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Kaplan Biochem and Genetics > Glygocen, Gluconeogenesis and the HMP Shunt > Flashcards

Glygocen, Gluconeogenesis and the HMP Shunt Flashcards

1
Q

Glycogen metabolism occurs in the

A

cytoplasm

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2
Q

the rate-limiting enzymes of glycogen metabolism are

A
  1. glycogen synthesis: glycogen synthase
    - activated by insulin in liver and muscle
  2. Glycogenolysis: glycogen phosphorylase
    - activated by glucagon in liver (hypoglycemia)
    - activated by epinephrine and AMP in skeletal muscle (exercise)
    - a phosphorylase breaks bonds using Pi rather than H20
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3
Q

Glucose 6 phosphate releases free glucose. Where is it found?

A
  • Glucose 6P is only found in the liver

- involved in glycogen metabolism

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4
Q

Glucose Deficiencies:

A
  • G6PD
  • Hepatic glycogen phosphorylase deficiency
  • muscle glycogen phosphorylase deficiency
  • lysosomal alpha 1,4-glucosidase deficiency
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5
Q

Where does gluconeogenesis occur?

A
  • the cytoplasm and the mitochondria

- predominantly in the liver

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6
Q
  • What is the rate-limiting enzyme of glycogenolysis?

- What is it activated by?

A
  • glycogen phosphorylase
  • activated by glucagon in liver (hypoglycemia)
  • activated by epinephrine and AMP in skeletal muscle (exercise)
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7
Q

What is the controlled enzyme of gluconeogenesis?

A
  1. Fructose 1,6 bisphosphatase
    - in the cytoplasm
    - activated by ATP
    - inhibited by AMP and fructose 2,6-bisP
    - Insulin (inhibits) and glucagon (activates) by their control of PFK-2 (produces Fructose 2,6-BP)
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8
Q

Pyruvate Carboxylase

A
  • involved in gluconeogenesis
  • activated by acetyl CoA from beta-oxidation
  • biotin
  • in the mitochondria
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9
Q

Phosphoenolpyruvate carboxykinase (PEPCK)

A
  • involved in gluconeogenesis
  • in the cytoplasm
  • induced by glucagon and cortisol
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10
Q
  • What is the rate-limiting enzyme of glycogen synthesis?

- What is it activated by?

A
  • glycogen synthase

- activated by insulin in liver and muscle

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11
Q

Glucose 6-Phosphatase (Endoplasmic Reticulum)

A
  • only in the liver
  • involved in gluconeogenesis
  • required to release free glucose from tissue
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12
Q

Where does the Hexose Monophosphate Shunt occur?

A

in the cytoplasm of most cells

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13
Q

What are the functions of the Hexose Monophosphate Shunt?

A
  • generates NADPH

- produces sugars for biosynthesis (ribose 5P for nucleotides)

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14
Q

What are the rate-limiting enzymes of the HMP?

A
  1. Glucose 6 Phosphate Dehydrogenase
    - inhibited by NADPH
    - induced by insulin in liver
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15
Q

G6PD deficiency

A
  • episodic hemolytic anemia (MC) induced by infection and drugs
  • chronic hemolysis, CGD-like symptoms (very rare)
  • heinz bodies are characteristic
  • X-linked
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16
Q

Glycogen synthesis and degradation occur primarily in

A
  • the liver and skeletal muscle,

- although other tissues (including cardiac muscle and the kidney) store smaller quantities

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17
Q
  • Glycogen is stored in the ____

- as either ______ or ______

A

Glycogen is stored in the cytoplasm as either:

  • single granules (skeletal muscle) or
  • clusters of granules (liver)
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18
Q

in white muscle fibers, the glucose is converted primarily to

A

lactate

  • white muscle fibers are “fast-twitch”
  • in red (slow-twitch) muscle fibers the glucose is completely oxidized
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19
Q
  • Synthesis of glycogen granules begins with a core of
  • glucose addition to the granule begins with
  • steps of glycogen metabolism
A
  • core protein glycogenin
  • glucose addition to the granule begins with Glucose 6P
  • which is converted to Glucose 1P and
  • activated to UDP-glucose for addition to the glycogen chain by glycogen synthase
  • glycogen synthase is the rate-limiting enzyme of glycogen synthesis
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20
Q
  • Glycogen Synthase in the liver is activated by

