CHAPTER 25: INITIAL RECTIONS IN ANAEROBIC GLYCOLYSIS
Chapter 25: Initial Reactions in Aerobic Glycolisis
We will now begin our examination of each reaction in the glycolytic pathway, realizing that most all living eukaryotic and prokaryotic cells are dependent upon them. The initial reactions convert glucose to fructose 1,6- bisphosphate (Frc-1,6-bisP). In most cells this conversion occurs in three steps, first a phosphorylation (reaction #1), then an isomerization (reaction #2), and then another phosphorylation (reaction #7). However, in some cell types glucose can take an alternate route to Frc-1,6-bisP through sorbitol and fructose. The initial steps in glycolysis trap glucose in the cell, and ultimately form a compound (Frc-1,6-bisP) that can be easily cleaved into phosphorylated three carbon units (i.e., glyceraldehyde 3-phosphate (Gl-3- P), and dihydroxyacetone phosphate (DHAP)).
Galactose, derived from dietary sources, is largely removed from the portal circulation by the liver and converted in a series of reactions to glucose 1-phosphate (Glc-1-P), and then to glucose 6-phosphate (Glc-6-P). The ability of the liver to accomplish this conversion forms the basis for a test of hepatic function (i.e., the galactose tolerance test). Since Glc-1-P can also be used to synthesize galactose, glucose can be converted to galactose in several different cell types, so that preformed galactose is not essential in the diet. Galactose is synthesized in the body for the formation of lactose (in lactating mammary glands), and it is also a constituent of glycolipids (cerebrosides), and glycoproteins.
The conversion of Glc-6-P to fructose 6- phosphate (Frc-6-P) is catalyzed by the enzyme phosphohexose (or glucosephosphate) isomerase (reaction #2). This reaction is readily reversible, and changes an aldopyranose (glucose) to a ketofuranose (fructose). Unlike the next step in glycolysis (#7, i.e., conversion of Frc-6-P to Frc-1,6-bisP), conversion of Glc-6- P to Frc-6-P is not stringently regulated. It should, however, be noted at this point that when Glc-6-P enters the hexose monophosphate shunt (HMS), its products return to the EMP at the level of Frc-6-P and Gl-3-P.
Fructose may also be converted in part to Frc-6-P (reaction #3), and then metabolized via Frc-1,6-bisP. The enzyme catalyzing formation of Frc-6-P is hexokinase, the same enzyme that catalyzes conversion of glucose to Glc-6-P. However, much more fructose is converted to fructose 1-phosphate (Frc-1-P) in a reaction catalyzed by a highly specific liver enzyme, fructokinase (reaction #4), which has a low Km (like hexokinase), and has also been demonstrated in kidney and intestine. This enzyme will not phosphorylate glucose, and, unlike hepatic glucokinase, its activity is not affected by starvation or by insulin, which helps to explain why fructose disappears from the blood of diabetic patients at a normal rate. Although it has been recommended that fructose be given to diabetic patients to replenish their carbohydrate stores, most, unfortunately, is metabolized in the intestine and liver, so its value in replenishing carbohydrate stores elsewhere in the body is limited.
It should be noted at this point that both fructose and sorbitol (a polyol also known as glucitol), are found in the lens, where they increase in concentration in hyperglycemic diabetic patients, and are involved in the pathogenesis of diabetic cataract. The sorbitol pathway from glucose (called the "Polyol Pathway"), is responsible for fructose formation, and increases in activity as the glucose concentration rises in diabetes mellitus (in those tissues that are not insulin sensitive (i.e., the lens, nerve tissue, intestinal mucosa, erythrocytes, renal tubules, and glomeruli)). Glucose undergoes reduction by NADPH to sorbitol, catalyzed by aldose reductase (reaction #5), followed by oxidation of sorbitol to fructose in the presence of NAD+ and sorbitol dehydrogenase (SDH, reaction #6). Although sorbitol and fructose can be metabolized to glycolytic intermediates, this process is slow. Additionally, sorbitol does not diffuse through cell membranes easily, and its accumulation causes osmotic damage by allowing ingress of water with consequent swelling, and eventually cataract formation (clouding of the liquid contents of the lens, probably due to a change in protein solubility). A related polyol, galactitol (also known as dulcitol), can be formed when galactose is reduced by aldose reductase and NADPH, and it may also accumulate in the lens and participate in the formation of cataracts, particularly in cases of defective hepatic galactose catabolism (i.e., galactosemia). This, unfortunately, can be even more serious than sorbitol accumulation since galactitol cannot be further metabolized in the lens.
