CHAPTER 28: HEXOSE MONOPHOSPHATE SHUNT
Chapter 28: Hexose Monophosphate Shunt The HMS (variously known as the pentose phosphate, phosphogluconate, or hexose monophosphate pathway, cycle, or shunt), is an alternate cytoplasmic route for the metabolism of glucose 6-phosphate (Glc-6-P). In most tissues, 80-90% of glucose oxidation occurs directly through the Embden-Meyerhoff Pathway (EMP); the other 10-20%, however, may occur in the HMS. This pathway does not generate ATP through substrate-level phosphorylation, but it does generate CO2 (unlike anaerobic glycolysis). This "alternative" pathway has two main functions:
Generation of NADPH for reductive biosynthesis of lipids (e.g., fatty acids, cholesterol and other steroids), and
Provision of ribose residues for nucleotide and nucleic acid biosynthesis (e.g., ATP, NAD+ , FAD, RNA, and DNA).
The HMS is one of three cytoplasmic routes for the production of NADPH (the other two being cytoplasmic isocitrate dehydrogenase and malic enzyme-catalyzed reactions). Since intestinal absorption of ribose is generally too limited to meet metabolic demands, the HMS and the hepatic uronic acid pathway become important sources of pentoses for nucleotide and nucleic acid biosynthesis. The HMS of animals has both oxidative (nonreversible) and nonoxidative (reversible) phases, and both can give rise to ribose 5- phosphate. Only the oxidative phase, however, gives rise to CO2 and NADPH. In plants, part of the HMS participates in the formation of hexoses from CO2 in photosynthesis. The nonoxidative phase interconverts three, four, five, six, and seven-carbon sugars. Most tissues are capable of catabolizing Glc-6-P through both phases however, muscle tissue is deficient in the rate-limiting enzyme of this shunt that converts Glc-6-P to 6-phosphoglconate (i.e., glucose 6-phosphate dehydrogenase (Glc-6-PD)). Therefore, muscle tissue produces only minor amounts of NADPH via the HMS, and has limited lipid biosynthetic capacity. Muscle tissue does, however, retain the ability to generate ribose 5-phosphate through the non-oxidative phase of the shunt, thereby providing sufficient quantities to meet demands for DNA, and thus protein biosynthesis.
Activity of the HMS is high in liver and adipose tissue, which require NADPH for the reductive biosynthesis of fatty acids from acetyl-CoA. High HMS activity is also found in endocrine tissues which need NADPH for synthesis of cholesterol and steroid hormones (e.g., testes, ovaries, and adrenal cortex), or use ribose for nucleic acids involved in the production of proteinaceous hormones (e.g., insulin, PTH, and the anterior pituitary hormones). In the adrenal medulla and in some nervous tissue, the HMS is needed to provide NADPH for hydroxylation reactions involved in dopamine, norepinephrine, and epinephrine biosynthesis. In the mammary gland, HMS activity is high during lactation for the production of milk fats and proteins, but low in the nonlactating state.
Hexose monophosphate shunt activity is also high in mature erythrocytes, the lens and cornea, all of which need NADPH for reduced glutathione production (which in turn protects them from oxidative damage). Glucose 6-phosphate dehydrogenase deficiency, with subsequent impaired erythrocytic NADPH generation, has been reported in Weimaraner dogs, and it is the most common genetic enzymopathy known in humans (particularly prevalent among individuals of Mediterranean, Asian, and African descent). Several hundred variants of this enzyme have been identified in erythrocytes. An erythrocytic deficiency in Glc-6-PD can cause an increase in the concentration of methemoglobin, a decrease in the amount of reduced glutathione, an increase in hydrogen peroxide (H2O2), and increased fragility of red blood cell membranes. The net result may be hemolysis, which can be exacerbated when subjects are given excessive amounts of oxidizing agents such as aspirin or sulfonamide antibiotics. On the other hand, a relative deficiency of Glc-6- PD in erythrocytes may protect some animals and people from certain parasitic infestations (e.g., falciparum malaria), since the parasites that cause this disease require the HMS and reduced glutathione for optimal growth. The overall equation for the HMS can be expressed as follows:
3 Glc-6-P + 6 NADP+ —> 3 CO2 + 2 Glc-6-P + Gl-3-P + 6 NADPH
This equation erroneously indicates that a single glucose molecule is progressively degraded. This is not, however, the case. The HMS is clearly a more complex pathway than glycolysis. It is multicyclic, in that 3 molecules of Glc-6-P can give rise to 3 molecules of CO2 and 3 five-carbon residues. The latter can be rearranged to regenerate 2 molecules of Glc-6- P and 1 molecule of the glycolytic intermediate, glyceraldehyde 3-phosphate (Gl-3-P). Since two molecules of Gl-3-P can regenerate Glc-6- P, this pathway can account for the complete oxidation of glucose.
