Lecture 17: Glycogen Metabolism, Disaccharide Metabolism and the Pentose Phosphate Pathway

Question 1

___________:

• Major storage form of carbohydrate in

animals

• Branched polymer consisting of D-glucose

units

• α1-4-linked glucose with α1-6-linked side branches
• In the ______ helps maintain euglycemia during fasting periods
• In ________ provides local energy but does not supply glucose for circulation

Answer 1

Glycogen

• Major storage form of carbohydrate in

animals

• Branched polymer consisting of D-glucose

units

• α1-4-linked glucose with α1-6-linked side branches
• In the Liver helps maintain euglycemia during fasting periods
• In ________ provides local energy but does not supply glucose for circulation

Question 2

Advantages to carbohydrate storage of Energy

Answer 2

• Energy cannot be yielded from fat in the same space of time as from glycogen
• Some organs such as the brain preferentially burn glucose – liver glycogen can provide this

during shorter stretches of fasting until depleted

• RBCs can only utilize glucose as their energy source through anaerobic glycolysis

Question 3

Glycogen synthesis – regulated by _______

Answer 3

Glycogen synthesis – regulated by glycogen synthase

Question 4

Answer 4

Question 5

Linkage of the first few glucose units to form the minimal “primer” needed for glycogen synthase is catalyzed by ________, which attaches to the first glucose and catalyzes linkage of the first eight glucose by alpha(1,4) bonds

Answer 5

Linkage of the first few glucose units to form the minimal “primer” needed for glycogen synthase is catalyzed by Glycogenin, which attaches to the first glucose and catalyzes linkage of the first eight glucose by alpha(1,4) bonds

Question 6

What does the formation of additional branches in Glycogen Synthesis do?

What Enzyme is responsible for this and by what mechanism?

Answer 6

Increases solubility and number of non-reducing ends upon which glucose units can be added (and in turn removed)

Enzyme = glucosyl 4:6 transferase (branching enzyme) breaks α1,4 bond to create α1,6 bonds

Question 7

__________: breaking down of glycogen to yield glucose

• Glycogen phosphorylase key enzyme
• Acts until there are 4 glucose units left till branch point
• Four units remaining are removed by ____________

Answer 7

Glycogenolysis: breaking down of glycogen to yield glucose

• Glycogen phosphorylase key enzyme
• Acts until there are 4 glucose units left till branch point
• Four units remaining are removed by Debranching enzyme

Question 8

______________ is used by both gluconeogenesis and glycogenolysis to release free glucose from glucose-6-phosphate.

Answer 8

Glucose-6-phosphatase is used by both gluconeogenesis and glycogenolysis to release free glucose from glucose-6-phosphate

Question 9

Von Gierke’s Glycogen Storage Disease: Genetic deficiency of ____________ results in profound ________ as both gluconeogenic and glycogenolytic pathways are affected.

Answer 9

Von Gierke’s Glycogen Storage Disease: Genetic deficiency of glucose-6-phosphatase results in profound hypoglycemia as both gluconeogenic and glycogenolytic pathways are affected.

Question 10

___________ and __________ are catabolic to release energy during periods of fasting/flight-fight response so they act to break down glycogen to glucose – use _____ as a second messenger and generally phosphorylate target enzymes.

Answer 10

Glucagon and epinephrine are catabolic to release energy during periods of fasting/flight-fight response so they act to break down glycogen to glucose – use cAMP as a second messenger and generally phosphorylate target enzymes

Question 11

_________ turns on glycogen synthase and turns off glycogen phosphorylase to stimulate glycogen synthesis (via dephosphorylation)

Answer 11

Insulin turns on glycogen synthase and turns off glycogen phosphorylase to stimulate glycogen synthesis (via dephosphorylation)

Question 12

_____________ turns off glycogen synthase and turns on glycogen phosphorylase to stimulate glycogen synthesis (via phosphorylation)

Answer 12

Glucagon/Epinephrine turns off glycogen synthase and turns on glycogen phosphorylase to stimulate glycogen synthesis (via phosphorylation)

Question 13

As glycogen stores deplete ____________ takes over as the major source of glucose

Answer 13

As glycogen stores deplete gluconeogenesis takes over as the major source of glucose

Question 14

Muscle does not contain _____________ so the glucose-1-P produced by glycogenolysis provides energy via glycolysis for contraction

Answer 14

Muscle does not contain glucose-6-phosphatase so the glucose-1-P produced by glycogenolysis provides energy via glycolysis for contraction

Question 15

__________ is often accompanied by high ketone levels and lactic acidosis as the body tries to restore glucose and provide alternative fuel sources for the body