Cataracts have been prevented in diabetic rats by the use of aldose reductase inhibitors. Aldose reductase is also found in the placenta of the ewe, and is responsible for the secretion of sorbitol into fetal blood. The presence of SDH in the livers of mammals, including the fetal liver, is responsible for the conversion of sorbitol to fructose. Its elevation in plasma is usually indicative of liver cell damage, particularly in large animal species. The Polyol Pathway, present in the seminal vesicles, is also reported to be responsible for the occurrence of fructose in seminal fluid.
When sorbitol is administered intravenously, it is converted to fructose rather than to glucose, although if given by mouth much apparently escapes intestinal absorption, and is fermented in the colon by bacteria to products such as acetate and histamine (thus sometimes causing abdominal pain). If the liver and intestine of an experimental animal are removed, for example, conversion of injected fructose to glucose does not take place, and the animal succumbs to hypoglycemia unless glucose is administered. Now, back to the EMP.
Reactions #2 and #3 are followed by another phosphorylation reaction with ATP (like that forming Glc-6-P), thus converting Frc-6-P to Frc-1,6-bisP (reaction #7). This reaction, catalyzed by phosphofructokinase (PFK), and also using Mg++ and K+ as cofactors, is a key regulatory step in glycolysis. In order to reverse this reaction in hepatic glyconeogenesis, PFK must be inhibited and fructose 1,6-bisphosphatase must be activated (by glucagon and the other diabetogenic hormones.)
Inhibitors of PFK: ATP, Phosphocreatine, Citrate, Glucagon (liver), H+
Stimulators of PFK: AMP and ADP, Frc-6-P, Inorganic phosphate (Pi), Ammonium ion (NH4 +), Epinephrine (muscle), Insulin
A fall in intracellular pH (↑[H+ ]) inhibits PFK activity. This inhibition helps to prevent excessive lactic acid formation, and a further precipitous drop in blood pH (acidemia). The concentration of ATP is typically about 50 times that of AMP in the cell. Consequently, conversion of only small amounts of ATP to ADP can produce a significant percentage increase in the AMP concentration. This fact, combined with allosteric PFK activation by AMP, makes PFK activity sensitive to small changes in a cell's energy status, so that the amount of precious carbohydrate spent on glycolysis is accurately controlled. On the other hand, ATP and citrate powerfully inhibit PFK. Breakdown of fat (in mitochondria) yields high levels of ATP and citrate. Under this condition in muscle tissue, energy is plentiful and PFK inhibition partially spares glucose from further glycolytic breakdown. However, a certain amount of glucose oxidation in muscle is still required during aerobic b-oxidation of fatty acids in order to assure sufficient oxaloacetate availability to keep the TCA cycle functioning.
Phosphocreatine is a short-term buffer for ATP, and helps to maintain ATP at normal concentrations, even at the start of a sudden energy demand:
ADP + Phosphocreatine ATP + Creatine
Phosphocreatine levels in resting muscle are typically two to three times greater than ATP levels, and usually fall following the onset of exercise. Therefore, when PFK needs to be activated, the potentiation of ATP inhibition by phosphocreatine is removed. Increased degradation of AMP during exercise leads to ammonium ion (NH4 +) and Pi formation, which stimulate PFK activity. Epinephrine, a hormone secreted from the adrenal medulla during exercise due to sympathetic nervous system stimulation, activates PFK in muscle tissue, but not in the liver, for during exercise the liver is in a gluconeogenic state.
