CHAPTER 37: GLUCONEOGENESIS
Chapter 37: Gluconeogenesis Gluconeogenesis is a major regulatory process in the liver and kidneys by which noncarbohydrate substrates; namely glycerol, lactate, propionate, and glucogenic amino acids; are converted to glucose 6-phosphate (Glc-6-P), and then to either free glucose or glycogen. The liver and kidneys are the major organs containing the full complement of gluconeogenic enzymes (i.e., pyruvate carboxylase, PEP carboxykinase, fructose 1,6-bisphosphatase, and glucose 6-phosphatase). Gluconeogenesis is needed to meet the demands for plasma glucose between meals, which then becomes particularly important as an energy substrate for nerves, erythrocytes, and other largely anaerobic cell types. Failure of this process can lead to brain dysfunction, coma, and death. In ruminant animals and carnivores, hepatic gluconeogenesis is a continual, ongoing process that has little or no relation to the frequency of food consumption. It is clear that even under conditions where fatty acid oxidation may be supplying most of the energy requirement of the organism, there is always a certain basal requirement for glucose, and glucose is a major fuel providing energy to skeletal muscle under anaerobic conditions. In addition, gluconeogenic mechanisms in the liver are used to clear certain products of metabolism from blood (e.g., lactate, produced by erythrocytes, the retina, kidney medulla, and anaerobic muscle fibers; and glycerol, which is continuously produced by adipose tissue when fat is being mobilized for energy purposes). Of the amino acids transported from muscle to liver during starvation, alanine (Ala) predominates. This amino acid is part of the glucose-alanine cycle which has the effect of cycling glucose from liver to muscle with formation of pyruvate, followed by transamination to Ala, then transport of Ala to liver, followed by gluconeogenesis back to glucose. During starvation, branched-chain amino acid (BCAA) oxidation in muscle serves as a source of ammonia (NH3). A net transfer of amino nitrogen from muscle to liver (and then to urea), and of potential energy (glucose) from liver to muscle is thus affected. The energy needed for hepatic synthesis of glucose from pyruvate (or lactate) is thought to be derived from the b-oxidation of fatty acids. Gluconeogenic Precursors Glucogenic Amino Acids Since amino acids are used for a variety of vital biosynthetic functions in the liver (e.g., protein production), they are generally used conservatively for gluconeogenesis. During their conversion to glucose, their amino groups are irretrievably lost to urea, which then enters blood (i.e., blood urea nitrogen (BUN)). The majority of amino acids form TCA intermediates and pyruvate, and are therefore glucogenic. Others form acetyl-CoA and, thus, are ketogenic. Acetyl-CoA is not a (net) substrate for gluconeogenesis since its two carbon atoms are lost as CO2 in the TCA cycle. Especially important for gluconeogenesis are Ala (in the liver), and glutamine (in the kidneys). It has been estimated that the contribution of amino acids to ruminant gluconeogenesis is about 5-7% of glucose produced in both the fed and fasted state. Lactate: A good source of glucose during exercise is lactate (Lactic Acid (Cori) Cycle), and during concentrated carbohydrate feeding (where rumen lactate concentrations are greatly increased), lactate becomes an important hepatic gluconeogenic substrate. Lactate is also readily oxidized in cardiac muscle (which is rich in mitochondria). Glycerol: Since glycerol kinase activity is absent in white adipose tissue, glycerol becomes a waste product of lipolysis, and is converted to glucose in the liver, and to a lesser extent in the kidney. This substrate becomes a significant source of glucose in hibernating animals (e.g., the black bear), where lipolysis becomes necessary for survival. It should be noted that the synthesis of glucose from glycerol requires fewer steps (and therefore less energy), than synthesis from other precursors. Glycerol utilization in gluconeogenesis also bypasses the dicarboxylic acid (DCA) shuttle, thereby allowing oxaloacetate (OAA) to be reutilized in the TCA cycle. Propionate: Propionate, a volatile fatty acid (VFA) produced from microbial carbohydrate digestion in ruminants and other herbivores, is a major hepatic gluconeogenic substrate. The percentage of glucose derived from propionate in the liver varies with diet (and species), from a maximum of about 70% under heavy grain feeding in ruminants, to very little during starvation. The importance of propionate as a gluconeogenic substrate is illustrated by the observation that the lactating udder of the goat may utilize 60- 85% of glucose produced by the liver for milk production. In contrast to propionate, acetate and butyrate, the other two major VFAs produced through microbial carbohydrate digestion, do not contribute carbon atoms directly to the net synthesis of glucose. Certain glucogenic amino acids (namely isoleucine, valine, threonine, and methionine), the terminal 3 carbons of odd-chain fatty acids undergoing mitochondrial b-oxidation, and the b-aminoisobutyrate generated from thymine degradation, can also enter hepatic gluconeogenesis at the level of propionyl-CoA. While the former may be quantitatively significant to carnivores, and to all animals during starvation, the latter two are not since:
Few odd-chain fatty acids exist in mammalian organisms (with the exception of ruminant animals;
Only small amounts of b-aminoisobutyrate normally become available to the liver through pyrimidine degradation. Entry of propionate into gluconeogenesis (as well as amino acids that are converted to propionyl-CoA), requires pantothenate (a source of coenzyme A.SH), vitamin B12, and biotin. These vitamins are normally synthesized by microbes inhabiting the digestive tract.