In the first irreversible reaction of the HMS, the NADP+ /NADPH concentration ratio exerts primary control over Glc-6-PD activity, with both NADP+ and NADPH competing for binding to this rate-limiting enzyme. As the ratio declines, so does the activity of Glc-6-PD. Glucose 6-phosphate dehydrogenase can also be induced by insulin.
The nonoxidative phase of the HMS is controlled primarily by substrate availability. The NADP+ /NADPH concentration ratio is normally about 0.014 in the cytosol of rat liver cells, several orders of magnitude below that for NAD+ /NADH (i.e., about 700). Mitochondrial ratios for both are about 10:1. A transhydrogenase is present on the inner mitochondrial membrane that passes electrons from NADH to NADP+. Mitochondrial NADPH can be used by glutamate dehydrogenase, by hydroxylases involved in the mitochondrial phase of steroid biosynthesis, or by mitochondrial enzymes involved in fatty acid chain elongation.
In the next reaction, 6-phosphogluconate is oxidized again by NADP+ and decarboxylated to produce ribulose 5-phosphate. This compound now serves as a substrate for two different enzymes. It can be isomerized to ribose 5-phosphate, the compound needed for nucleotide biosynthesis, or in a separate reaction it can be epimerized at carbon 3 to yield xylulose 5-phosphate. These 2 five-carbon sugar phosphates form the starting point for the next series of reactions catalyzed by transketolase and transaldolase. Transketolase transfers a two-carbon unit from a ketose to an aldose, a reaction requiring as a coenzyme the B1 vitamin, thiamin, in addition to Mg++. This reaction is severely limited in thiamin deficiency, and measurement of erythrocytic transketolase activity is sometimes used as a measure of such. Transaldolase transfers a three-carbon unit from an aldose to a ketose.
Two-carbon unit is transferred by transketolase from xylulose 5-phosphate to ribose 5- phosphate, thus yielding a three-carbon sugar phosphate, Gl-3-P, and a seven-carbon sugar phosphate, sedoheptulose 7-phosphate. Using these two sugar phosphates, transaldolase allows the transfer of a three-carbon dihydroxyacetone moiety from the ketose sedoheptulose 7-phosphate, to the aldose Gl-3-P, thus forming the ketose fructose 6-phosphate (Frc-6-P), and the four-carbon aldose, erythrose 4- phosphate. Fructose 6-phosphate can now enter the EMP for further oxidation. In another reaction catalyzed by transketolase, xylulose 5-phosphate and erythrose 4-phosphate exchange a two-carbon unit, yielding Frc-6-P and Gl-3-P.
In order to completely oxidize glucose to CO2 via the HMS, it is necessary that enzymes be present to convert Gl-3-P to Glc-6-P. This involves enzymes of the glycolytic pathway working in the reverse direction and, in addition, the gluconeogenic enzyme Frc-1,6- bisphosphatase, which converts Frc-1,6-bisP (produced from condensation of Gl-3-P and dihydroxyacetone phosphate), to Frc-6-P. This is unlikely, however, in the liver, since insulin activates Glc-6-PD and inhibits Frc-1,6-bisphosphatase.