Answer 15

Hypoglycemia is often accompanied by high ketone levels and lactic acidosis as the body tries to restore glucose and provide alternative fuel sources for the bod

problem with fatty acid oxidation, not enough energy being created to create the negative regulators of glycolysis and positive of gluconeogenesis

Question 16

__________________________________:

• Build-up of glycogen in the body’s cells
• Hypoglycemia and lactic acidosis can occur
• Mutation in Glucose-6- phosphatase

Answer 16

Type I - Glycogen STrogae Disease (aka Von Gierke disease)

• Build-up of glycogen in the body’s cells
• Hypoglycemia and lactic acidosis can occur
• Mutation in Glucose-6- phosphatase

Question 17

_______________________________\_:

• Debranching enzyme mutation leading to deficiency
• Characterized by storage of structurally abnormal glycogen
• Poor muscle tone in children is often the first sign of this disease
• Ketone/FA levels elevated as the body switches to other fuel sources other than glycogen
• Indistinguishable clinically from Type 1

Answer 17

Type III Glycogen Storage Disease (aka. Cori’s Disease) :

• Debranching enzyme mutation leading to deficiency
• Characterized by storage of structurally abnormal glycogen
• Poor muscle tone in children is often the first sign of this disease
• Ketone/FA levels elevated as the body switches to other fuel sources other than glycogen
• Indistinguishable clinically from Type 1

Question 18

________________________________\_:

• Muscle glycogen phosphorylase absent = exercise intolerance.
• The least severe form of the disease

Answer 18

Type V Glycogen Storage Disease (aka. McArdle’s):

• Muscle glycogen phosphorylase absent = exercise intolerance.
• The least severe form of the disease

Question 19

_________________________________:

• Acid alpha-glucosidase (GAA) (acid maltase) mutation (also called α-1,4-glucosidase)
• The classic form is an infantile-onset inherited and often fatal disorder that disables the heart and skeletal muscles.
• Infants with this disorder typically experience muscle weakness (myopathy), poor muscle tone (hypotonia), an enlarged liver (hepatomegaly), and heart defects.
• Lysosomal glycogen is not necessary for maintaining blood glucose so hypoglycemia is not observed
• Enzyme replacement therapy

Answer 19

Type II Glycogen storage disease/lysosomal dysfunction (aka. Pompe Disease):

• Acid alpha-glucosidase (GAA) (acid maltase) mutation (also called α-1,4-glucosidase)
• The classic form is an infantile-onset inherited and often fatal disorder that disables the heart and skeletal muscles.
• Infants with this disorder typically experience muscle weakness (myopathy), poor muscle tone (hypotonia), an enlarged liver (hepatomegaly), and heart defects.
• Lysosomal glycogen is not necessary for maintaining blood glucose so hypoglycemia is not observed
• Enzyme replacement therapy

Question 20

_________ +_________use the sodium-glucose co-transporter system for absorption into the enterocyte (active transport – required energy)

_______ uses the GLUT5 transporter for absorption into the enterocyte

All three sugars enter the portal circulation where they are readily taken up by ______ in the liver.

Answer 20

Glucose** and G_alactose_** use the sodium-glucose co-transporter system for absorption into the enterocyte (active transport)

Fructose uses the GLUT5 transporter for absorption into the enterocyte

All three sugars enter the portal circulation where they are readily taken up by GLUT2 in the liver.

Question 21

Absorption of fructose does not induce an insulin response (T/F)

Answer 21

True

Question 22

Sucrose does not undergo reactions that are typical of aldehydes and ketones. Therefore, sucrose is a __________ sugar.

Answer 22

Sucrose does not undergo reactions that are typical of aldehydes and ketones. Therefore, sucrose is a nonreducing sugar.

Question 23

Age upon weaning and when disorders of fructose metabolism usually present?

Answer 23

6 months

Question 24

In tissues other than the liver fructose is phosphorylated by ______ to form fructose-6-phosphate which enters glycolysis.

Answer 24

In tissues other than the liver fructose is phosphorylated by Hexokinase to form fructose-6-phosphate which enters glycolysis.