In summary, the initial cytoplasmic reactions in anaerobic glycolysis generally use either galactose, fructose, glycogen, or more often glucose as substrates. In hyperglycemic patients, the “polyol pathway” becomes important in insulin-independent tissues. Phosphofructokinase is a key regulatory enzyme in anaerobic glycolysis, and the activity of this enzyme is regulated by various factors including the ATP/ADP ratio, the H+ concentration, phosphocreatine, citrate, glucagon, Frc-6-P, Pi, NH4 + , and epinephrine.
SUMMARY
Chapter 25 discusses the initial reactions in aerobic glycolysis. These reactions convert glucose to fructose 1,6-bisphosphate (Frc-1,6-bisP) through a series of phosphorylation and isomerization steps. Galactose, derived from dietary sources, is converted to glucose 1-phosphate (Glc-1-P) and then to glucose 6-phosphate (Glc-6-P) in the liver. The conversion of Glc-6-P to fructose 6-phosphate (Frc-6-P) is catalyzed by phosphohexose isomerase. Fructose can be converted to Frc-6-P or fructose 1-phosphate (Frc-1-P) by hexokinase and fructokinase, respectively. The sorbitol pathway, also known as the "Polyol Pathway," converts glucose to sorbitol and then to fructose, and is involved in the pathogenesis of diabetic cataract. The key regulatory step in glycolysis is the conversion of Frc-6-P to Frc-1,6-bisP, catalyzed by phosphofructokinase (PFK). PFK activity is regulated by various factors including ATP, phosphocreatine, citrate, glucagon, H+, Frc-6-P, Pi, NH4+, and epinephrine.
OUTLINE
I. Introduction to the glycolytic pathway
Importance of glycolysis in eukaryotic and prokaryotic cells
Conversion of glucose to fructose 1,6-bisphosphate (Frc-1,6-bisP) in initial reactions
II. Three-step conversion of glucose to Frc-1,6-bisP
Phosphorylation of glucose (reaction #1)
Isomerization of glucose (reaction #2)
Phosphorylation of fructose (reaction #7)
III. Alternate route of glucose to Frc-1,6-bisP through sorbitol and fructose
Occurs in some cell types
Traps glucose in the cell and forms easily cleaved compounds
IV. Conversion of galactose to glucose
Galactose is converted to glucose 1-phosphate (Glc-1-P) and then to glucose 6-phosphate (Glc-6-P) in the liver
Basis for galactose tolerance test to assess hepatic function
V. Metabolism of fructose
Conversion of fructose to Frc-6-P (reaction #3)
Formation of fructose 1-phosphate (Frc-1-P) by fructokinase (reaction #4)
Limited value of fructose in replenishing carbohydrate stores
VI. Polyol pathway and its implications
Sorbitol pathway from glucose leading to fructose formation
Accumulation of sorbitol and fructose in hyperglycemic diabetic patients and its role in diabetic cataract formation
Formation of galactitol and its role in cataracts in cases of defective hepatic galactose catabolism
VII. Inhibition and activation of phosphofructokinase (PFK)
Key regulatory step in glycolysis
Inhibitors of PFK: ATP, phosphocreatine, citrate, glucagon, H+
Stimulators of PFK: AMP, ADP, Frc-6-P, inorganic phosphate (Pi), ammonium ion (NH4+), epinephrine
VIII. Factors affecting PFK activity
Intracellular pH and lactic acid formation
QUESTIONS
Qcard 1:
Question: What is the initial reaction in aerobic glycolysis?
Answer: The initial reactions convert glucose to fructose 1,6-bisphosphate (Frc-1,6-bisP).
Qcard 2:
Question: How is galactose converted to glucose in the liver?
Answer: Galactose is converted to glucose 1-phosphate (Glc-1-P), and then to glucose 6-phosphate (Glc-6-P) in a series of reactions.
Qcard 3:
Question: What enzyme catalyzes the conversion of Glc-6-P to Frc-6-P?
Answer: The enzyme phosphohexose (or glucosephosphate) isomerase catalyzes this conversion.
Qcard 4:
Question: What enzyme catalyzes the formation of Frc-6-P from fructose?
Answer: Hexokinase catalyzes the formation of Frc-6-P from fructose.
Qcard 5:
Question: What is the Polyol Pathway and what is its significance in diabetes?