In summary, the cytoplasmic HMS provides a means for degrading the hexose carbon chain one unit at a time. However, in contrast to the mitochondrial TCA cycle, this shunt does not constitute a consecutive set of reactions that lead directly from Glc-6-P to six molecules of CO2. Rather, in the nonreversible oxidative phase hexose is decarboxylated to pentose via two NADPH-forming oxidative reactions, and in the reversible non-oxidative phase 3, 4, 5, 6 and 7-carbon sugars are interconverted. NADPH can be used in many different tissues for the reductive biosynthesis of lipids, while ribose 5-phosphate can be used for RNA, DNA, ATP, NAD+ and FAD biosynthesis. As sugars are rearranged in the HMS, hexoses formed can re-enter the glycolytic sequence, and xyluose 5-phosphate can be accepted from the uronic acid pathway.
SUMMARY
The Hexose Monophosphate Shunt (HMS) is an alternate pathway for the metabolism of glucose 6-phosphate (Glc-6-P). It has two main functions: generating NADPH for lipid biosynthesis and providing ribose for nucleotide biosynthesis. The HMS is one of three pathways for NADPH production and is important for pentose production in nucleotide biosynthesis. The pathway has oxidative and nonoxidative phases, with the oxidative phase producing CO2 and NADPH. The nonoxidative phase interconverts different carbon sugars. Muscle tissue has limited HMS activity, resulting in limited lipid biosynthesis but sufficient ribose production for DNA and protein biosynthesis. The HMS is highly active in liver, adipose tissue, endocrine tissues, adrenal medulla, mammary gland, erythrocytes, lens, and cornea. Glucose 6-phosphate dehydrogenase deficiency can lead to hemolysis and increased susceptibility to certain parasitic infestations. The HMS is a complex pathway that can account for the complete oxidation of glucose. Control of the pathway is primarily regulated by the NADP+/NADPH ratio and substrate availability. The pathway involves several reactions, including oxidation, decarboxylation, isomerization, and epimerization. The pathway also requires enzymes from the glycolytic pathway and Frc-1,6-bisphosphatase for complete glucose oxidation. Overall, the HMS provides a means for stepwise degradation of the hexose carbon chain and plays a crucial role in NADPH and ribose production.
OUTLINE
Introduction to the Hexose Monophosphate Shunt (HMS)
Functions of the HMS:
Generation of NADPH for reductive biosynthesis of lipids
Provision of ribose residues for nucleotide and nucleic acid biosynthesis
Importance of the HMS in NADPH production and ribose synthesis
HMS activity in different tissues:
High activity in liver and adipose tissue for fatty acid biosynthesis
High activity in endocrine tissues for hormone synthesis
High activity in adrenal medulla and nervous tissue for neurotransmitter biosynthesis
High activity in mammary gland during lactation for milk production
High activity in erythrocytes, lens, and cornea for reduced glutathione production
Glucose 6-phosphate dehydrogenase deficiency and its effects on NADPH generation and red blood cell function
Overall equation for the HMS
Complexity of the HMS pathway compared to glycolysis
Control of HMS activity by NADP+/NADPH ratio and insulin
Nonoxidative phase of the HMS and its control by substrate availability
Reactions and enzymes involved in the nonoxidative phase
Conversion of Gl-3-P to Glc-6-P for complete oxidation of glucose
Summary of the HMS as a means of degrading the hexose carbon chain and its role in NADPH and ribose synthesis
QUESTIONS
Qcard 1:
Question: What is the Hexose Monophosphate Shunt (HMS)?
Answer: The HMS is an alternate cytoplasmic route for the metabolism of glucose 6-phosphate (Glc-6-P), involved in the generation of NADPH and ribose residues.
Qcard 2:
Question: What are the two main functions of the HMS?
Answer: The HMS functions in the reductive biosynthesis of lipids and the provision of ribose residues for nucleotide and nucleic acid biosynthesis.
Qcard 3:
Question: What are the sources of pentoses for nucleotide and nucleic acid biosynthesis?
Answer: The HMS and the hepatic uronic acid pathway are important sources of pentoses for nucleotide and nucleic acid biosynthesis.
Qcard 4:
Question: What is the difference between the oxidative and nonoxidative phases of the HMS?
Answer: The oxidative phase gives rise to CO2 and NADPH, while the nonoxidative phase interconverts three, four, five, six, and seven-carbon sugars.
Qcard 5:
Question: Which tissues have high activity of the HMS?
Answer: Liver, adipose tissue, endocrine tissues, adrenal medulla, nervous tissue, mammary gland, mature erythrocytes, lens, and cornea have high activity of the HMS.