Gluconeogenic Enzymes: The pathway of gluconeogenesis is a partial reversal of the Embden-Meyerhoff pathway. There are four steps, however, in the latter pathway that must be circumnavigated using separate enzymes.
Pyruvate Carboxylase: The metabolic route from pyruvate to OAA and then on to PEP is called the DCA shuttle. It allows pyruvate and compounds that can be converted to pyruvate, such as lactate and amino acids, to be metabolized to PEP without having to traverse the physiologically irreversible step from PEP to pyruvate in the opposite direction. Pyruvate carboxylase is a mitochondrial enzyme that is activated by acetyl-CoA (although acetyl-CoA itself is not a substrate for this reaction). The level of acetyl-CoA begins to rise when fatty acids are broken down to fill a demand for energy. Since OAA itself cannot cross mitochondrial membranes, its reversible conversion to malate (and aspartate (Asp)) allows carbon atoms to be transported into the cytoplasm where OAA can then be regenerated.
PEP Carboxykinase: Cytoplasmic conversion of OAA to PEP is catalyzed by PEP carboxykinase, which requires GTP to drive this reaction energetically in an uphill direction. This high energy compound (GTP) is normally derived from the conversion of succinyl-CoA to succinate in the TCA cycle. In most mammals the PEP carboxykinase enzyme is located predominantly in the cytosol. However, in the guinea pig liver, 50% of PEP carboxykinase activity is found in mitochondria, and in birds this figure approaches 100%. This reaction is the focal point of gluconeogenesis, and the rate-limiting step. PEP carboxykinase, like fructose 1,6-bisphosphatase and glucose 6-phosphatase below, is stimulated by the diabetogenic hormones (i.e., epinephrine, growth hormone, glucagon, and the glucocorticoids), and inhibited by insulin. Thyroxine also plays a stimulatory roll. Epinephrine and glucagon act by increasing intracellular cyclic-AMP levels, and the glucocorticoids act by increasing the synthesis and activity of the four major gluconeogenic enzymes. Although gluconeogenesis also takes place in proximal renal tubular epithelial cells of the kidney, neither insulin nor glucagon are thought to affect that process.
Fructose 1,6-Bisphosphatase: This enzyme is inducible, and in addition to the diabetogenic hormones above, is activated by high cytoplasmic ATP and citrate levels. This reaction bypasses the regulatory reaction of glycolysis catalyzed by phosphofructokinase (PFK), which is inhibited by glucagon, ATP, and citrate.
Glucose 6-Phosphatase: In liver and kidney tissue (but not in muscle), this enzyme is present to remove phosphate from Glc-6-P, enabling glucose to diffuse into blood. This is usually the final step in gluconeogenesis and in hepatic glycogenolysis, which is reflected by a rise in the blood glucose concentration. When hepatic Glc-6-P is being overproduced through gluconeogenesis (e.g., during glucocorticoid stimulation), then some may pass on into glycogen formation, thus replenishing intracellular reserves.
Glycerol Kinase: In addition to the four enzymes above, glycerol kinase, with the assistance of ATP, converts glycerol (from white adipose tissue) to glycerol 3-P, and it is also a gluconeogenic enzyme (although it does not participate in reversal of the EMP). This enzyme is found in the liver, kidneys, intestine, brown adipose tissue and the lactating mammary gland.