Answer: The Polyol Pathway is responsible for the formation of fructose from glucose and is involved in the pathogenesis of diabetic cataract.
Qcard 6:
Question: What is the key regulatory step in glycolysis?
Answer: The conversion of Frc-6-P to Frc-1,6-bisP catalyzed by phosphofructokinase (PFK) is the key regulatory step in glycolysis.
Qcard 7:
Question: What are the inhibitors of PFK?
Answer: ATP, phosphocreatine, citrate, glucagon (liver), and H+ are inhibitors of PFK.
Qcard 8:
Question: What are the stimulators of PFK?
Answer: AMP and ADP, Frc-6-P, inorganic phosphate (Pi), ammonium ion (NH4+), and insulin are stimulators of PFK.
Qcard 9:
Question: How does intracellular pH affect PFK activity?
Answer: A fall in intracellular pH inhibits PFK activity.
Qcard 10:
Question: How does phosphocreatine affect PFK activity?
Answer: Phosphocreatine removes the potentiation of ATP inhibition, leading to the activation of PFK.
Qcard 11:
Question: What hormone activates PFK in muscle tissue during exercise?
Answer
The initial reactions in aerobic glycolysis convert glucose to fructose 1,6-bisphosphate (Frc-1,6-bisP).
Glucose to Frc-1,6-bisP conversion
Galactose metabolism
Fructose metabolism
Polyol pathway and its implications
Regulation of phosphofructokinase (PFK) activity
Phosphorylation (reaction #1)
Isomerization (reaction #2)
Another phosphorylation (reaction #7)
Conversion to Glc-1-P
Conversion to Glc-6-P
Conversion to Frc-6-P (reaction #3)
Conversion to Frc-1-P (reaction #4)
Sorbitol pathway from glucose (reaction #5)
Conversion of sorbitol to fructose (reaction #6)
Accumulation of sorbitol and fructose in the lens
Formation of cataracts
Inhibitors of PFK: ATP, Phosphocreatine, Citrate, Glucagon (liver), H+
Stimulators of PFK: AMP and ADP, Frc-6-P, Inorganic phosphate (Pi), Ammonium ion (NH4 +), Epinephrine (muscle), Insulin
Factors affecting PFK activity: intracellular pH, ATP/ADP ratio, phosphocreatine, citrate, glucagon, Frc-6-P, Pi, NH4 + , epinephrine
Note: The mind map is not exhaustive and only includes the main branches and sub-branches mentioned in the given text.
Read and understand the introduction to Chapter 25, focusing on the significance of the initial reactions in aerobic glycolysis.
Take notes on the conversion of glucose to fructose 1,6-bisphosphate (Frc-1,6-bisP) and the alternate route of glucose to Frc-1,6-bisP through sorbitol and fructose.
Study the trapping of glucose in the cell and the formation of glyceraldehyde 3-phosphate (Gl-3-P) and dihydroxyacetone phosphate (DHAP).
Review the role of galactose in the formation of glucose 1-phosphate (Glc-1-P) and glucose 6-phosphate (Glc-6-P).
Review the conversion of Glc-6-P to fructose 6-phosphate (Frc-6-P) catalyzed by phosphohexose (or glucosephosphate) isomerase.
Understand the reversibility of this reaction and its regulation.
Study the conversion of fructose to fructose 1-phosphate (Frc-1-P) catalyzed by fructokinase and its differences from hepatic glucokinase.
Take note of the metabolic pathways involving fructose and sorbitol and their implications in diabetic cataract formation.
Focus on the sorbitol pathway and its role in fructose formation.
Understand the conversion of glucose to sorbitol and sorbitol to fructose.
Study the consequences of sorbitol accumulation and its impact on diabetic cataracts.
Take note of the formation of galactitol and its involvement in cataract formation in cases of defective hepatic galactose catabolism.
Review the prevention of cataracts in diabetic rats through aldose reductase inhibitors.
Understand the role of aldose reductase in the placenta and the liver.
Study the Polyol Pathway in seminal vesicles and its relation to fructose in seminal fluid.
Take note of the metabolism of sorbitol when administered intravenously or orally.