Qcard 6:
Question: What can happen in Glucose 6-phosphate dehydrogenase deficiency?
Answer: Glucose 6-phosphate dehydrogenase deficiency can lead to impaired erythrocytic NADPH generation, resulting in increased methemoglobin, decreased reduced glutathione, increased hydrogen peroxide, and increased red blood cell membrane fragility.
Qcard 7:
Question: How is the activity of Glucose 6-phosphate dehydrogenase controlled?
Answer: The activity of Glucose 6-phosphate dehydrogenase is primarily controlled by the NADP+/NADPH concentration ratio, with both NADP+ and NADPH competing for binding to the enzyme.
Qcard 8:
Question: What is the role of transketolase and transaldolase in the HMS?
Answer: Transketolase transfers a two-carbon unit from a ketose to an aldose, while transaldolase transfers a three-carbon unit from an aldose to a ketose.
Functions of HMS
Generation of NADPH for lipid biosynthesis
Provision of ribose for nucleotide biosynthesis
Tissues with High HMS Activity
Liver and adipose tissue
Endocrine tissues
Adrenal medulla and nervous tissue
Mammary gland
Mature erythrocytes, lens, and cornea
Glucose 6-Phosphate Dehydrogenase (Glc-6-PD) Deficiency
Impaired NADPH generation in erythrocytes
Hemolysis and increased fragility of red blood cell membranes
Protection against certain parasitic infestations
Overall Equation of HMS
3 Glc-6-P + 6 NADP+ -> 3 CO2 + 2 Glc-6-P + Gl-3-P + 6 NADPH
Complexity of HMS
Multicyclic pathway
Complete oxidation of glucose
Control of Glc-6-PD activity by NADP+ /NADPH ratio
Nonoxidative Phase of HMS
Substrate availability control
Isomerization and epimerization reactions
Transketolase and transaldolase reactions
Conversion of Gl-3-P to Glc-6-P
Involvement of glycolytic enzymes and Frc-1,6-bisphosphatase
Unlikely in the liver due to insulin regulation
Summary of HMS
Degradation of hexose carbon chain one unit at a time
NADPH generation for lipid biosynthesis
Ribose generation for nucleotide biosynthesis
Interconversion of sugars in nonoxidative phase
Reentry of hexoses into glycolytic sequence
Generation of NADPH for lipid biosynthesis
Reductive biosynthesis of lipids
Fatty acids, cholesterol, and steroids
Provision of ribose for nucle
Read and understand the overview of the Hexose Monophosphate Shunt (HMS).
Focus on the main functions of the HMS: generation of NADPH and provision of ribose residues.
Take notes on the importance of the HMS in different tissues and its role in reductive biosynthesis of lipids and nucleotide biosynthesis.
Dive deeper into the oxidative and nonoxidative phases of the HMS.
Understand the production of CO2 and NADPH in the oxidative phase.
Study the interconversion of sugars in the nonoxidative phase.
Take notes on the differences between animal and plant HMS.
Explore the significance of HMS activity in specific tissues like liver, adipose tissue, endocrine tissues, and nervous tissue.
Understand the role of HMS in the production of milk fats and proteins in the mammary gland.
Study the importance of HMS in mature erythrocytes, lens, and cornea for reduced glutathione production.
Take notes on the consequences of Glucose 6-phosphate dehydrogenase deficiency.
Review the overall equation for the HMS and understand its complexity.
Focus on the control mechanisms of the HMS, including the NADP+/NADPH concentration ratio and insulin induction.
Study the substrate availability control in the nonoxidative phase.
Take notes on the role of transketolase and transaldolase in the interconversion of sugar phosphates.
Recap the complete oxidation of glucose via the HMS.
Understand the involvement of glycolytic enzymes and Frc-1,6-bisphosphatase in converting Gl-3-P to Glc-6-P.
Review the importance of NADPH and ribose 5-phosphate in various biosynthetic processes.
Take notes on the rearrangement of sugars and the connection between the HMS and the uronic acid pathway.
Note: Throughout the study plan, make sure to create concise summaries and diagrams to aid in understanding the concepts. Regularly review the notes and actively engage in self-assessment to reinforce the learned material.