- is inhibited by

A
  • insulin

- glucagon and epinephrine

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21
Q

Step 1 of Glycogen Metabolism

A
  • Glucose is converted to Glucose 6P by Glucokinase
  • phosphorylating Glucose traps it in the cell
  • this occurs in the liver
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22
Q

Step 2 of Glycogen Metabolism

A
  • Glucose 6P is converted to Glucose 1P by a mutase
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23
Q
  • Glycogen Synthase in skeletal muscle is activated by

- is inhibited by

A
  • insulin

- epinephrine

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24
Q

Glucose 1P is converted to

A

Glucose 1P is converted to UDP-Glucose

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25
Q

Glycogen is converted back to Glucose 1P by

A
  • glycogen phosphorylase (and debranching enzyme)
  • Glucagon stimulates in liver
  • epinephrine stimulates in liver and muscle
  • AMP stimulates in muscle
  • Glycogen phosphorylase is active when PHOSPHORYLATED
  • Glucagon binds to g-protein coupled receptor –> cAMP –> activates kinase –> phosphorylates glycogen phosphorylase
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26
Q

UDP-Glucose is added to the growing chain by

A
  • Glycogen synthase (and branching enzyme)
  • rate-limiting step in glycogen metabolism
  • active when DE-phosphorylated
  • activated by insulin in liver and muscle
  • Glucagon inhibits (in liver): (Glucagon binds to g-protein coupled receptor –> cAMP –> kinase activated –> glycogen synthase phosphorylated and thus, deactivated
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27
Q

How does Glucagon inhibit glycogen synthase in the liver?

A
  • Glycogen Synthase is active when de-phosphorylated
  • Glucagon binds to g-protein coupled receptor –> cAMP –> activates kinase –> glycogen synthase phosphorylated and thus, deactivated
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28
Q

How does Glycogen Synthase work?

A
  1. glycogen synthase forms a linear alpha 1,4 glycosidic polyglucose chain
  2. branching enzyme hydrolyzes an alpha 1,4 bond to release a block of oligoglucose
  3. branching enzyme transfers that unit to a different location and attaches it with an alpha 1,6 bond (to create a branch)
  4. Glycogen synthase extends both branches
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29
Q

How is Glycogen phosphorylase controlled?

A
  • Glycogen phosphorylase is active when PHOSPHORYLATED
  • Glucagon binds to g-protein coupled receptor –> cAMP –> activates kinase –> phosphorylates glycogen phosphorylase
  • Glucose 1P is converted back to Glucose 6P by a mutate
  • GLucose 6P is converted to Glucose by Glucose 6-Phosphatase (found in the liver)
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30
Q

How does Glucagon stimulate glycogenolysis in the liver?

A
  • glycogen phosphorylase (and debranching enzyme) convert Glycogen back to Glucose 1P
  • a phosphorylase breaks bonds using Pi rather than H20
  • Glycogen phosphorylase breaks alpha 1,4 bonds, releasing Glucose 1P from the periphery of the granule.
  • can’t break alpha 1,6 bonds, so it stops when it reaches the outermost branch points
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31
Q
  • Glycogen Phosphorylase in the liver is activated by

- inhibited by

A
  • activated by epinephrine and glucagon

- inhibited by insulin

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32
Q

Important substrates for gluconeogenesis are:

A
  • glycerol 3P (from TG in adipose)
  • lactate (from anaerobic glycolysis)
  • gluconeogenic AA (protein from muscle, Alanine is the major gluconeogenic AA)
  • although Alanine is the major gluconeogenic AA, 18 of the 20 (all but leucine and lysine) are also gluconeogenic
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33
Q

Ketogenic AA

A
  • leucine and lysine
  • ketogenic amino acid is an amino acid that can be degraded directly into acetyl-CoA, ( = precursor of ketone bodies)
  • glucogenic amino acids (converted into glucose)
  • All AA that are NOT either ketogenic or both ketogenic and glucogenic are glucogenic
  • ALL AA are glucogenic EXCEPT leucine and lysine
34
Q
  • Glycogen Phosphorylase in skeletal muscle is activated by

- inhibited by

A
  • activated by epinephrine, AMP, Ca2+ (through calmodulin)

