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Flashcards in Metabolism 4 Deck (44):
1

How is glycolysis in the liver affected by glucagon and epinephrine?

Glucagon and epinephrine shut down glycolysis in the liver, so that glucose is preserved.

2

What hormones promote gluconeogenesis?

What is the first step?

Glucagon and epinephrine promote gluconeogenesis, and they increase the transcription
and synthesis of the key enzymes of gluconeogenesis.

Both of them will promote the degradation of glycogen in the liver, so that glucose-6-
phosphate is generated.

3

Glucose homeostatis requires two pathways. Where do they take place? Describe both.

1. gluconeogenesis
2. glycogen degradation

(both are highly regulated and highly active in the liver)

4

Describe gluconeogenesis.
What is its purpose?

What substrates are used?

How many ATP required?

essential for survival of humans and animals

helps maintain normal blood glucose levels

Results in synthesis of glucose from non carbohydrate carbon substrates like pyruvate, lactate, glycerol, glucogenic aa

-Requires 6 ATP’s.

5

Describe the first step of gluconeogenesis.

Note: Non-carbohydrate precursors are first converted to glucose 6-phosphate.

Glucose 6-phosphatase enzyme releases the phosphate from glucose 6-phosphate
generated by BOTH pathways (gluconeogenesis & glycogen degradation).

6

What would occur if there was a lack of glucose 6- phosphatase?

Glucose 6-phosphatase enzyme releases the phosphate from glucose 6-phosphate
generated by BOTH pathways (gluconeogenesis & glycogen degradation).
- Remember, phosphorylated sugars are trapped.
- W/o this enzyme, gluconeogenesis and glycogen degradation cannot
occur.
- If you have a defect in this enzyme, you cannot maintain normal blood
glucose levels without eating for long periods of time.

7

What will stimulate gluconeogenesis? (Hormone/conditions)

Low blood sugar (hypoglycemia) stimulates gluconeogenesis through the hormone glucagon (glucagon is increased in these conditions).
- Takes place mainly in the liver and to some extent in the kidney.
- Glycolytic flux is decreased.
- In other words, gluconeogenesis and glycolysis are reciprocally
regulated.

8

Gluconeogenesis is activated after ...

dietary glucose has been oxidized

glycogen has been used up

9

How is pyruvate converted to phosphoenolpyruvate?

2 step process via oxaloacetate.

Oxaloacetate can be viewed as an “activated” form of pyruvate.
- Bicarbonate and the cofactor biotin are involved in this activation,
which requires the expenditure of ATP.

10

Describe the relative changes in the levels of blood glucose, hepatic glycogen, and other fuels (fatty acids and ketone bodies) during a 24-hour fast, and relative changes in hormone levels.

p 4

insulin drops
glucagon rises

free fatty acids and blood ketone bodies shoot up


liver glycogen drops a lot
blood glucose drops some

11

Describe what happens to glucose right after eating vs after some time.

Right after eating:
- Blood glucose levels are at their highest.
- Glucose molecules are transported into the liver through the GLUT-2 transporter.
- “ “ into skeletal muscle/heart muscle/adipose tissue using GLUT-4.
- Insulin will also be at its highest level.
- Remember: elevated blood glucose is a key stimulus for the release of
insulin.

After Some Time..
- Blood glucose levels start to increase, along with insulin levels .
Remember! The brain has an absolute requirement for glucose. It cannot metabolize fatty
acids, so it needs glucose to generate ATP, and it needs ATP to establish ion gradients!

12

Compare exogenous glucose, glycogen, and gluconeogenesis on a graph that compares time phases of glucose homeostasis.

Phase I (0-4 hours)
Phase II (6-16 hours)
Phase III (16- 28 hours)
Phase IV (1- 16 days)
Phase V (17-32 days)

Slide 11
P5

See chart p 6

Phase I- exogenous glucose, all tissues use glucose, glucose used by brain

Phase II- use glycogen and hepatic gluconeogensis, all tissues use glucose except liver, muscle and adipose tissue all diminished rates

Phase III- use hepatic gluconeogensis and glycogen, all tissues use glucose except liver, muscle and adipose tissue at rates between II and IV

Phase IV- gluconeogenesis hepatic and renal, brain, RBC renal medulla and small amt muscle use glucose, fuel for brain is glucose and ketone bodies

Phase V- gluconeogenesis hepatic and renal, brain uses glucose at diminished rate, RBCs, renal medulla, fuel for brain is ketone bodies and glucose

13

When does brain start to generate ketone bodies?

After three or four days of starvation, the body will start generating ketone bodies levels that are
high enough that they can enter the brain. The transport of ketone bodies is also up-regulated to
move the ketone bodies into the brain.

14

Describe the lens of the eye and its glucose needs.

The lens of the eye also can only metabolize glucose. It does not have mitochondria for the citric
acid cycle.