In summary, gluconeogenesis is the process whereby noncarbohydrate substrates such as glycerol, lactate, pyruvate, propionate, and gluconeogenic amino acids are converted to either free glucose or glycogen. The liver and kidneys are the major organs containing the full complement of gluconeogenic enzymes, and thus are the only organs that can synthesize and export glucose into blood. Gluconeogenesis becomes necessary for meeting the demands for plasma glucose between meals, particularly in tissues that store little glycogen, in those lacking mitochondria, and in those that are insulin-independent. In the livers of ruminants and carnivores, gluconeogenesis is an ongoing process that has little or no correlation to the frequency of food intake. Failure of this essential, hormonally-mediated hepatorenal process in animals can lead to brain dysfunction, coma, and death.
SUMMARY
Gluconeogenesis is a crucial process in the liver and kidneys that converts noncarbohydrate substrates into glucose. This process is necessary to provide glucose for energy to various tissues, especially during periods of fasting. Gluconeogenesis also helps clear certain metabolic byproducts from the blood. The major substrates for gluconeogenesis include glycerol, lactate, propionate, and glucogenic amino acids. Gluconeogenesis is regulated by several enzymes, including pyruvate carboxylase, PEP carboxykinase, fructose 1,6-bisphosphatase, and glucose 6-phosphatase. These enzymes allow the conversion of substrates into glucose or glycogen. Gluconeogenesis is particularly important in tissues that store little glycogen, lack mitochondria, or are insulin-independent. Failure of gluconeogenesis can lead to severe consequences such as brain dysfunction and death.
OUTLINE
Gluconeogenesis is a regulatory process in the liver and kidneys that converts noncarbohydrate substrates to glucose 6-phosphate (Glc-6-P) and then to glucose or glycogen.
Gluconeogenesis is important for providing plasma glucose between meals and as an energy substrate for certain cell types.
Failure of gluconeogenesis can lead to brain dysfunction, coma, and death.
Gluconeogenesis is always needed to meet the basal requirement for glucose, even when fatty acid oxidation is supplying most of the energy.
Gluconeogenic mechanisms in the liver also clear certain metabolic products from the blood, such as lactate and glycerol.
Glucogenic amino acids, lactate, glycerol, and propionate are important gluconeogenic precursors.
Gluconeogenesis from propionate is a major pathway in ruminants and other herbivores.
Certain glucogenic amino acids, odd-chain fatty acids, and b-aminoisobutyrate can also enter gluconeogenesis at the level of propionyl-CoA.
Gluconeogenesis requires pantothenate, vitamin B12, and biotin, which are normally synthesized by microbes in the digestive tract.
Gluconeogenesis involves several key enzymes, including pyruvate carboxylase, PEP carboxykinase, fructose 1,6-bisphosphatase, glucose 6-phosphatase, and glycerol kinase.
Pyruvate carboxylase converts pyruvate to oxaloacetate (OAA) in the mitochondria, allowing carbon atoms to be transported into the cytoplasm.
PEP carboxykinase converts OAA to phosphoenolpyruvate (PEP) in the cytoplasm, using GTP as an energy source.
Fructose 1,6-bisphosphatase bypasses the regulatory step of glycolysis and is activated by high ATP and citrate levels.
Glucose 6-phosphatase removes phosphate from Glc-6-P, allowing glucose to diffuse into the blood.
Glycerol kinase converts glycerol to glycerol 3-phosphate, which can be used in gluconeogenesis.
Gluconeogenesis occurs primarily in the liver and kidneys, which are the only organs that can synthesize and export glucose into the blood.
QUESTION
Q: What is gluconeogenesis?
A: Gluconeogenesis is a process in the liver and kidneys where noncarbohydrate substrates are converted to glucose.
Q: Why is gluconeogenesis important?
A: Gluconeogenesis is important to meet the demands for plasma glucose between meals and provide energy to certain cell types.
Q: What can happen if gluconeogenesis fails?
A: Failure of gluconeogenesis can lead to brain dysfunction, coma, and death.
Q: What are the major organs involved in gluconeogenesis?
A: The liver and kidneys are the major organs containing the full complement of gluconeogenic enzymes.
Q: What are some key substrates for gluconeogenesis?
A: Glycerol, lactate, propionate, and glucogenic amino acids are key substrates for gluconeogenesis.
Q: What is the role of gluconeogenesis in muscle?