Chapter 28: Hexose Monophosphate Shunt The HMS (variously known as the pentose phosphate, phosphogluconate, or hexose monophosphate pathway, cycle, or shunt), is an alternate cytoplasmic route for the metabolism of glucose 6-phosphate (Glc-6-P). In most tissues, 80-90% of glucose oxidation occurs directly through the Embden-Meyerhoff Pathway (EMP); the other 10-20%, however, may occur in the HMS. This pathway does not generate ATP through substrate-level phosphorylation, but it does generate CO2 (unlike anaerobic glycolysis). This "alternative" pathway has two main functions:
Generation of NADPH for reductive biosynthesis of lipids (e.g., fatty acids, cholesterol and other steroids), and
Provision of ribose residues for nucleotide and nucleic acid biosynthesis (e.g., ATP, NAD+ , FAD, RNA, and DNA).
The HMS is one of three cytoplasmic routes for the production of NADPH (the other two being cytoplasmic isocitrate dehydrogenase and malic enzyme-catalyzed reactions). Since intestinal absorption of ribose is generally too limited to meet metabolic demands, the HMS and the hepatic uronic acid pathway become important sources of pentoses for nucleotide and nucleic acid biosynthesis. The HMS of animals has both oxidative (nonreversible) and nonoxidative (reversible) phases, and both can give rise to ribose 5- phosphate. Only the oxidative phase, however, gives rise to CO2 and NADPH. In plants, part of the HMS participates in the formation of hexoses from CO2 in photosynthesis. The nonoxidative phase interconverts three, four, five, six, and seven-carbon sugars. Most tissues are capable of catabolizing Glc-6-P through both phases however, muscle tissue is deficient in the rate-limiting enzyme of this shunt that converts Glc-6-P to 6-phosphoglconate (i.e., glucose 6-phosphate dehydrogenase (Glc-6-PD)). Therefore, muscle tissue produces only minor amounts of NADPH via the HMS, and has limited lipid biosynthetic capacity. Muscle tissue does, however, retain the ability to generate ribose 5-phosphate through the non-oxidative phase of the shunt, thereby providing sufficient quantities to meet demands for DNA, and thus protein biosynthesis.
Activity of the HMS is high in liver and adipose tissue, which require NADPH for the reductive biosynthesis of fatty acids from acetyl-CoA. High HMS activity is also found in endocrine tissues which need NADPH for synthesis of cholesterol and steroid hormones (e.g., testes, ovaries, and adrenal cortex), or use ribose for nucleic acids involved in the production of proteinaceous hormones (e.g., insulin, PTH, and the anterior pituitary hormones). In the adrenal medulla and in some nervous tissue, the HMS is needed to provide NADPH for hydroxylation reactions involved in dopamine, norepinephrine, and epinephrine biosynthesis. In the mammary gland, HMS activity is high during lactation for the production of milk fats and proteins, but low in the nonlactating state.
Hexose monophosphate shunt activity is also high in mature erythrocytes, the lens and cornea, all of which need NADPH for reduced glutathione production (which in turn protects them from oxidative damage). Glucose 6-phosphate dehydrogenase deficiency, with subsequent impaired erythrocytic NADPH generation, has been reported in Weimaraner dogs, and it is the most common genetic enzymopathy known in humans (particularly prevalent among individuals of Mediterranean, Asian, and African descent). Several hundred variants of this enzyme have been identified in erythrocytes. An erythrocytic deficiency in Glc-6-PD can cause an increase in the concentration of methemoglobin, a decrease in the amount of reduced glutathione, an increase in hydrogen peroxide (H2O2), and increased fragility of red blood cell membranes. The net result may be hemolysis, which can be exacerbated when subjects are given excessive amounts of oxidizing agents such as aspirin or sulfonamide antibiotics. On the other hand, a relative deficiency of Glc-6- PD in erythrocytes may protect some animals and people from certain parasitic infestations (e.g., falciparum malaria), since the parasites that cause this disease require the HMS and reduced glutathione for optimal growth. The overall equation for the HMS can be expressed as follows:
3 Glc-6-P + 6 NADP+ —> 3 CO2 + 2 Glc-6-P + Gl-3-P + 6 NADPH
This equation erroneously indicates that a single glucose molecule is progressively degraded. This is not, however, the case. The HMS is clearly a more complex pathway than glycolysis. It is multicyclic, in that 3 molecules of Glc-6-P can give rise to 3 molecules of CO2 and 3 five-carbon residues. The latter can be rearranged to regenerate 2 molecules of Glc-6- P and 1 molecule of the glycolytic intermediate, glyceraldehyde 3-phosphate (Gl-3-P). Since two molecules of Gl-3-P can regenerate Glc-6- P, this pathway can account for the complete oxidation of glucose.