- inhibited by insulin, ATP

35
Q

Ketogenic and Glucogenic AA

A
  • phenylalanine
  • tyrosine
  • tryptophan
  • isoleucine
  • threonine
  • ketogenic amino acid is an amino acid that can be degraded directly into acetyl-CoA, ( = precursor of ketone bodies)
  • glucogenic amino acids (converted into glucose)
36
Q

Von Gierke’s Disease

  • deficient enzyme
  • glycogen structure
  • clinical features
A
  1. AKA glycogen storage disease Type 1
    - prevents conversion of G6P to glucose
  2. deficient in Glucose 6 phosphatase
  3. glycogen structure normal
  4. Clinical Features: severe hypoglycemia bc G6Ptase is supposed to convert G6P to glucose
    - lactic acidosis
    - hepatomegaly (glycogen deposits in liver bc G6P stimulates glycogen synthesis and glycogenolysis is inhibited)
    - hyperlipidemia with skin xanthomas; elevation of VLDL
    - fatty liver
    - hyperuricemia predisposing to gout (decreased Pi causes increased AMP, which is degraded to uric acid. Lactate shows uric acid excretion in the kidney)
    - short stature
    - doll-like facies
    - protruding abdomen (hepatomegaly)
    - emaciated extremities
37
Q

Pompe Disease

  • deficient enzyme
  • glycogen structure
  • clinical features
A
  1. AKA glycogen storage disease Type II
  2. deficient in lysosomal alpha 1,4 glucosidase
    - responsible for digesting glycogen-like material accumulating in endosomses
  3. glycogen-like material in inclusion bodies
    - tissues most severely affected are those that normally have glycogen stores (liver, muscle)
    - affects the pump –> cardiomegaly
  4. Clinical features: cardiomegaly
    - muscle weakness (progressing, can affect breathing)
    - hepatomegaly
    - Muscle biopsy would show degeneration and many prominent lysosomes filled with clusters of electron-dense granules
    - death by 2 years
    - Tx: enzyme replacement therapy
38
Q

Cori Disease

  • deficient enzyme
  • glycogen structure
  • clinical features
A
  1. AKA glycogen storage disease Type III
  2. deficient in glycogen debranching enzyme
  3. glycogen structure: shorter branches, single glucose residue at outer branch (alpha 1,6)
    - C#1 bound to C#6 of the next molecule
  4. clinical features: mild hypoglycemia
    - enlarged liver
39
Q

Andersen Disease aka (amylopectinosis)

  • deficient enzyme
  • glycogen structure
  • clinical features
A
  1. AKA glycogen storage disease Type IV
  2. deficient in branching enzyme
  3. glycogen structure: very few branches, especially toward periphery
  4. clinical features: infantile hypotonia
    - cirrhosis
    - death by 2 years (if no tx)
40
Q

McArdle Disease

  • deficient enzyme
  • glycogen structure
  • clinical features
A
  1. AKA glycogen storage disease Type V
  2. Deficient in muscle glycogen phosphorylase (aka myophosphorylase)
    - there’s a decrease ONLY in glycogen metabolism in muscle
    - can’t break down glycogen to Glucose 6P therefore can’t get energy from muscle glycogen stores
  3. glycogen structure: normal
  4. clinical features: muscle cramps and weakness on initial phase of high-intensity exercise
    - myoglobinuria = pathological state
    - accumulated glycogen in muscle biopsy.
    - NO increase in lactic acid in blood as would normally see
    - recovery or “second wind” after 10-15 mins of exercise
    - glycogen is utilized first by muscles as a source of energy
    - without an adequate supply of glucose, sufficient energy via glycolysis for carrying out muscle contraction can’t be obtained
    - so patients will have muscle cramps after few seconds of starting the exercise.
    - may be improved by drinking a sucrose-containing drink, which provides dietary glucose for muscles to use.
    - But once beta oxidation kicks (muscles use more FA and less glucose for energy) in they will experience the classical “second wind”.
  • can be confused with myopathic CAT deficiency. deficiency, both present with muscle cramps with exercise and myoglobinuria
41
Q

Hers Disease

  • deficient enzyme
  • glycogen structure
  • clinical features
A
  1. AKA glycogen storage disease Type Vi
    - prevents conversion of glycogen to G6P
  2. deficient in hepatic glycogen phosphorylase
  3. glycogen structure: normal
  4. clinical features: mild fasting hypoglycemia bc gluconeogenesis in the liver maintains blood glucose
    - hepatomegaly
    - cirrhosis
42
Q

Why do you get severe hypoglycemia with Von Gierke’s but not with Hers?