A: Glucose is a major fuel providing energy to skeletal muscle under anaerobic conditions.
Q: What are some important enzymes involved in gluconeogenesis?
A: Pyruvate carboxylase, PEP carboxykinase, fructose 1,6-bisphosphatase, and glucose 6-phosphatase are important enzymes in gluconeogenesis.
Q: What vitamins are required for gluconeogenesis?
A: Pantothenate, vitamin B12, and biotin are required for the entry of propionate into gluconeogenesis.
Q: What are some key regulatory steps in gluconeogenesis?
A: Pyruvate carboxylase, PEP carboxykinase, fructose 1,6-bisphosphatase, and glucose 6-phosphatase are key regulatory steps in gluconeogenesis.
Q: What is the final step in gluconeogenesis
A: Glucose 6-phosphatase removes phosphate from Glc-6-P, enabling glucose to diffuse into the blood.
Q: What are the consequences of gluconeogenesis failure in animals?
A: Gluconeogenesis failure can lead to brain dysfunction, coma, and death in animals.
Gluconeogenesis is a major regulatory process in the liver and kidneys that converts noncarbohydrate substrates into glucose, which is essential for meeting the body's energy needs.
Gluconeogenic Precursors
Gluconeogenic Enzymes
Glucogenic Amino Acids
Majority of amino acids form TCA intermediates and pyruvate
Alanine (Ala) and glutamine are especially important for gluconeogenesis
Lactate
Glycerol
Propionate
Pyruvate Carboxylase
Converts pyruvate to OAA
Activated by acetyl-CoA
PEP Carboxykinase
Converts OAA to PEP
Requires GTP
Rate-limiting step
Fructose 1,6-Bisphosphatase
Bypasses the regulatory reaction of glycolysis
Activated by high ATP and citrate levels
Glucose 6-Phosphatase
Removes phosphate from Glc-6-P
Enables glucose to diffuse into blood
Glycerol Kinase
Converts glycerol to glycerol 3-P
Found in various tissues
Provides glucose for plasma between meals
Essential for energy supply to certain tissues
Clears certain metabolic products from blood
Plays a role in the glucose-alanine cycle
Required for survival in hibernating animals
Gluconeogenesis is a vital process that ensures the body has a constant supply of glucose. It involves the conversion of noncarbohydrate substrates into glucose through a series of enzymatic reactions. The liver and kidneys are the main organs involved in gluconeogenesis, and failure of this process can have severe consequences.
Read and understand the concept of gluconeogenesis as a major regulatory process in the liver and kidneys.
Familiarize yourself with the noncarbohydrate substrates involved in gluconeogenesis, such as glycerol, lactate, propionate, and glucogenic amino acids.
Learn about the importance of gluconeogenesis in meeting the demands for plasma glucose between meals and its role as an energy substrate for certain cell types.
Understand the consequences of failure in gluconeogenesis, including brain dysfunction, coma, and death.
Study the continuous nature of hepatic gluconeogenesis in ruminant animals and carnivores, independent of food consumption frequency.
Focus on the basal requirement for glucose and its significance as a major fuel for skeletal muscle under anaerobic conditions.
Learn about the role of gluconeogenic mechanisms in clearing certain metabolic products from the blood, such as lactate and glycerol.
Understand the glucose-alanine cycle and its importance in cycling glucose from the liver to muscle during starvation.
Study the contribution of amino acids, especially alanine and glutamine, to gluconeogenesis in ruminant animals.
Explore the utilization of lactate as a source of glucose during exercise and concentrated carbohydrate feeding.
Dive deeper into the conversion of glycerol to glucose in the liver and its significance as a source of glucose in hibernating animals.
Understand the fewer steps and less energy required for gluconeogenesis from glycerol compared to other precursors.
Learn about the role of propionate, a volatile fatty acid produced in ruminants, as a major hepatic gluconeogenic substrate.
Explore the variation in the percentage of glucose derived from propionate based on diet and species.
Understand the importance of propionate as a gluconeogenic substrate for milk production in lactating animals.
Focus on the entry of certain glucogenic amino acids and odd-chain fatty acids into hepatic gluconeogenesis at the level of propionyl-CoA.
Learn about the vitamin requirements (pantothenate, vitamin B12, and biotin) for the entry of propionate into gluconeogenesis.