In the first irreversible reaction of the HMS, the NADP+ /NADPH concentration ratio exerts primary control over Glc-6-PD activity, with both NADP+ and NADPH competing for binding to this rate-limiting enzyme. As the ratio declines, so does the activity of Glc-6-PD. Glucose 6-phosphate dehydrogenase can also be induced by insulin.
The nonoxidative phase of the HMS is controlled primarily by substrate availability. The NADP+ /NADPH concentration ratio is normally about 0.014 in the cytosol of rat liver cells, several orders of magnitude below that for NAD+ /NADH (i.e., about 700). Mitochondrial ratios for both are about 10:1. A transhydrogenase is present on the inner mitochondrial membrane that passes electrons from NADH to NADP+. Mitochondrial NADPH can be used by glutamate dehydrogenase, by hydroxylases involved in the mitochondrial phase of steroid biosynthesis, or by mitochondrial enzymes involved in fatty acid chain elongation.
In the next reaction, 6-phosphogluconate is oxidized again by NADP+ and decarboxylated to produce ribulose 5-phosphate. This compound now serves as a substrate for two different enzymes. It can be isomerized to ribose 5-phosphate, the compound needed for nucleotide biosynthesis, or in a separate reaction it can be epimerized at carbon 3 to yield xylulose 5-phosphate. These 2 five-carbon sugar phosphates form the starting point for the next series of reactions catalyzed by transketolase and transaldolase. Transketolase transfers a two-carbon unit from a ketose to an aldose, a reaction requiring as a coenzyme the B1 vitamin, thiamin, in addition to Mg++. This reaction is severely limited in thiamin deficiency, and measurement of erythrocytic transketolase activity is sometimes used as a measure of such. Transaldolase transfers a three-carbon unit from an aldose to a ketose.
Two-carbon unit is transferred by transketolase from xylulose 5-phosphate to ribose 5- phosphate, thus yielding a three-carbon sugar phosphate, Gl-3-P, and a seven-carbon sugar phosphate, sedoheptulose 7-phosphate. Using these two sugar phosphates, transaldolase allows the transfer of a three-carbon dihydroxyacetone moiety from the ketose sedoheptulose 7-phosphate, to the aldose Gl-3-P, thus forming the ketose fructose 6-phosphate (Frc-6-P), and the four-carbon aldose, erythrose 4- phosphate. Fructose 6-phosphate can now enter the EMP for further oxidation. In another reaction catalyzed by transketolase, xylulose 5-phosphate and erythrose 4-phosphate exchange a two-carbon unit, yielding Frc-6-P and Gl-3-P.
In order to completely oxidize glucose to CO2 via the HMS, it is necessary that enzymes be present to convert Gl-3-P to Glc-6-P. This involves enzymes of the glycolytic pathway working in the reverse direction and, in addition, the gluconeogenic enzyme Frc-1,6- bisphosphatase, which converts Frc-1,6-bisP (produced from condensation of Gl-3-P and dihydroxyacetone phosphate), to Frc-6-P. This is unlikely, however, in the liver, since insulin activates Glc-6-PD and inhibits Frc-1,6-bisphosphatase.
In summary, the cytoplasmic HMS provides a means for degrading the hexose carbon chain one unit at a time. However, in contrast to the mitochondrial TCA cycle, this shunt does not constitute a consecutive set of reactions that lead directly from Glc-6-P to six molecules of CO2. Rather, in the nonreversible oxidative phase hexose is decarboxylated to pentose via two NADPH-forming oxidative reactions, and in the reversible non-oxidative phase 3, 4, 5, 6 and 7-carbon sugars are interconverted. NADPH can be used in many different tissues for the reductive biosynthesis of lipids, while ribose 5-phosphate can be used for RNA, DNA, ATP, NAD+ and FAD biosynthesis. As sugars are rearranged in the HMS, hexoses formed can re-enter the glycolytic sequence, and xyluose 5-phosphate can be accepted from the uronic acid pathway.