Review the final reactions in the initial steps of aerobic glycolysis, including the phosphorylation of Frc-6-P to F
Chapter 25: Initial Reactions in Aerobic Glycolisis
We will now begin our examination of each reaction in the glycolytic pathway, realizing that most all living eukaryotic and prokaryotic cells are dependent upon them. The initial reactions convert glucose to fructose 1,6- bisphosphate (Frc-1,6-bisP). In most cells this conversion occurs in three steps, first a phosphorylation (reaction #1), then an isomerization (reaction #2), and then another phosphorylation (reaction #7). However, in some cell types glucose can take an alternate route to Frc-1,6-bisP through sorbitol and fructose. The initial steps in glycolysis trap glucose in the cell, and ultimately form a compound (Frc-1,6-bisP) that can be easily cleaved into phosphorylated three carbon units (i.e., glyceraldehyde 3-phosphate (Gl-3- P), and dihydroxyacetone phosphate (DHAP)).
Galactose, derived from dietary sources, is largely removed from the portal circulation by the liver and converted in a series of reactions to glucose 1-phosphate (Glc-1-P), and then to glucose 6-phosphate (Glc-6-P). The ability of the liver to accomplish this conversion forms the basis for a test of hepatic function (i.e., the galactose tolerance test). Since Glc-1-P can also be used to synthesize galactose, glucose can be converted to galactose in several different cell types, so that preformed galactose is not essential in the diet. Galactose is synthesized in the body for the formation of lactose (in lactating mammary glands), and it is also a constituent of glycolipids (cerebrosides), and glycoproteins.
The conversion of Glc-6-P to fructose 6- phosphate (Frc-6-P) is catalyzed by the enzyme phosphohexose (or glucosephosphate) isomerase (reaction #2). This reaction is readily reversible, and changes an aldopyranose (glucose) to a ketofuranose (fructose). Unlike the next step in glycolysis (#7, i.e., conversion of Frc-6-P to Frc-1,6-bisP), conversion of Glc-6- P to Frc-6-P is not stringently regulated. It should, however, be noted at this point that when Glc-6-P enters the hexose monophosphate shunt (HMS), its products return to the EMP at the level of Frc-6-P and Gl-3-P.
Fructose may also be converted in part to Frc-6-P (reaction #3), and then metabolized via Frc-1,6-bisP. The enzyme catalyzing formation of Frc-6-P is hexokinase, the same enzyme that catalyzes conversion of glucose to Glc-6-P. However, much more fructose is converted to fructose 1-phosphate (Frc-1-P) in a reaction catalyzed by a highly specific liver enzyme, fructokinase (reaction #4), which has a low Km (like hexokinase), and has also been demonstrated in kidney and intestine. This enzyme will not phosphorylate glucose, and, unlike hepatic glucokinase, its activity is not affected by starvation or by insulin, which helps to explain why fructose disappears from the blood of diabetic patients at a normal rate. Although it has been recommended that fructose be given to diabetic patients to replenish their carbohydrate stores, most, unfortunately, is metabolized in the intestine and liver, so its value in replenishing carbohydrate stores elsewhere in the body is limited.
It should be noted at this point that both fructose and sorbitol (a polyol also known as glucitol), are found in the lens, where they increase in concentration in hyperglycemic diabetic patients, and are involved in the pathogenesis of diabetic cataract. The sorbitol pathway from glucose (called the "Polyol Pathway"), is responsible for fructose formation, and increases in activity as the glucose concentration rises in diabetes mellitus (in those tissues that are not insulin sensitive (i.e., the lens, nerve tissue, intestinal mucosa, erythrocytes, renal tubules, and glomeruli)). Glucose undergoes reduction by NADPH to sorbitol, catalyzed by aldose reductase (reaction #5), followed by oxidation of sorbitol to fructose in the presence of NAD+ and sorbitol dehydrogenase (SDH, reaction #6). Although sorbitol and fructose can be metabolized to glycolytic intermediates, this process is slow. Additionally, sorbitol does not diffuse through cell membranes easily, and its accumulation causes osmotic damage by allowing ingress of water with consequent swelling, and eventually cataract formation (clouding of the liquid contents of the lens, probably due to a change in protein solubility). A related polyol, galactitol (also known as dulcitol), can be formed when galactose is reduced by aldose reductase and NADPH, and it may also accumulate in the lens and participate in the formation of cataracts, particularly in cases of defective hepatic galactose catabolism (i.e., galactosemia). This, unfortunately, can be even more serious than sorbitol accumulation since galactitol cannot be further metabolized in the lens.