Study the gluconeogenic enzymes involved in the pathway, including pyruvate carboxylase, PEP carboxykinase
Chapter 37: Gluconeogenesis Gluconeogenesis is a major regulatory process in the liver and kidneys by which noncarbohydrate substrates; namely glycerol, lactate, propionate, and glucogenic amino acids; are converted to glucose 6-phosphate (Glc-6-P), and then to either free glucose or glycogen. The liver and kidneys are the major organs containing the full complement of gluconeogenic enzymes (i.e., pyruvate carboxylase, PEP carboxykinase, fructose 1,6-bisphosphatase, and glucose 6-phosphatase). Gluconeogenesis is needed to meet the demands for plasma glucose between meals, which then becomes particularly important as an energy substrate for nerves, erythrocytes, and other largely anaerobic cell types. Failure of this process can lead to brain dysfunction, coma, and death. In ruminant animals and carnivores, hepatic gluconeogenesis is a continual, ongoing process that has little or no relation to the frequency of food consumption. It is clear that even under conditions where fatty acid oxidation may be supplying most of the energy requirement of the organism, there is always a certain basal requirement for glucose, and glucose is a major fuel providing energy to skeletal muscle under anaerobic conditions. In addition, gluconeogenic mechanisms in the liver are used to clear certain products of metabolism from blood (e.g., lactate, produced by erythrocytes, the retina, kidney medulla, and anaerobic muscle fibers; and glycerol, which is continuously produced by adipose tissue when fat is being mobilized for energy purposes). Of the amino acids transported from muscle to liver during starvation, alanine (Ala) predominates. This amino acid is part of the glucose-alanine cycle which has the effect of cycling glucose from liver to muscle with formation of pyruvate, followed by transamination to Ala, then transport of Ala to liver, followed by gluconeogenesis back to glucose. During starvation, branched-chain amino acid (BCAA) oxidation in muscle serves as a source of ammonia (NH3). A net transfer of amino nitrogen from muscle to liver (and then to urea), and of potential energy (glucose) from liver to muscle is thus affected. The energy needed for hepatic synthesis of glucose from pyruvate (or lactate) is thought to be derived from the b-oxidation of fatty acids. Gluconeogenic Precursors Glucogenic Amino Acids Since amino acids are used for a variety of vital biosynthetic functions in the liver (e.g., protein production), they are generally used conservatively for gluconeogenesis. During their conversion to glucose, their amino groups are irretrievably lost to urea, which then enters blood (i.e., blood urea nitrogen (BUN)). The majority of amino acids form TCA intermediates and pyruvate, and are therefore glucogenic. Others form acetyl-CoA and, thus, are ketogenic. Acetyl-CoA is not a (net) substrate for gluconeogenesis since its two carbon atoms are lost as CO2 in the TCA cycle. Especially important for gluconeogenesis are Ala (in the liver), and glutamine (in the kidneys). It has been estimated that the contribution of amino acids to ruminant gluconeogenesis is about 5-7% of glucose produced in both the fed and fasted state. Lactate: A good source of glucose during exercise is lactate (Lactic Acid (Cori) Cycle), and during concentrated carbohydrate feeding (where rumen lactate concentrations are greatly increased), lactate becomes an important hepatic gluconeogenic substrate. Lactate is also readily oxidized in cardiac muscle (which is rich in mitochondria). Glycerol: Since glycerol kinase activity is absent in white adipose tissue, glycerol becomes a waste product of lipolysis, and is converted to glucose in the liver, and to a lesser extent in the kidney. This substrate becomes a significant source of glucose in hibernating animals (e.g., the black bear), where lipolysis becomes necessary for survival. It should be noted that the synthesis of glucose from glycerol requires fewer steps (and therefore less energy), than synthesis from other precursors. Glycerol utilization in gluconeogenesis also bypasses the dicarboxylic acid (DCA) shuttle, thereby allowing oxaloacetate (OAA) to be reutilized in the TCA cycle. Propionate: Propionate, a volatile fatty acid (VFA) produced from microbial carbohydrate digestion in ruminants and other herbivores, is a major hepatic gluconeogenic substrate. The percentage of glucose derived from propionate in the liver varies with diet (and species), from a maximum of about 70% under heavy grain feeding in ruminants, to very little during starvation. The importance of propionate as a gluconeogenic substrate is illustrated by the observation that the lactating udder of the goat may utilize 60- 85% of glucose produced by the liver for milk production. In contrast to propionate, acetate and butyrate, the other two major VFAs produced through microbial carbohydrate digestion, do not contribute carbon atoms directly to the net synthesis of glucose. Certain glucogenic amino acids (namely isoleucine, valine, threonine, and methionine), the terminal 3 carbons of odd-chain fatty acids undergoing mitochondrial b-oxidation, and the b-aminoisobutyrate generated from thymine degradation, can also enter hepatic gluconeogenesis at the level of propionyl-CoA. While the former may be quantitatively significant to carnivores, and to all animals during starvation, the latter two are not since:
Few odd-chain fatty acids exist in mammalian organisms (with the exception of ruminant animals;
Only small amounts of b-aminoisobutyrate normally become available to the liver through pyrimidine degradation. Entry of propionate into gluconeogenesis (as well as amino acids that are converted to propionyl-CoA), requires pantothenate (a source of coenzyme A.SH), vitamin B12, and biotin. These vitamins are normally synthesized by microbes inhabiting the digestive tract.