SUMMARY
The Hexose Monophosphate Shunt (HMS) is an alternate pathway for the metabolism of glucose 6-phosphate (Glc-6-P). It has two main functions: generating NADPH for lipid biosynthesis and providing ribose for nucleotide biosynthesis. The HMS is one of three pathways for NADPH production and is important for pentose production in nucleotide biosynthesis. The pathway has oxidative and nonoxidative phases, with the oxidative phase producing CO2 and NADPH. The nonoxidative phase interconverts different carbon sugars. Muscle tissue has limited HMS activity, resulting in limited lipid biosynthesis but sufficient ribose production for DNA and protein biosynthesis. The HMS is highly active in liver, adipose tissue, endocrine tissues, adrenal medulla, mammary gland, erythrocytes, lens, and cornea. Glucose 6-phosphate dehydrogenase deficiency can lead to hemolysis and increased susceptibility to certain parasitic infestations. The HMS is a complex pathway that can account for the complete oxidation of glucose. Control of the pathway is primarily regulated by the NADP+/NADPH ratio and substrate availability. The pathway involves several reactions, including oxidation, decarboxylation, isomerization, and epimerization. The pathway also requires enzymes from the glycolytic pathway and Frc-1,6-bisphosphatase for complete glucose oxidation. Overall, the HMS provides a means for stepwise degradation of the hexose carbon chain and plays a crucial role in NADPH and ribose production.
OUTLINE
Introduction to the Hexose Monophosphate Shunt (HMS)
Functions of the HMS:
Generation of NADPH for reductive biosynthesis of lipids
Provision of ribose residues for nucleotide and nucleic acid biosynthesis
Importance of the HMS in NADPH production and ribose synthesis
HMS activity in different tissues:
High activity in liver and adipose tissue for fatty acid biosynthesis
High activity in endocrine tissues for hormone synthesis
High activity in adrenal medulla and nervous tissue for neurotransmitter biosynthesis
High activity in mammary gland during lactation for milk production
High activity in erythrocytes, lens, and cornea for reduced glutathione production
Glucose 6-phosphate dehydrogenase deficiency and its effects on NADPH generation and red blood cell function
Overall equation for the HMS
Complexity of the HMS pathway compared to glycolysis
Control of HMS activity by NADP+/NADPH ratio and insulin
Nonoxidative phase of the HMS and its control by substrate availability
Reactions and enzymes involved in the nonoxidative phase
Conversion of Gl-3-P to Glc-6-P for complete oxidation of glucose
Summary of the HMS as a means of degrading the hexose carbon chain and its role in NADPH and ribose synthesis
QUESTIONS
Qcard 1:
Question: What is the Hexose Monophosphate Shunt (HMS)?
Answer: The HMS is an alternate cytoplasmic route for the metabolism of glucose 6-phosphate (Glc-6-P), involved in the generation of NADPH and ribose residues.
Qcard 2:
Question: What are the two main functions of the HMS?
Answer: The HMS functions in the reductive biosynthesis of lipids and the provision of ribose residues for nucleotide and nucleic acid biosynthesis.
Qcard 3:
Question: What are the sources of pentoses for nucleotide and nucleic acid biosynthesis?
Answer: The HMS and the hepatic uronic acid pathway are important sources of pentoses for nucleotide and nucleic acid biosynthesis.
Qcard 4:
Question: What is the difference between the oxidative and nonoxidative phases of the HMS?
Answer: The oxidative phase gives rise to CO2 and NADPH, while the nonoxidative phase interconverts three, four, five, six, and seven-carbon sugars.
Qcard 5:
Question: Which tissues have high activity of the HMS?
Answer: Liver, adipose tissue, endocrine tissues, adrenal medulla, nervous tissue, mammary gland, mature erythrocytes, lens, and cornea have high activity of the HMS.