Cataracts have been prevented in diabetic rats by the use of aldose reductase inhibitors. Aldose reductase is also found in the placenta of the ewe, and is responsible for the secretion of sorbitol into fetal blood. The presence of SDH in the livers of mammals, including the fetal liver, is responsible for the conversion of sorbitol to fructose. Its elevation in plasma is usually indicative of liver cell damage, particularly in large animal species. The Polyol Pathway, present in the seminal vesicles, is also reported to be responsible for the occurrence of fructose in seminal fluid.
When sorbitol is administered intravenously, it is converted to fructose rather than to glucose, although if given by mouth much apparently escapes intestinal absorption, and is fermented in the colon by bacteria to products such as acetate and histamine (thus sometimes causing abdominal pain). If the liver and intestine of an experimental animal are removed, for example, conversion of injected fructose to glucose does not take place, and the animal succumbs to hypoglycemia unless glucose is administered. Now, back to the EMP.
Reactions #2 and #3 are followed by another phosphorylation reaction with ATP (like that forming Glc-6-P), thus converting Frc-6-P to Frc-1,6-bisP (reaction #7). This reaction, catalyzed by phosphofructokinase (PFK), and also using Mg++ and K+ as cofactors, is a key regulatory step in glycolysis. In order to reverse this reaction in hepatic glyconeogenesis, PFK must be inhibited and fructose 1,6-bisphosphatase must be activated (by glucagon and the other diabetogenic hormones.)
Inhibitors of PFK: ATP, Phosphocreatine, Citrate, Glucagon (liver), H+
Stimulators of PFK: AMP and ADP, Frc-6-P, Inorganic phosphate (Pi), Ammonium ion (NH4 +), Epinephrine (muscle), Insulin
A fall in intracellular pH (↑[H+ ]) inhibits PFK activity. This inhibition helps to prevent excessive lactic acid formation, and a further precipitous drop in blood pH (acidemia). The concentration of ATP is typically about 50 times that of AMP in the cell. Consequently, conversion of only small amounts of ATP to ADP can produce a significant percentage increase in the AMP concentration. This fact, combined with allosteric PFK activation by AMP, makes PFK activity sensitive to small changes in a cell's energy status, so that the amount of precious carbohydrate spent on glycolysis is accurately controlled. On the other hand, ATP and citrate powerfully inhibit PFK. Breakdown of fat (in mitochondria) yields high levels of ATP and citrate. Under this condition in muscle tissue, energy is plentiful and PFK inhibition partially spares glucose from further glycolytic breakdown. However, a certain amount of glucose oxidation in muscle is still required during aerobic b-oxidation of fatty acids in order to assure sufficient oxaloacetate availability to keep the TCA cycle functioning.
Phosphocreatine is a short-term buffer for ATP, and helps to maintain ATP at normal concentrations, even at the start of a sudden energy demand:
ADP + Phosphocreatine ATP + Creatine
Phosphocreatine levels in resting muscle are typically two to three times greater than ATP levels, and usually fall following the onset of exercise. Therefore, when PFK needs to be activated, the potentiation of ATP inhibition by phosphocreatine is removed. Increased degradation of AMP during exercise leads to ammonium ion (NH4 +) and Pi formation, which stimulate PFK activity. Epinephrine, a hormone secreted from the adrenal medulla during exercise due to sympathetic nervous system stimulation, activates PFK in muscle tissue, but not in the liver, for during exercise the liver is in a gluconeogenic state.
In summary, the initial cytoplasmic reactions in anaerobic glycolysis generally use either galactose, fructose, glycogen, or more often glucose as substrates. In hyperglycemic patients, the “polyol pathway” becomes important in insulin-independent tissues. Phosphofructokinase is a key regulatory enzyme in anaerobic glycolysis, and the activity of this enzyme is regulated by various factors including the ATP/ADP ratio, the H+ concentration, phosphocreatine, citrate, glucagon, Frc-6-P, Pi, NH4 + , and epinephrine.