Gluconeogenic Enzymes: The pathway of gluconeogenesis is a partial reversal of the Embden-Meyerhoff pathway. There are four steps, however, in the latter pathway that must be circumnavigated using separate enzymes.
Pyruvate Carboxylase: The metabolic route from pyruvate to OAA and then on to PEP is called the DCA shuttle. It allows pyruvate and compounds that can be converted to pyruvate, such as lactate and amino acids, to be metabolized to PEP without having to traverse the physiologically irreversible step from PEP to pyruvate in the opposite direction. Pyruvate carboxylase is a mitochondrial enzyme that is activated by acetyl-CoA (although acetyl-CoA itself is not a substrate for this reaction). The level of acetyl-CoA begins to rise when fatty acids are broken down to fill a demand for energy. Since OAA itself cannot cross mitochondrial membranes, its reversible conversion to malate (and aspartate (Asp)) allows carbon atoms to be transported into the cytoplasm where OAA can then be regenerated.
PEP Carboxykinase: Cytoplasmic conversion of OAA to PEP is catalyzed by PEP carboxykinase, which requires GTP to drive this reaction energetically in an uphill direction. This high energy compound (GTP) is normally derived from the conversion of succinyl-CoA to succinate in the TCA cycle. In most mammals the PEP carboxykinase enzyme is located predominantly in the cytosol. However, in the guinea pig liver, 50% of PEP carboxykinase activity is found in mitochondria, and in birds this figure approaches 100%. This reaction is the focal point of gluconeogenesis, and the rate-limiting step. PEP carboxykinase, like fructose 1,6-bisphosphatase and glucose 6-phosphatase below, is stimulated by the diabetogenic hormones (i.e., epinephrine, growth hormone, glucagon, and the glucocorticoids), and inhibited by insulin. Thyroxine also plays a stimulatory roll. Epinephrine and glucagon act by increasing intracellular cyclic-AMP levels, and the glucocorticoids act by increasing the synthesis and activity of the four major gluconeogenic enzymes. Although gluconeogenesis also takes place in proximal renal tubular epithelial cells of the kidney, neither insulin nor glucagon are thought to affect that process.
Fructose 1,6-Bisphosphatase: This enzyme is inducible, and in addition to the diabetogenic hormones above, is activated by high cytoplasmic ATP and citrate levels. This reaction bypasses the regulatory reaction of glycolysis catalyzed by phosphofructokinase (PFK), which is inhibited by glucagon, ATP, and citrate.
Glucose 6-Phosphatase: In liver and kidney tissue (but not in muscle), this enzyme is present to remove phosphate from Glc-6-P, enabling glucose to diffuse into blood. This is usually the final step in gluconeogenesis and in hepatic glycogenolysis, which is reflected by a rise in the blood glucose concentration. When hepatic Glc-6-P is being overproduced through gluconeogenesis (e.g., during glucocorticoid stimulation), then some may pass on into glycogen formation, thus replenishing intracellular reserves.
Glycerol Kinase: In addition to the four enzymes above, glycerol kinase, with the assistance of ATP, converts glycerol (from white adipose tissue) to glycerol 3-P, and it is also a gluconeogenic enzyme (although it does not participate in reversal of the EMP). This enzyme is found in the liver, kidneys, intestine, brown adipose tissue and the lactating mammary gland.