A
  • Von Gierke’s prevents conversion of G6P to glucose
  • Hers prevents conversion of glycogen to G6P, but you can still get G6P from Gluconeogenesis
  • thus Gluconeogenesis –> G6P –> Glucose
43
Q

Difference between McArdle’s and myopathic carnitine acyl transferase (CAT) deficiency

A
  • both present with muscle cramps with exercise and myoglobinuria
  • McArdle you have difficulty in the beginning of the exercise
  • while in myopathic carnitine acyl transferase (CAT) deficiency you have a problem after a prolonged exercise.
  • glycogen is utilized first by muscles as a source of energy so in McArdle you have a problem in the beginning and patients will have muscle cramps after few seconds of starting the exercise.
  • But once beta oxidation kicks in they will experience the classical “second wind”.
  • While in Muslce carnitine deficiency you have a problem later on when FA oxidation is needed.
  • In muscle carnitine you’ll see accumulated TG in biopsy
  • in McArdle (also called Type V glycogen storage disease) you will have accumulated glycogen in muscle biopsy.
44
Q

In a person with Glucose 6 phosphatase deficiency, ingestion of galactose or fructose causes

A
  • In a person with Glucose 6 phosphatase deficiency, ingestion of galactose or fructose causes:
  • no increase in blood glucose
  • nor does administration of glucagon or epinephrine
45
Q

What enzyme converts Glucose to Glucose 6P

A
  • glucokinase
  • irreversible step of glycolysis
  • requires ATP
  • Glucose 6P is trapped in the liver
46
Q

What enzyme converts Glucose 6P to Glucose?

A
  • Glucose 6-Phosphatase
  • reversible
  • Glucose 6P is trapped in the liver
47
Q

Where does a fasting liver get acetyl CoA?

A
  • beta-oxidation of FA –> Acetyl CoA
  • Acetyl CoA then inhibits pyruvate dehydrogenase and stimulates pyruvate carboxylase (mitochondria)
  • when PDH is inhibited, pyruvate is converted into OAA (mitochondria)
  • OAA then enters the cytoplasm
  • OAA –> PEP –> Glyceraldehyde 3P –> Fructose 1,6 BP –> Fructose 6P –> Glucose 6P –> Glucose
  • Remember: The liver can convert Glucose to FA, but can’t convert FA back to Glucose
  • Acetyl CoA is made from Pyruvate by Pyruvate Dehydrogenase. This is an irreversible step.
  • However, Acetyl CoA from FA can help induce gluconeogenesis stimulating pyruvate carboxylase
  • and can be converted to ketone bodies as an alternative fuel for cells
48
Q

In a fasting liver mitochondria, pyruvate is converted to

A
  • OAA
  • OAA can’t leave the mitochondria but is reduced to malate and exits via the malate shuttle
  • in the cytoplasm malate is deoxidized to OAA
  • OAA –> PEP –> Glyceraldehyde 3P –> Fructose 1,6 BP –> Fructose 6P –> Glucose 6P –> Glucose
  • Remember: The liver can convert Glucose to FA, but can’t convert FA back to Glucose.
49
Q
  1. Symptoms of Biotin deficiency

2. cause

A
  1. Sx
    - alopecia
    - scaly dermatitis
    - waxy pallor
    - acidosis (mild)
  2. causes:
    - MCC = raw egg whites (avidin)
    - long-term TPN
50
Q

Phosphoenolpyruvate carboxykinase (PEPCK)

A
  • found in the cytoplasm
  • enzyme involved in guconeogenesis
  • Converts OAA to PEP
  • induced by glucagon and cortisol (secreted when blood sugar is low to induce gluconeogenesis)
  • regulated at a genetic level
  • requires GTP, gives off CO2
  • OAA –> PEP –> Glyceraldehyde 3P –> Fructose 1,6 BP –> Fructose 6P –> Glucose 6P –> Glucose
  • Remember: Pyruvate Kinase converts PEP to Pyruvate. but this is an irreversible step! So a new pathway involving OAA was required.
  • Also, Acetyl CoA CAN’T be converted to Glucose
  • but it IS required to stimulate OAA synthesis from Pyruvate
51
Q