Qcard 6:
Question: What can happen in Glucose 6-phosphate dehydrogenase deficiency?
Answer: Glucose 6-phosphate dehydrogenase deficiency can lead to impaired erythrocytic NADPH generation, resulting in increased methemoglobin, decreased reduced glutathione, increased hydrogen peroxide, and increased red blood cell membrane fragility.
Qcard 7:
Question: How is the activity of Glucose 6-phosphate dehydrogenase controlled?
Answer: The activity of Glucose 6-phosphate dehydrogenase is primarily controlled by the NADP+/NADPH concentration ratio, with both NADP+ and NADPH competing for binding to the enzyme.
Qcard 8:
Question: What is the role of transketolase and transaldolase in the HMS?
Answer: Transketolase transfers a two-carbon unit from a ketose to an aldose, while transaldolase transfers a three-carbon unit from an aldose to a ketose.
Functions of HMS
Generation of NADPH for lipid biosynthesis
Provision of ribose for nucleotide biosynthesis
Tissues with High HMS Activity
Liver and adipose tissue
Endocrine tissues
Adrenal medulla and nervous tissue
Mammary gland
Mature erythrocytes, lens, and cornea
Glucose 6-Phosphate Dehydrogenase (Glc-6-PD) Deficiency
Impaired NADPH generation in erythrocytes
Hemolysis and increased fragility of red blood cell membranes
Protection against certain parasitic infestations
Overall Equation of HMS
3 Glc-6-P + 6 NADP+ -> 3 CO2 + 2 Glc-6-P + Gl-3-P + 6 NADPH
Complexity of HMS
Multicyclic pathway
Complete oxidation of glucose
Control of Glc-6-PD activity by NADP+ /NADPH ratio
Nonoxidative Phase of HMS
Substrate availability control
Isomerization and epimerization reactions
Transketolase and transaldolase reactions
Conversion of Gl-3-P to Glc-6-P
Involvement of glycolytic enzymes and Frc-1,6-bisphosphatase
Unlikely in the liver due to insulin regulation
Summary of HMS
Degradation of hexose carbon chain one unit at a time
NADPH generation for lipid biosynthesis
Ribose generation for nucleotide biosynthesis
Interconversion of sugars in nonoxidative phase
Reentry of hexoses into glycolytic sequence
Generation of NADPH for lipid biosynthesis
Reductive biosynthesis of lipids
Fatty acids, cholesterol, and steroids
Provision of ribose for nucle
Read and understand the overview of the Hexose Monophosphate Shunt (HMS).
Focus on the main functions of the HMS: generation of NADPH and provision of ribose residues.
Take notes on the importance of the HMS in different tissues and its role in reductive biosynthesis of lipids and nucleotide biosynthesis.
Dive deeper into the oxidative and nonoxidative phases of the HMS.
Understand the production of CO2 and NADPH in the oxidative phase.
Study the interconversion of sugars in the nonoxidative phase.
Take notes on the differences between animal and plant HMS.
Explore the significance of HMS activity in specific tissues like liver, adipose tissue, endocrine tissues, and nervous tissue.
Understand the role of HMS in the production of milk fats and proteins in the mammary gland.
Study the importance of HMS in mature erythrocytes, lens, and cornea for reduced glutathione production.
Take notes on the consequences of Glucose 6-phosphate dehydrogenase deficiency.
Review the overall equation for the HMS and understand its complexity.
Focus on the control mechanisms of the HMS, including the NADP+/NADPH concentration ratio and insulin induction.
Study the substrate availability control in the nonoxidative phase.
Take notes on the role of transketolase and transaldolase in the interconversion of sugar phosphates.
Recap the complete oxidation of glucose via the HMS.
Understand the involvement of glycolytic enzymes and Frc-1,6-bisphosphatase in converting Gl-3-P to Glc-6-P.
Review the importance of NADPH and ribose 5-phosphate in various biosynthetic processes.
Take notes on the rearrangement of sugars and the connection between the HMS and the uronic acid pathway.
Note: Throughout the study plan, make sure to create concise summaries and diagrams to aid in understanding the concepts. Regularly review the notes and actively engage in self-assessment to reinforce the learned material.
