Glygocen, Gluconeogenesis and the HMP Shunt Flashcards
1
Q
Glycogen metabolism occurs in the
A
cytoplasm
2
Q
the rate-limiting enzymes of glycogen metabolism are
A
- glycogen synthesis: glycogen synthase
- activated by insulin in liver and muscle - 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
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
4
Q
Glucose Deficiencies:
A
- G6PD
- Hepatic glycogen phosphorylase deficiency
- muscle glycogen phosphorylase deficiency
- lysosomal alpha 1,4-glucosidase deficiency
5
Q
Where does gluconeogenesis occur?
A
- the cytoplasm and the mitochondria
- predominantly in the liver
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)
7
Q
What is the controlled enzyme of gluconeogenesis?
A
- 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)
8
Q
Pyruvate Carboxylase
A
- involved in gluconeogenesis
- activated by acetyl CoA from beta-oxidation
- biotin
- in the mitochondria
9
Q
Phosphoenolpyruvate carboxykinase (PEPCK)
A
- involved in gluconeogenesis
- in the cytoplasm
- induced by glucagon and cortisol
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
11
Q
Glucose 6-Phosphatase (Endoplasmic Reticulum)
A
- only in the liver
- involved in gluconeogenesis
- required to release free glucose from tissue
12
Q
Where does the Hexose Monophosphate Shunt occur?
A
in the cytoplasm of most cells
13
Q
What are the functions of the Hexose Monophosphate Shunt?
A
- generates NADPH
- produces sugars for biosynthesis (ribose 5P for nucleotides)
14
Q
What are the rate-limiting enzymes of the HMP?
A
- Glucose 6 Phosphate Dehydrogenase
- inhibited by NADPH
- induced by insulin in liver
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
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
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)
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
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
20
Q
- Glycogen Synthase in the liver is activated by
- is inhibited by
A
- insulin
- glucagon and epinephrine
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
22
Q
Step 2 of Glycogen Metabolism
A
- Glucose 6P is converted to Glucose 1P by a mutase
23
Q
- Glycogen Synthase in skeletal muscle is activated by
- is inhibited by
A
- insulin
- epinephrine
24
Q
Glucose 1P is converted to
A
Glucose 1P is converted to UDP-Glucose
25
Glycogen is converted back to Glucose 1P by
- 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
26
UDP-Glucose is added to the growing chain by
- 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
27
How does Glucagon inhibit glycogen synthase in the liver?
- Glycogen Synthase is active when de-phosphorylated
- Glucagon binds to g-protein coupled receptor --> cAMP --> activates kinase --> glycogen synthase phosphorylated and thus, deactivated
28
How does Glycogen Synthase work?
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
29
How is Glycogen phosphorylase controlled?
- 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)
30
How does Glucagon stimulate glycogenolysis in the liver?
- 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
31
- Glycogen Phosphorylase in the liver is activated by
| - inhibited by
- activated by epinephrine and glucagon
| - inhibited by insulin
32
Important substrates for gluconeogenesis are:
- 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
33
Ketogenic AA
- 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
- Glycogen Phosphorylase in skeletal muscle is activated by
| - inhibited by
- activated by epinephrine, AMP, Ca2+ (through calmodulin)
| - inhibited by insulin, ATP
35
Ketogenic and Glucogenic AA
- 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
Von Gierke's Disease
- deficient enzyme
- glycogen structure
- clinical features
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
Pompe Disease
- deficient enzyme
- glycogen structure
- clinical features
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
Cori Disease
- deficient enzyme
- glycogen structure
- clinical features
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
Andersen Disease aka (amylopectinosis)
- deficient enzyme
- glycogen structure
- clinical features
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
McArdle Disease
- deficient enzyme
- glycogen structure
- clinical features
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
Hers Disease
- deficient enzyme
- glycogen structure
- clinical features
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
Why do you get severe hypoglycemia with Von Gierke's but not with Hers?
- 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
Difference between McArdle's and myopathic carnitine acyl transferase (CAT) deficiency
- 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
In a person with Glucose 6 phosphatase deficiency, ingestion of galactose or fructose causes
- 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
What enzyme converts Glucose to Glucose 6P
- glucokinase
- irreversible step of glycolysis
- requires ATP
- Glucose 6P is trapped in the liver
46
What enzyme converts Glucose 6P to Glucose?
- Glucose 6-Phosphatase
- reversible
- Glucose 6P is trapped in the liver
47
Where does a fasting liver get acetyl CoA?
- 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
In a fasting liver mitochondria, pyruvate is converted to
- 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
1. Symptoms of Biotin deficiency
| 2. cause
1. Sx
- alopecia
- scaly dermatitis
- waxy pallor
- acidosis (mild)
2. causes:
- MCC = raw egg whites (avidin)
- long-term TPN
50
Phosphoenolpyruvate carboxykinase (PEPCK)
- 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
Fructose 1,6 bisphosphatase
- 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
Glucose 6 Phosphatase
- 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
Pyruvate Carboxylase
- 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
Phosphatases Oppose
- 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
Fructose 2,6 bisphosphate
- product of
- controls
- 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
Glycogen is stored in muscle, but why can't muscle glycogen serve as a source of blood glucose?
- 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
Is glucose produced by hepatic gluconeogenesis an energy source for the liver?
- 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
Can Acetyl CoA be converted to glucose?
- 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
What 2 major mitochondrial enzymes use Pyruvate?
- pyruvate carboxylase and pyruvate dehydrogenase
| - both are regulated by acetyl-coA
60
Role of Acetyl CoA in a fasting state
- 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
Role of Acetyl CoA in a well-fed state
- 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
What is the Cori Cycle
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
- Alcoholics are very susceptible to hypoglycemia. Why?
- 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
What is the Alanine Cycle?
- 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
High [NADH] favors the formation of
- 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
Alcohol Metabolism
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
Mechanism by which alcohol metabolism may contribute to lipid accumulation in alcoholic liver disease
- 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
- What happens if a marathoner (or anyone completing extreme exercise) consumes alcohol?
- 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
Why shouldn't a marathoner drink alcohol?
- 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
AHD
- catalyzes
- inhibited by
- Alcohol to Acetaldehyde
- inhibited by Fomepizole (given in EM when someone drinks methanol)
- reduces NAD to NADH
71
When Hb levels drop below __ you give a transfusion
When Hb is less than 8 you transfuse
72
Functions of NADPH (don't confuse with NADH)
- FA synthesis
- steroid synthesis
- NT synthesis
- deoxynucleotide synthesis
- maintaining reduced glutathione in RBC
- bactericidal activity (PMNs) via superoxide synthesis
73
Acetaldehyde Dehydrogenase
- catalyzes
- inhibited by
- Acetaldehyde to Acetate
- inhibited by disulfiram
- reduces NAD to NADH
74
Chronic Granulomatous Disease
- MCC
- risks associated
- Diagnosis
- 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
Why G6PDH deficiency give protection against malaria?
- 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
Role of the HMP shunt in neutrophils
- 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
Role of the HMP shunt in RBC (erythrocytes)
- 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
MCC of hemolytic episode in a pt with G6PDH deficiency in the US
overwhelming infection:
- ie pneumonia (bacterial or viral) or
- infectious hepatitis
79
G6PD function
- 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
Transketolase (TPP)
- 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
6 Phosphogluconate Dehydrogenase
- 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