Fructose 1,6 bisphosphatase

A
  • enzyme involved in guconeogenesis
  • found in the cytoplasm
  • converts Fructose 1,6 BP to Fructose 6P
  • hydrolyzes P from fructose 1,6 BP rather than using it to generate ATP from ADP
  • Activated by ATP
  • induced by glucagon and cortisol
  • inhibited by AMP
  • Inhibited by Fructose 2,6BP (product of PFK-2; glucagon inhibits PFK-2)
  • Remember: PFK-1 converts Fructose 6P to Fructose 1,6 BP
52
Q

Glucose 6 Phosphatase

A
  • enzyme involved in guconeogenesis
  • found in the lumen of the endoplasmic reticulum
  • Found ONLY in the liver
  • converts Glucose 6P to Glucose
  • Glucose 6P is transported into the ER, and free glucose is transported back into the cytoplasm (and from there can leave the cell)
  • the absence of G6Phosphatase in skeletal muscle accounts for the fact that muscle glycogen cannot serve as a source of blood glucose.
53
Q

Pyruvate Carboxylase

A
  • mitochondrial enzyme involved in gluconeogenesis
  • converts Pyruvate to OAA
  • Requires ABC:
    A: ATP
    B: Biotin
    C: Co2
  • activated by Acetyl CoA (from beta oxidation)
  • (FA –> Acetyl CoA, which inhibits pyruvate dehydrogenase and stimulates pyruvate carboxylase)
  • OAA can’t leave the mitochondria but is reduced to malate and exits via the malate shuttle
  • in the cytoplasm malate is deoxidized to OAA
54
Q

Phosphatases Oppose

A
  • Kinases
    Ex 1. fructose 1,6 bisphosphatase opposes PFK-1
  • F16BPtase: F16BP to F6P
  • PFK-1: F6P to F16BP
    Ex 2. glucose 6 phosphatase opposes Glucokinase
  • G6Ptase: G6P to Glucose
  • Glucokinase: Glucose to G6P (trapping glucose in liver)
55
Q

Fructose 2,6 bisphosphate

  • product of
  • controls
A
  • produced by PFK-1 in the liver
  • controls both gluconeogenesis and glycolysis in the liver
  • PFK-2 is activated by insulin and inhibited by glucagon
  • thus, glucagon will lower F2,6BP and stimulate gluconeogenesis
  • insulin will increase F2,6BP and inhibit gluconeogenesis (bc F2,6BP inhibits F1,6BP)
56
Q

Glycogen is stored in muscle, but why can’t muscle glycogen serve as a source of blood glucose?

A
  • Glucose 6Phosphatase is the enzyme that converts G6P back to free Glucose.
  • it is ONLY located in the ER of liver cells
  • G6P is trapped inside the cell
  • the absence of G6Phosphatase in skeletal muscle accounts for the fact that muscle glycogen cannot serve as a source of blood glucose.
57
Q

Is glucose produced by hepatic gluconeogenesis an energy source for the liver?

A
  • NO!
  • gluconeogenesis costs 1 ATP
  • this ATP is provided by beta-oxidation of FA
  • so, hepatic gluconeogenesis is always dependent on beta-oxidation of FA in the liver
  • During hypoglycemia, adipose tissue releases these FA by breaking down TG
58
Q

Can Acetyl CoA be converted to glucose?

A
  • NO
  • Acetyl CoA is made from Pyruvate by Pyruvate Dehydrogenase. This is an irreversible step.
  • However, Acetyl CoA from FA can be converted to ketone bodies as an alternative fuel for cells
  • Also, Acetyl CoA from FA can help induce gluconeogenesis by stimulating pyruvate carboxylase
  • chronic hypoglycemia is accompanied by an increase in ketone bodies
59
Q

What 2 major mitochondrial enzymes use Pyruvate?

A
  • pyruvate carboxylase and pyruvate dehydrogenase

- both are regulated by acetyl-coA

60
Q

Role of Acetyl CoA in a fasting state

A
  • between meals, when FA are oxidized in the liver for energy, Acetyl CoA accumulates
  • Acetyl CoA activates pyruvate carboxylase and gluconeogenesis
  • and inhibits Pyruvate dehydrogenase, thus preventing conversion of lactate and alanine to acetyl-coA
61
Q

Role of Acetyl CoA in a well-fed state

A
  • accumulating acetyl CoA is shuttled into the cytoplasm for FA synthesis
  • OAA is necessary for this transport
  • Acetyl CoA stimulates the formation of OAA from Pyruvate by activating pyruvate carboxylase
62
Q