Question 25

**Fructose Metabolism in the Liver** Glucokinase does not recognize fructose meaning metabolism is different in the liver. Fructose is phosphorylated on C1 by ________ to form fructose-1-P which enters glycolysis

Answer 25

**Fructose Metabolism in the Liver** Glucokinase does not recognize fructose meaning metabolism is different in the liver. Fructose is phosphorylated on C1 by **_fructokinase_** to form fructose-1-P which enters glycolysis

Question 26

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ Deficiency : * Infants are healthy until they ingest fructose * **Fructose-1- phosphate** accumulates causing hypoglycemia, nausea & vomiting, abdominal pain, sweating, tremors, confusion, lethargy, seizures, and coma * Fructose-1-phosphate is a _________ inhibitor of **phosphorylase** (glycogen degradation) and thus accumulation is linked to hypoglycemia. * *Patients maintained on a diet free of both fructose and sucrose remain symptom-free*

Answer 26

**_Aldose B Deficiency_**: * Infants are healthy until they ingest fructose * **Fructose-1- phosphate** accumulates causing hypoglycemia, nausea & vomiting, abdominal pain, sweating, tremors, confusion, lethargy, seizures, and coma * Fructose-1-phosphate is a **_competitive inhibitor_** of **phosphorylase** (glycogen degradation) and thus accumulation is linked to hypoglycemia. * Prolonged ingestion may cause cirrhosis (liver disease), mental deterioration, and proximal renal tubular acidosis with urinary loss of phosphate and glucose * *Patients maintained on a diet free of both fructose and sucrose remain symptom-free*

Question 27

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ Deficiency: * This deficiency causes benign elevation of blood and urine fructose levels (benign fructosuria). * The condition is asymptomatic and diagnosed accidentally when a non-glucose-reducing substance is detected in urine.

Answer 27

**_Fructokinase Deficiency_**: * This deficiency causes benign elevation of blood and urine fructose levels (benign fructosuria). * The condition is asymptomatic and diagnosed accidentally when a non-glucose-reducing substance is detected in urine.

Question 28

Galactose: * Found in milk/dairy products * Converted to intermediates of the ______ pathway * ___________ is also used for the synthesis of glycoproteins/glycolipids and proteoglycans

Answer 28

Galactose: * Found in milk/dairy products * Converted to intermediates of the **_glucose_** pathway * **_UDP galactose_** is also used for the synthesis of glycoproteins/glycolipids and proteoglycans

Question 29

The appearance of high concentrations of galactose in the blood after lactose intake may be due to either a ________ **deficiency** or a _______________ **deficiency**.

Answer 29

The appearance of high concentrations of galactose in the blood after lactose intake may be due to either a **_galactokinase deficiency**_ or a _**uridylyl transferase deficiency_**

Question 30

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_: * Results from deficiency of **galactose-1-phosphate uridyl transferase** * Is the most common cause of galactosemia * The clinical features of this illness include vomiting, lethargy, and failure to thrive soon after breastfeeding is begun.

Answer 30

**_Classic Galactosemia_**: * Results from deficiency of **galactose-1-phosphate uridyl transferase** * Is the most common cause of galactosemia * The clinical features of this illness include vomiting, lethargy, and failure to thrive soon after breastfeeding is begun.

Question 31

**_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_:_** * Results due to galactokinase deficiency * Galactose accumulates and is reduced to **galactinol**, which causes **cataracts.**

Answer 31

**_Non-classical Galactosemia:_** * Results due to galactokinase deficiency * Galactose accumulates and is reduced to **galactinol**, which causes **cataracts.**

Question 32

Which is more serious, Classical or Non-Classical Galactosemia? Why?

Answer 32

**_Classical Galactosemia_** Lack of uridylyltransferase is more serious as **galactose-1-phosphate** accumulates and interferes with glycogen synthesis and degradation.

Question 33

Accumulation of fructose-1-phosphate or galactose-1-phosphate is __________ to the cell than fructose or galactose. Enzymes that impair their metabolism, resulting in accumulation of the monophosphate-sugar, presents with ___________ disease.

Answer 33

Accumulation of fructose-1-phosphate or galactose-1-phosphate is **_more toxic**_ to the cell than fructose or galactose and thus enzymes that impair their metabolism, resulting in accumulation of the monophosphate-sugar, presents with _**more severe_** disease.