In summary, gluconeogenesis is the process whereby noncarbohydrate substrates such as glycerol, lactate, pyruvate, propionate, and gluconeogenic amino acids are converted to either free glucose or glycogen. The liver and kidneys are the major organs containing the full complement of gluconeogenic enzymes, and thus are the only organs that can synthesize and export glucose into blood. Gluconeogenesis becomes necessary for meeting the demands for plasma glucose between meals, particularly in tissues that store little glycogen, in those lacking mitochondria, and in those that are insulin-independent. In the livers of ruminants and carnivores, gluconeogenesis is an ongoing process that has little or no correlation to the frequency of food intake. Failure of this essential, hormonally-mediated hepatorenal process in animals can lead to brain dysfunction, coma, and death.
SUMMARY
Gluconeogenesis is a crucial process in the liver and kidneys that converts noncarbohydrate substrates into glucose. This process is necessary to provide glucose for energy to various tissues, especially during periods of fasting. Gluconeogenesis also helps clear certain metabolic byproducts from the blood. The major substrates for gluconeogenesis include glycerol, lactate, propionate, and glucogenic amino acids. Gluconeogenesis is regulated by several enzymes, including pyruvate carboxylase, PEP carboxykinase, fructose 1,6-bisphosphatase, and glucose 6-phosphatase. These enzymes allow the conversion of substrates into glucose or glycogen. Gluconeogenesis is particularly important in tissues that store little glycogen, lack mitochondria, or are insulin-independent. Failure of gluconeogenesis can lead to severe consequences such as brain dysfunction and death.
OUTLINE
Gluconeogenesis is a regulatory process in the liver and kidneys that converts noncarbohydrate substrates to glucose 6-phosphate (Glc-6-P) and then to glucose or glycogen.
Gluconeogenesis is important for providing plasma glucose between meals and as an energy substrate for certain cell types.
Failure of gluconeogenesis can lead to brain dysfunction, coma, and death.
Gluconeogenesis is always needed to meet the basal requirement for glucose, even when fatty acid oxidation is supplying most of the energy.
Gluconeogenic mechanisms in the liver also clear certain metabolic products from the blood, such as lactate and glycerol.
Glucogenic amino acids, lactate, glycerol, and propionate are important gluconeogenic precursors.
Gluconeogenesis from propionate is a major pathway in ruminants and other herbivores.
Certain glucogenic amino acids, odd-chain fatty acids, and b-aminoisobutyrate can also enter gluconeogenesis at the level of propionyl-CoA.
Gluconeogenesis requires pantothenate, vitamin B12, and biotin, which are normally synthesized by microbes in the digestive tract.
Gluconeogenesis involves several key enzymes, including pyruvate carboxylase, PEP carboxykinase, fructose 1,6-bisphosphatase, glucose 6-phosphatase, and glycerol kinase.
Pyruvate carboxylase converts pyruvate to oxaloacetate (OAA) in the mitochondria, allowing carbon atoms to be transported into the cytoplasm.
PEP carboxykinase converts OAA to phosphoenolpyruvate (PEP) in the cytoplasm, using GTP as an energy source.
Fructose 1,6-bisphosphatase bypasses the regulatory step of glycolysis and is activated by high ATP and citrate levels.
Glucose 6-phosphatase removes phosphate from Glc-6-P, allowing glucose to diffuse into the blood.
Glycerol kinase converts glycerol to glycerol 3-phosphate, which can be used in gluconeogenesis.
Gluconeogenesis occurs primarily in the liver and kidneys, which are the only organs that can synthesize and export glucose into the blood.
QUESTION
Q: What is gluconeogenesis?
A: Gluconeogenesis is a process in the liver and kidneys where noncarbohydrate substrates are converted to glucose.
Q: Why is gluconeogenesis important?
A: Gluconeogenesis is important to meet the demands for plasma glucose between meals and provide energy to certain cell types.
Q: What can happen if gluconeogenesis fails?
A: Failure of gluconeogenesis can lead to brain dysfunction, coma, and death.
Q: What are the major organs involved in gluconeogenesis?
A: The liver and kidneys are the major organs containing the full complement of gluconeogenic enzymes.
Q: What are some key substrates for gluconeogenesis?
A: Glycerol, lactate, propionate, and glucogenic amino acids are key substrates for gluconeogenesis.
Q: What is the role of gluconeogenesis in muscle?
A: Glucose is a major fuel providing energy to skeletal muscle under anaerobic conditions.