What is the Cori Cycle

A

during fasting, lactate from RBC (or possibly exercising skeletal muscle) is converted in the liver to glucose

  • this glucose can then be returned to the RBC or muscle
  • summary: Lactate from RBC goes to liver
  • in liver: Lactate –> glucose –> goes back to RBC
63
Q
  • Alcoholics are very susceptible to hypoglycemia. Why?
A
  • alcohol is metabolized to Acetate
  • the high [cytoplasmic NADH] formed by ADH and acetaldehyde dehydrogenase interfere with gluconeogenesis
  • High [NADH] favors the formation of:
    1. lactate from pyruvate
    2. malate from OAA in the cytoplasm
    3. Glycerol 3P from DHAP
  • the effect is to divert important gluconeogenic substrates from entering the pathway
64
Q

What is the Alanine Cycle?

A
  • similar to the Cori Cycle
  • muscle releases Alanine, delivering both a gluconeogenic substrate (pyruvate) and an amino group for urea synthesis to the liver
65
Q

High [NADH] favors the formation of

A
  • lactate from pyruvate
  • malate from OAA in the cytoplasm
  • Glycerol 3P from DHAP
  • the effect is to divert important gluconeogenic substrates from entering the pathway
66
Q

Alcohol Metabolism

A
  1. Alcohol Dehydrogenase converts Alcohol to Acetaldehyde
    - acetaldehyde is what causes a hangover, staggering
    - reduces NAD to NADH (can go into the ETC)
    - ADH is inhibited by Fomepizole (used in emergency medicine when someone drinks methanol
  2. Acetaldehyde Dehydrogenase converts Acetaldehyde to Acetate
    - reduces NAD to NADH (can go into the ETC)
    - Acetaldehyde dehydrogenase can be inhibited by disulfiram
67
Q

Mechanism by which alcohol metabolism may contribute to lipid accumulation in alcoholic liver disease

A
  • The metabolism of Alcohol produces NADH
  • high [NADH] favors formation of Glycerol 3P from DHAP
  • accumulation of cytoplasmic NADH and Glycerol3P may also contribute to lipid accumulation in alcoholic liver disease
  • FFA released from adipose in part enter the liver where beta-oxidation is very slow (bc of the high NADH)
  • in the presence of high Glycerol 3P, FA are inappropriately stored in the liver as TG
68
Q
  • What happens if a marathoner (or anyone completing extreme exercise) consumes alcohol?
A
  • They’ll develop metabolic acidosis and hypoglycemia
  • Sx: will become very weak and lightheaded
  • muscle cramping and pain
  • when engaging in extreme exercise you become extremely dehydrated and thirsty
  • but bc of the exercise they’re already at risk for lactic acidosis bc lactic acid has built up due to anaerobic glycolysis. This causes cramping and pain.
  • lactate spills into the blood and is converted to glucose in the liver as part of the Cori cycle
  • but to carry out gluconeogenesis, NAD is required by LDH to oxidize lactate to pyruvate.
  • when they consume alcohol, the alcohol metabolism will consume their NAD that is needed to convert lactate to pyruvate
  • it takes approx 1 hour to get rid of lactate in the blood
69
Q

Why shouldn’t a marathoner drink alcohol?

A
  • when engaging in extreme exercise you become extremely dehydrated and thirsty
  • but bc of the exercise they’re already at risk for lactic acidosis bc lactic acid has built up due to anaerobic glycolysis. This causes cramping and pain.
  • lactate spills into the blood and is converted to glucose in the liver as part of the Cori cycle
  • but to carry out gluconeogenesis, NAD is required by LDH to oxidize lactate to pyruvate.
  • when they consume alcohol, the alcohol metabolism will consume their NAD that is needed to convert lactate to pyruvate
  • thus they’ll have Sx: weakness, lightheadedness, muscle cramping and pain in addition to metabolic acidosis and hypoglycemia
  • it takes approx 1 hour to get rid of lactate in the blood
70
Q

AHD

  • catalyzes
  • inhibited by
A
  • Alcohol to Acetaldehyde
  • inhibited by Fomepizole (given in EM when someone drinks methanol)
  • reduces NAD to NADH
71
Q

