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
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
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
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
28
Q
How does Glycogen Synthase work?
A
- glycogen synthase forms a linear alpha 1,4 glycosidic polyglucose chain
- branching enzyme hydrolyzes an alpha 1,4 bond to release a block of oligoglucose
- branching enzyme transfers that unit to a different location and attaches it with an alpha 1,6 bond (to create a branch)
- Glycogen synthase extends both branches
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)
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
31
Q
- Glycogen Phosphorylase in the liver is activated by
- inhibited by
A
- activated by epinephrine and glucagon
- inhibited by insulin
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
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
- AKA glycogen storage disease Type 1
- prevents conversion of G6P to glucose - deficient in Glucose 6 phosphatase
- glycogen structure normal
- 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
- AKA glycogen storage disease Type II
- deficient in lysosomal alpha 1,4 glucosidase
- responsible for digesting glycogen-like material accumulating in endosomses - glycogen-like material in inclusion bodies
- tissues most severely affected are those that normally have glycogen stores (liver, muscle)
- affects the pump –> cardiomegaly - 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
- AKA glycogen storage disease Type III
- deficient in glycogen debranching enzyme
- glycogen structure: shorter branches, single glucose residue at outer branch (alpha 1,6)
- C#1 bound to C#6 of the next molecule - clinical features: mild hypoglycemia
- enlarged liver
39
Q
Andersen Disease aka (amylopectinosis)
- deficient enzyme
- glycogen structure
- clinical features
A
- AKA glycogen storage disease Type IV
- deficient in branching enzyme
- glycogen structure: very few branches, especially toward periphery
- clinical features: infantile hypotonia
- cirrhosis
- death by 2 years (if no tx)
40
Q
McArdle Disease
- deficient enzyme
- glycogen structure
- clinical features
A
- AKA glycogen storage disease Type V
- 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 - glycogen structure: normal
- 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
- AKA glycogen storage disease Type Vi
- prevents conversion of glycogen to G6P - deficient in hepatic glycogen phosphorylase
- glycogen structure: normal
- 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
- Symptoms of Biotin deficiency
2. cause
A
- Sx
- alopecia
- scaly dermatitis
- waxy pallor
- acidosis (mild) - 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
- 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 - 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