Q: What are some important enzymes involved in gluconeogenesis?
A: Pyruvate carboxylase, PEP carboxykinase, fructose 1,6-bisphosphatase, and glucose 6-phosphatase are important enzymes in gluconeogenesis.
Q: What vitamins are required for gluconeogenesis?
A: Pantothenate, vitamin B12, and biotin are required for the entry of propionate into gluconeogenesis.
Q: What are some key regulatory steps in gluconeogenesis?
A: Pyruvate carboxylase, PEP carboxykinase, fructose 1,6-bisphosphatase, and glucose 6-phosphatase are key regulatory steps in gluconeogenesis.
Q: What is the final step in gluconeogenesis
A: Glucose 6-phosphatase removes phosphate from Glc-6-P, enabling glucose to diffuse into the blood.
Q: What are the consequences of gluconeogenesis failure in animals?
A: Gluconeogenesis failure can lead to brain dysfunction, coma, and death in animals.
Gluconeogenesis is a major regulatory process in the liver and kidneys that converts noncarbohydrate substrates into glucose, which is essential for meeting the body's energy needs.
Gluconeogenic Precursors
Gluconeogenic Enzymes
Glucogenic Amino Acids
Majority of amino acids form TCA intermediates and pyruvate
Alanine (Ala) and glutamine are especially important for gluconeogenesis
Lactate
Glycerol
Propionate
Pyruvate Carboxylase
Converts pyruvate to OAA
Activated by acetyl-CoA
PEP Carboxykinase
Converts OAA to PEP
Requires GTP
Rate-limiting step
Fructose 1,6-Bisphosphatase
Bypasses the regulatory reaction of glycolysis
Activated by high ATP and citrate levels
Glucose 6-Phosphatase
Removes phosphate from Glc-6-P
Enables glucose to diffuse into blood
Glycerol Kinase
Converts glycerol to glycerol 3-P
Found in various tissues
Provides glucose for plasma between meals
Essential for energy supply to certain tissues
Clears certain metabolic products from blood
Plays a role in the glucose-alanine cycle
Required for survival in hibernating animals
Gluconeogenesis is a vital process that ensures the body has a constant supply of glucose. It involves the conversion of noncarbohydrate substrates into glucose through a series of enzymatic reactions. The liver and kidneys are the main organs involved in gluconeogenesis, and failure of this process can have severe consequences.
Read and understand the concept of gluconeogenesis as a major regulatory process in the liver and kidneys.
Familiarize yourself with the noncarbohydrate substrates involved in gluconeogenesis, such as glycerol, lactate, propionate, and glucogenic amino acids.
Learn about the importance of gluconeogenesis in meeting the demands for plasma glucose between meals and its role as an energy substrate for certain cell types.
Understand the consequences of failure in gluconeogenesis, including brain dysfunction, coma, and death.
Study the continuous nature of hepatic gluconeogenesis in ruminant animals and carnivores, independent of food consumption frequency.
Focus on the basal requirement for glucose and its significance as a major fuel for skeletal muscle under anaerobic conditions.
Learn about the role of gluconeogenic mechanisms in clearing certain metabolic products from the blood, such as lactate and glycerol.
Understand the glucose-alanine cycle and its importance in cycling glucose from the liver to muscle during starvation.
Study the contribution of amino acids, especially alanine and glutamine, to gluconeogenesis in ruminant animals.
Explore the utilization of lactate as a source of glucose during exercise and concentrated carbohydrate feeding.
Dive deeper into the conversion of glycerol to glucose in the liver and its significance as a source of glucose in hibernating animals.
Understand the fewer steps and less energy required for gluconeogenesis from glycerol compared to other precursors.
Learn about the role of propionate, a volatile fatty acid produced in ruminants, as a major hepatic gluconeogenic substrate.
Explore the variation in the percentage of glucose derived from propionate based on diet and species.
Understand the importance of propionate as a gluconeogenic substrate for milk production in lactating animals.
Focus on the entry of certain glucogenic amino acids and odd-chain fatty acids into hepatic gluconeogenesis at the level of propionyl-CoA.
Learn about the vitamin requirements (pantothenate, vitamin B12, and biotin) for the entry of propionate into gluconeogenesis.
Study the gluconeogenic enzymes involved in the pathway, including pyruvate carboxylase, PEP carboxykinase