15

During starvation, about when would you run out of glycogen stores?

about a day ( I think)

(phase 3)

16

What are the major gluconeogenic precursors? Describe.

The major gluconeogenic precursors include lactate, glucogenic amino
acids, and glycerol.

Lactate – general metabolism, RBC metabolism, and muscle metabolism.

Glucogenic amino acids (e.g., alanine) – overnight degradation of muscle amino acids.

Glycerol – degradation of adipose tissue; triacyglycerols

Note: Fatty acids with an even number of carbons DO NOT contribute to a
net synthesis of glucose. Most fatty acids have an even number of carbons.

17

Fatty acids with an even or odd number of carbons contribute to net synthesis of glucose

ODD

Fatty acids with an even number of carbons DO NOT contribute to a
net synthesis of glucose. Most fatty acids have an even number ofcarbons.

18

When considering gluconeogenesis:

2 pyruvate
2 oxaloacetate
2 triose phosphates
glucose

Where can substrates/aa enter along this pathway?

p 7

19

Describe the neonate's brain and risks.

The neonate’s brain is very dependent on glucose from glycogen degradation and
gluconeogenesis.

PEP carboxykinase is an enzyme that is needed to make glucose from lactate or alanine. It takes a few hours to induce PEP carboxykinase. Therefore, neonates are at risk of having
hypoglycemia.

20

Describe where gluconeogenesis and glycolysis are mainly active.

Gluconeogenesis takes place predominantly in the liver and kidney,
while glycolysis is active in nearly every living cell.

21

Gluconeogenesis (from all gluconeogenic precursors) requires ATP. When
glucogenic amino acids are the precursors, additional ATP is needed. Why?

to dispose of
the amino groups through ureagenesis.

22

Describe the conversion of fructose into lactate.

fructolysis

Slide 21

23

Show conversion of galactose to glucose.

Slide 23

24

During an overnight fast, which serves as the major source of ATP for gluconeogenesis?

lactate
fatty acids
alanine

During an overnight fast, oxidation of fatty acids serves as the major source of ATP for
gluconeogenesis (need more ATPs) not from the source of lactate or alanine-mediated
gluconeogenesis.

25

Once acetyl-CoA is made, can it be used as a substrate to make glucose?

Once acetyl-CoA is made, it cannot be used to make glucose; it is committed to either
fatty acid synthesis or the Krebs cycle.

26

What is glycerol a precuror for? Where?

What must happen to glycerol before it can be used in glycolysis or gluconeogensis?

Glycerol is a precursor for synthesis of triacylglycerols and of phospholipids in the liver
and adipose tissue. When the body uses stored fat as a source of energy, glycerol and
fatty acids are released into the bloodstream.

Glycerol will be converted to their intermediate, glyceraldehyde 3-phosphate before
entering the pathway of glycolysis or gluconeogenesis (depending on physiological
conditions).

slide 27

27

Describe propionyl CoA.

What is it a product of?

Propionyl CoA is a good precursor for gluconeogenesis. Propionyl CoA is formed as a product for beta oxidation of odd chain fatty acid, isoleucine and valine and alpaketobutyric
acid.

p 10, slide 29

propionyl CoA will then form oxaloacetate and then 1/2 glucose

28

Where is oxaloacetate formed? How does it reach the cytosol?

Oxaloacetate is formed in the mitochondria but cannot be transported out of the
mitochondria. Instead, it is converted to another compound, e.g., malate, which is
transported to the cytosol and converted to oxaloacetate.

29

Draw an overview of gluconeogenesis from pyruvate.

p 11

30

What are the four enzymes that are required to reverse the three irreversible steps of glycolysis?


Show the effects of glycolysis vs gluconeogensis on a graph with arrows. Show how Glycolysis and gluconeogenesis require separate enzymes.

Mitochondrial Enzyme - Pyruvate Carboxylase

Cytoplasmic Enzymes - Phosphoenolpyruvate (PEP) Carboxykinase
Fructose 1,6-Bisphosphatase
Glucose 6-Phosphatase


p 12

31

Describe pyruvate carboxylase. Where does it operate? Describe the role of biotin. What is an activator of this enzyme?

Pyruvate carboxylase is a mitochondrial enzyme which carboxylates pyruvate to form
oxaloacetate. ATP provides the energy to add the carboxyl group to biotin, the carrier of
the activated CO2 group. Acetyl CoA is an allosteric activator of this enzyme.

32

Because oxaloacetate cannot cross the mitochondrial membrane additional reactions
are required. One mechanism - conversion of mitochondrial oxaloacetate to malate,
transport of malate across the mitochondrial membrane, and conversion of cytosolic
malate to oxaloacetate.

What is required? How is this activated?

Requires Biotin. Activated by Acetyl CoA.

33

When might pyruvate carboxylase (PC) deficiency be suspected in individuals?