When Hb levels drop below __ you give a transfusion

A

When Hb is less than 8 you transfuse

72
Q

Functions of NADPH (don’t confuse with NADH)

A
  • FA synthesis
  • steroid synthesis
  • NT synthesis
  • deoxynucleotide synthesis
  • maintaining reduced glutathione in RBC
  • bactericidal activity (PMNs) via superoxide synthesis
73
Q

Acetaldehyde Dehydrogenase

  • catalyzes
  • inhibited by
A
  • Acetaldehyde to Acetate
  • inhibited by disulfiram
  • reduces NAD to NADH
74
Q

Chronic Granulomatous Disease

  • MCC
  • risks associated
  • Diagnosis
A
  • MCC by genetic deficiency of NADPH oxidase in the PMN
  • susceptible to infection by catalase-positive organisms:
  • Staph aureus
  • Klebsiella
  • E. Coli
  • Candida
  • Aspergillus
  • a negative nitroblue tetrazolium test is useful in confirming the diagnosis
75
Q

Why G6PDH deficiency give protection against malaria?

A
  • in G6PDH, the ability of RBC to detoxify oxygen radicals is impaired, so they accumulate
  • the accumulation of radicals in RBC is what gives these patients protection against malaria
  • bc plasmodium is deficient in antioxidant mechanisms, making it particularly susceptible to oxygen radicals
76
Q

Role of the HMP shunt in neutrophils

A
  • produces pentose phosphates (make nucleotides)
  • G6PDH also produces NADPH
  • NADPH acts as an electron donor
  • NADPH oxidase converts NADPH back to NADP+
  • NADPH oxidase transfers this electron to superoxide (O2-) to make H2O2
  • this H2O2 is used to kill bacteria
  • NADPH oxidase is defective in chronic granulomatous disease
77
Q

Role of the HMP shunt in RBC (erythrocytes)

A
  • produces pentose phosphates (make nucleotides)
  • G6PDH also produces NADPH
  • NADPH acts as an electron donor
  • Glutathione reductase ruses the electron from converting NADPH back to NADP+ to reduce glutathione (GSSH –> 2GSH)
  • Glutathione Peroxidase (Se) Oxidizes reduced glutathione (2GSH) back to GSSH.
  • in RBC O2 spontaneously turns into H2O2
  • Glutathione Peroxidase oxidizes glutathione to convert toxic H2O2 to H2O
  • thus, glutathione reductase regenerates the required reduced glutathione using NADPH
  • oxidant stresses can cause H2O2 to accumulate
  • Ex) fava beans (BIG ON EXAM)
  • Ex) Drugs (ie Sulfonamides, TMP/SMX, quinine)
  • Ex) infection
  • these will cause serious reaction in someone with G6PDH deficiency
  • if H2O2 accumulates it can cause Hb denaturation = Heinz bodies
  • Heinz bodies: see hyperpigmented Hb at periphery of RBC
  • Accumulated H2O2 can also cause membrane damage –> hemolytic anemia
78
Q

MCC of hemolytic episode in a pt with G6PDH deficiency in the US

A

overwhelming infection:

  • ie pneumonia (bacterial or viral) or
  • infectious hepatitis
79
Q

G6PD function

A
  • part of HMP shunt
  • converts Glucose 6P –> 6-phosphogluconate
  • reduces NADP –> NADPH
  • insulin and NADP activate G6PD
  • NADPH inhibits G6PD
  • 6-phosphogluconate then converted into ribulose 5P by 6 Phosphogluconate Dehydrogenase (also reduces NADP –> NADPH and releases CO2)
  • x-linked gene
80
Q

Transketolase (TPP)

A
  • requires thiamine (only thiamine-requiring enzyme in RBC)
  • important for interconversions btw:
  • Fructose 6P other sugars Ribose 5P
  • glyceraldehyde 3P other sugars Ribose 5P
  • Thiamine also required for α-ketoglutarate dehydrogenase, branched-chain α-ketoacid dehydrogenase, pyruvate dehydrogenase and transketolase
81
Q

6 Phosphogluconate Dehydrogenase

A
  • converts 6 Phosphogluconate –> ribulose 5P in the HMP shunt and reduces NADP –> NADPH
  • NADPH used for biosynthesis (liver) or generating superoxide to kill bacteria (neutrophil) and for protecting RBC membranes from oxidative damage and hemolysis

Kaplan Biochem and Genetics (21 decks)

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