Question 34

Answer 34

Question 35

**Pentose Phosphate Pathway (the hexose monophosphate shunt)** * Main pathway for the generation of _______ and **\_\_\_\_\_\_\_\_\_\_\_\_** _(_synthesis of nucleotides) * Occurs in the \_\_\_\_\_\_\_\_\_\_\_\_ * Branches from glycolysis at the level of **glucose-6-phosphate** * Is it energy-yielding? * NADPH produced is an important reduction reagent required for **\_\_\_\_\_\_\_\_\_\_** as well as glutathione reduction (protects against oxidative damage)

Answer 35

**Pentose Phosphate Pathway (the hexose monophosphate shunt)** * Main pathway for **generation of _NADPH_ and _ribulose-5-phosphate (_**synthesis of nucleotides) * Occurs in the **_cytoplasm_** * Branches from glycolysis at the level of **glucose-6-phosphate** * Not a direct energy-yielding pathway * NADPH produced is an important reduction reagent required for **_Fatty Acid Synthesis_** as well as glutathione reduction (protects against oxidative damage)

Question 36

**_\_\_\_\_\_\_\_\_\_\_\_ Pathway:_** * Part of the pentose phosphate pathway which generates NADPH and ribulose-5-phosphate * \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_is responsible for the decarboxylation of 6- phosphogluconate to yield the 5C sugar ribulose-5- phosphate * is an ____________ reaction * When NADPH levels are **_low_** the oxidative reactions of the pathway are used to generate ribose-5- phosphate for nucleotide synthesis

Answer 36

**_Oxidative Pathway:_** * Part of the pentose phosphate pathway which generates NADPH and ribulose-5-phosphate * **_6-phosphogluconate dehydrogenase_** is responsible for the decarboxylation of 6- phosphogluconate to yield the 5C sugar ribulose-5- phosphate * is an **_Irreversible_** reaction * When NADPH levels are **_low_** this pathway is used to generate ribose-5- phosphate for nucleotide synthesis

Question 37

NADPH is a ________ agent NADPH is required for the redox reactions in tissues with _____________ (cholesterol, bile salts, steroid hormones, triglycerides) The liver also uses NADPH for detoxification of and excretion of drugs NADPH is also used for the reduction of the important __________ glutathione

Answer 37

NADPH is a **_reducing_** agent NADPH is required for the redox reactions in tissues with **_active lipid synthesis_** (cholesterol, bile salts, steroid hormones, triglycerides) The liver also uses NADPH for detoxification of and excretion of drugs NADPH is also used for the reduction of the important **_antioxidant_** glutathione

Question 38

**\_\_\_\_\_\_\_\_\_\_ pathway** * Pentose-phosphates produced can be used for the generation of glycolytic intermediates * Glycolytic intermediates can be used to generate ribose-5- phosphate for nucleotide synthesis via this pathway * This reaction is \_\_\_\_\_\_\_\_\_ * When NADPH levels are **_high_** this pathway can be used to generate ribose-5- phosphate

Answer 38

**Non-Oxidative pathway** * Pentose-phosphates produced can be used for the generation of glycolytic intermediates * Glycolytic intermediates can be used to generate ribose-5- phosphate for nucleotide synthesis via this pathway * This reaction is **_Reversible_** * When NADPH levels are high this pathway can be used to generate ribose-5- phosphate

Question 39

In non-dividing cells where requirements for nucleotides are \_\_\_\_\_\_, Ribose-5-Phosphate is reconverted back to glycolytic pathway

Answer 39

In non-dividing cells where requirements for nucleotides are **_Low_**, Ribose-5-Phosphate is reconverted back to glycolytic pathway

Question 40

**Glucose-6-phosphate _____________ Deficiency:** * _______ chromosomal disorder * Mainly affects red blood cells (RBC) * Hemolytic anemia in response to a trigger (anti-malarial drugs) * Insufficient production of ______ in affected persons causes excessive oxidative damage to RBC and lysis occurs * Natural protection against \_\_\_\_\_\_\_

Answer 40

**Glucose-6-phosphate _Dehydrogenase_ Deficiency:** * **_X-linked_** chromosomal disorder * Mainly affects red blood cells (RBC) * Hemolytic anemia in response to a trigger (anti-malarial drugs) * Insufficient production of **_NADPH_** in affected persons causes excessive oxidative damage to RBC and lysis occurs * Natural protection against **_malaria_**

Question 41

_Aldolase B_ and _galactose-1-phosphate uridyl transferase_ result in severe forms of ________ and \_\_\_\_\_\_\_\_, due to the accumulation of fructose-1-phosphate and galactose-1-phosphate respectively

Answer 41

**Aldolase B** and **galactose-1-phosphate uridyl transferase** result in severe forms of **_Fructosemia**_ and _**Galactosemia_**, due to the accumulation of fructose-1-phosphate and galactose-1-phosphate respectively

Question 42

The pentose phosphate pathway is a critical pathway for the synthesis of ________ and for the generation of ________ which is essential for cellular redox reactions

Answer 42

The pentose phosphate pathway is a critical pathway for the synthesis of **_nucleotides**_ and for the generation of _**NADPH_** which is essential for cellular redox reactions