What will a lack of PC enzyme cause?

In the serum what will increase?

Pyruvate carboxylase (PC) deficiency is suspected in individuals with failure
to thrive, developmental delay, recurrent seizures, and metabolic acidosis.
- The lack of PC enzyme activity causes the accumulation of pyruvate in the
plasma, which is subsequently converted into lactate by the enzyme lactate
dehydrogenase, causing an elevated plasma concentration of lactic acid.
- In serum, a high increase in alanine is formed.

Slide 35

34

What provides the energy for PEP carboxykinase activity?

Where does PEP carboxykinase operate? Cytoplasm or mitochondria?

PEP carboxykinase is a cytosolic enzyme. GTP hydrolysis provides the energy for
the decarboxylation reaction that is catalyzed by this enzyme. Therefore, GTP is required.

35

Describe the action of fructose 1,6 bisphosphatase.

What inhibits this enzyme?

Fructose 1,6-bisphosphatase catalyzes the conversion of fructose 1,6 bisphosphate
to fructose 6-phosphate. This enzyme is inhibited by fructose 2,6-bisphosphate and
AMP.

36

Describe the enzyme that is required to release glucose from the liver into circulation.


What results when glucose 6 phosphate reacts with H2O?

Glucose 6-phosphatase is essential to release glucose from the liver into the circulation. This liver enzyme is required for both gluconeogenesis and glycogenolysis.

Glucose 6-phosphate + H2O ----------> glucose + Pi

37

Where is glucose 6-phosphate hydrolyzed by glucose 6-phosphatase? Describe the transporters involved.

What would a genetic defect in a transporter or phosphatase result in?

Glucose 6-phosphate is hydrolyzed by glucose 6-phosphatase located on the cisternal
surface of the endoplasmic reticulum. Three transporters are involved: one moves
glucose 6-phosphate into the lumen, a second moves Pi back to the cytosol, and a third
moves glucose back into the cytosol.

A genetic defect in either the transporter or the phosphatase interferes with gluconeogenesis, and results in the accumulation of glycogen in liver.

38

Describe glucose-6-phosphatase deficiency. How will it manifest?

What will be elevated in serum?

-It is a group of inherited, autosomal recessive, metabolic diseases.
-Falls under glycogen storage diseases (GSDs)
-Is also referred to as GSD type I or von Gierke disease.
- It is characterized by poor intolerance to fasting, growth retardation and hepatomegaly
resulting from accumulation of glycogen and fat in the liver (enlarged), elevated serum uric acid and elevated serum lactate.

Slide 43, p 16

39

There is a reciprocal regulation of the enzymes that catalyze the three
irreversible steps of glycolysis and gluconeogenesis.

Glycolysis and Gluconeogenesis Require Separate Enzymes to
Catalyze the Three Irreversible Steps
Reciprocal Regulation of Some Key Enzymes

Describe the enzymes and factors that increase/decrease their activity for both glycolysis and gluconeogenesis.

- glucose to glucose 6-phosphate
- fructose 6 phosphate to fructose 1,6 bisphosphate
- phosphoenolpyruvate to pyruvate

p 17

40

Describe the regulation of the Synthesis of Key Hepatic Glycolytic and Gluconeogenic Enzymes.

Synthesis/levels of gluconeogenic enzymes are increased by what?

an increase in cAMP (caused by an elevation of glucagon or epinephrine) or an increase in cortisol results in increased synthesis of following four enzymes:

glucose 6 phosphatase
fructose 1,6 bisphosphatase
PEP carboxykinase
pyruvate carboxylase

41

Describe the regulation of the Synthesis of Key Hepatic Glycolytic and Gluconeogenic Enzymes.

Synthesis/levels of glycolytic enzymes are increased by what?

an increase in insulin or decrease in cAMP (caused by decreased glucagon or epinephrine) leads to increased synthesis of the following 3 glycolytic enzymes:

glucokinase
PFK 1
pyruvate kinase

42

How does glucagon alter the transcription of genes? Use PEP carboxykinase as an example.

Glucagon promotes transcription
of the gene that encodes PEP carboxykinase.

Abbreviations:

PEPCK, PEP
carboxykinase; CRE, cAMP-response
element; CREB, cAMP-response
element binding protein.

43

How will ethanol affect gluconeogeneis/glycolysis? What can it lead to?

Explain.

Ethanol ingestion inhibits gluconeogenesis and can lead to
hypoglycemia.

(Caused by increased NADH/NAD+ ratio)

The increased NADH from ethanol metabolism reduces the
gluconeogenic precursors pyruvate and OAA to lactate and malate.
This removes pyruvate and oxaloacetate from the pool of glucogenic precursors –
hypoglycemia.

p20

44

What effect will increased/decreased NADH have?

Increased NADH leads to increased lactate formation
Decreased NADH leads to decreased lactate formation