions?
- Can be converted into intermediates that feed into gluconeogenesis
- All except leucine and lysine
What are ketogenic amino acids? When is it useful?
Can be converted into ketone bodies, which can be used as an alternative fuel, particularly during periods of prolonged starvation
Where can dietary fructose and lactose be converted to glucose?
In the liver
Why aren't fatty acids a major source of glucose?
- Because most fatty acids are metabolized solely to acetyl-CoA
- It is not possible to convert acetyl-CoA back to glucose
What kind of fatty acids CAN be glucogenic?
Fatty acids with an odd number of carbon atoms (ex: 17 carbons), which yield a small amount of propionyl-CoA, which is glucogenic
What are the three important glucogeogenic intermediates? How do they relate to glycolytic intermediates?
- Lactate, alanine, and glycerol-3-phosphate
- Have enzymes that convert them into glycolytic intermediates
How is lactate, a glucogeogenic intermediate, converted to a glycolytic intermediate?
Lactate is converted to pyruvate by lactate dehydrogenase
How is alanine, a glucogeogenic intermediate, converted to a glycolytic intermediate?
Alanine is converted to pyruvate by alanine aminotransferase
How is glycerol-3-phosphate, a glucogeogenic intermediate, converted to a glycolytic intermediate?
Glycerol-3-phosphate is converted to DHAP by glycerol-3-phosphate dehydrogenase
How does gluconeogenesis compare to glycolysis?
- Most of gluconeogenesis is simply the reverse of glycolysis, using the same enzymes
- The three irreversible steps of glycolysis must be bypassed by different enzymes
What are the four gluconegenic enzymes that replace the irreversible glycolytic enzymes?
- Pyruvate carboxylase
- Phosphoenoylpyruvate carboxykinase (PEPCK)
In gluconeogenesis, which irreversible glycolytic enzyme does pyruvate carboxylase replace?
In gluconeogenesis, which irreversible glycolytic enzyme does phosphoenoylpyruvate carboxykinase (PEPCK) replace?
In gluconeogenesis, which irreversible glycolytic enzyme does fructose-2,6-bisphosphatase replace?
In gluconeogenesis, which irreversible glycolytic enzyme does glucose-6-phosphate replace?
Under what physiological conditions should the body carry out gluconeogenesis?
Occurs when an individual has been fasting >12 hours. To carry out gluconeogenesis, hepatic (and renal) cells must have enough energy to drive the process of glucose creation, which requires sufficient fat stores to undergo B-oxidation
How does acetyl-CoA shift the metabolism of pyruvate? What does it inhibit? What does it activate? Where does the acetyl-CoA for this regulation come from?
- Inhibits pyruvate dehydrogenase complex while activating pyruvate carboxylase
- Shift from burning pyruvate in the TCA cycle to creating new glucose molecules for the rest of the body
- Acetyl-CoA comes predominantly from B-oxidation, not glycolysis
In gluconeogenesis, where is pyruvate carboxylase situated in the cell? What is it activated by?
- Mitochondrial enzyme
- Activated by acetyl-CoA from B-oxidation
- Source of acetyl-CoA is not from glycolysis and pyruvate dehydrogenase, but from fatty acids
What step is necessary to produce glucose in the liver during gluconeogenesis?
Fatty acids must be burned to provide this energy, stop the forward flow of the TCA cycle, and produce massive amounts of oxaloacetate that can eventually lead to glucose production for the rest of the body
In gluconeogenesis, what is PEPCK activated by? Where is it located in the cell?
- Glucagon and cortisol
In gluconeogenesis, how do pyruvate carboxylase and PEPCK bypass pyruvate kinase?
- Pyruvate carboxylase converts pyruvate to oxaloacetate
- PEPCK converts oxaloacetate to phosphoenolpyruvate
What is the rate-limiting step of gluconeogenesis? Where is this enzyme located in the cell?
- Located in the cytoplasm
Phosphatases oppose _________
In gluconeogenesis, what is fructose-1,6-bisphosphatase activated and inhibited by?
Activated: ATP and glucagon indirectly (via decreased levels of fructose-2,6-bisphosphate
Inhibited: AMP directly and insulin indirectly (via increased levels of fructose-2,6-biphosphate)