SUMMARY
Chapter 25 discusses the initial reactions in aerobic glycolysis. These reactions convert glucose to fructose 1,6-bisphosphate (Frc-1,6-bisP) through a series of phosphorylation and isomerization steps. Galactose, derived from dietary sources, is converted to glucose 1-phosphate (Glc-1-P) and then to glucose 6-phosphate (Glc-6-P) in the liver. The conversion of Glc-6-P to fructose 6-phosphate (Frc-6-P) is catalyzed by phosphohexose isomerase. Fructose can be converted to Frc-6-P or fructose 1-phosphate (Frc-1-P) by hexokinase and fructokinase, respectively. The sorbitol pathway, also known as the "Polyol Pathway," converts glucose to sorbitol and then to fructose, and is involved in the pathogenesis of diabetic cataract. The key regulatory step in glycolysis is the conversion of Frc-6-P to Frc-1,6-bisP, catalyzed by phosphofructokinase (PFK). PFK activity is regulated by various factors including ATP, phosphocreatine, citrate, glucagon, H+, Frc-6-P, Pi, NH4+, and epinephrine.
OUTLINE
I. Introduction to the glycolytic pathway
Importance of glycolysis in eukaryotic and prokaryotic cells
Conversion of glucose to fructose 1,6-bisphosphate (Frc-1,6-bisP) in initial reactions
II. Three-step conversion of glucose to Frc-1,6-bisP
Phosphorylation of glucose (reaction #1)
Isomerization of glucose (reaction #2)
Phosphorylation of fructose (reaction #7)
III. Alternate route of glucose to Frc-1,6-bisP through sorbitol and fructose
Occurs in some cell types
Traps glucose in the cell and forms easily cleaved compounds
IV. Conversion of galactose to glucose
Galactose is converted to glucose 1-phosphate (Glc-1-P) and then to glucose 6-phosphate (Glc-6-P) in the liver
Basis for galactose tolerance test to assess hepatic function
V. Metabolism of fructose
Conversion of fructose to Frc-6-P (reaction #3)
Formation of fructose 1-phosphate (Frc-1-P) by fructokinase (reaction #4)
Limited value of fructose in replenishing carbohydrate stores
VI. Polyol pathway and its implications
Sorbitol pathway from glucose leading to fructose formation
Accumulation of sorbitol and fructose in hyperglycemic diabetic patients and its role in diabetic cataract formation
Formation of galactitol and its role in cataracts in cases of defective hepatic galactose catabolism
VII. Inhibition and activation of phosphofructokinase (PFK)
Key regulatory step in glycolysis
Inhibitors of PFK: ATP, phosphocreatine, citrate, glucagon, H+
Stimulators of PFK: AMP, ADP, Frc-6-P, inorganic phosphate (Pi), ammonium ion (NH4+), epinephrine
VIII. Factors affecting PFK activity
Intracellular pH and lactic acid formation
QUESTIONS
Qcard 1:
Question: What is the initial reaction in aerobic glycolysis?
Answer: The initial reactions convert glucose to fructose 1,6-bisphosphate (Frc-1,6-bisP).
Qcard 2:
Question: How is galactose converted to glucose in the liver?
Answer: Galactose is converted to glucose 1-phosphate (Glc-1-P), and then to glucose 6-phosphate (Glc-6-P) in a series of reactions.
Qcard 3:
Question: What enzyme catalyzes the conversion of Glc-6-P to Frc-6-P?
Answer: The enzyme phosphohexose (or glucosephosphate) isomerase catalyzes this conversion.
Qcard 4:
Question: What enzyme catalyzes the formation of Frc-6-P from fructose?
Answer: Hexokinase catalyzes the formation of Frc-6-P from fructose.
Qcard 5:
Question: What is the Polyol Pathway and what is its significance in diabetes?
Answer: The Polyol Pathway is responsible for the formation of fructose from glucose and is involved in the pathogenesis of diabetic cataract.
Qcard 6:
Question: What is the key regulatory step in glycolysis?
Answer: The conversion of Frc-6-P to Frc-1,6-bisP catalyzed by phosphofructokinase (PFK) is the key regulatory step in glycolysis.
Qcard 7:
Question: What are the inhibitors of PFK?
Answer: ATP, phosphocreatine, citrate, glucagon (liver), and H+ are inhibitors of PFK.
Qcard 8:
Question: What are the stimulators of PFK?
Answer: AMP and ADP, Frc-6-P, inorganic phosphate (Pi), ammonium ion (NH4+), and insulin are stimulators of PFK.
Qcard 9:
Question: How does intracellular pH affect PFK activity?
Answer: A fall in intracellular pH inhibits PFK activity.
Qcard 10:
Question: How does phosphocreatine affect PFK activity?
Answer: Phosphocreatine removes the potentiation of ATP inhibition, leading to the activation of PFK.
Qcard 11:
Question: What hormone activates PFK in muscle tissue during exercise?
Answer
The initial reactions in aerobic glycolysis convert glucose to fructose 1,6-bisphosphate (Frc-1,6-bisP).
Glucose to Frc-1,6-bisP conversion
Galactose metabolism
Fructose metabolism
Polyol pathway and its implications
Regulation of phosphofructokinase (PFK) activity
Phosphorylation (reaction #1)
Isomerization (reaction #2)
Another phosphorylation (reaction #7)
Conversion to Glc-1-P
Conversion to Glc-6-P
Conversion to Frc-6-P (reaction #3)
Conversion to Frc-1-P (reaction #4)
Sorbitol pathway from glucose (reaction #5)
Conversion of sorbitol to fructose (reaction #6)
Accumulation of sorbitol and fructose in the lens
Formation of cataracts
Inhibitors of PFK: ATP, Phosphocreatine, Citrate, Glucagon (liver), H+
Stimulators of PFK: AMP and ADP, Frc-6-P, Inorganic phosphate (Pi), Ammonium ion (NH4 +), Epinephrine (muscle), Insulin
Factors affecting PFK activity: intracellular pH, ATP/ADP ratio, phosphocreatine, citrate, glucagon, Frc-6-P, Pi, NH4 + , epinephrine
Note: The mind map is not exhaustive and only includes the main branches and sub-branches mentioned in the given text.
Read and understand the introduction to Chapter 25, focusing on the significance of the initial reactions in aerobic glycolysis.
Take notes on the conversion of glucose to fructose 1,6-bisphosphate (Frc-1,6-bisP) and the alternate route of glucose to Frc-1,6-bisP through sorbitol and fructose.
Study the trapping of glucose in the cell and the formation of glyceraldehyde 3-phosphate (Gl-3-P) and dihydroxyacetone phosphate (DHAP).
Review the role of galactose in the formation of glucose 1-phosphate (Glc-1-P) and glucose 6-phosphate (Glc-6-P).
Review the conversion of Glc-6-P to fructose 6-phosphate (Frc-6-P) catalyzed by phosphohexose (or glucosephosphate) isomerase.
Understand the reversibility of this reaction and its regulation.
Study the conversion of fructose to fructose 1-phosphate (Frc-1-P) catalyzed by fructokinase and its differences from hepatic glucokinase.
Take note of the metabolic pathways involving fructose and sorbitol and their implications in diabetic cataract formation.
Focus on the sorbitol pathway and its role in fructose formation.
Understand the conversion of glucose to sorbitol and sorbitol to fructose.
Study the consequences of sorbitol accumulation and its impact on diabetic cataracts.
Take note of the formation of galactitol and its involvement in cataract formation in cases of defective hepatic galactose catabolism.
Review the prevention of cataracts in diabetic rats through aldose reductase inhibitors.
Understand the role of aldose reductase in the placenta and the liver.
Study the Polyol Pathway in seminal vesicles and its relation to fructose in seminal fluid.
Take note of the metabolism of sorbitol when administered intravenously or orally.
Review the final reactions in the initial steps of aerobic glycolysis, including the phosphorylation of Frc-6-P to F
