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PHGY 313 > Pincez > Flashcards

Pincez Flashcards

1
Q

What are 2 possible solutions to the problem that passive diffusion is poorly effective to bring O2 from lungs to tissues and to extract CO2 from tissues to lungs?

A
  1. Dramatically increase Cardiac Output (from 5 L/min → 166 L/min at rest and up to 1600 L/min at exercise)
  2. Highly adaptable oxygen-carrying molecule transported through the blood flow (Hemoglobin)
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2
Q

What are the major roles of Hemoglobin in vertebrates?

A
  1. Transport molecular oxygen inside red blood cells in support of aerobic cellular metabolism

*Also major role in CO2 extraction

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3
Q

How effective is Hemoglobin at carrying O2?

A

Solubility coefficient aO2 for human plasma = 3mL of O2/L (at PO2 = 100 mmHg)

Hb binds 1.34mL of Oxygen/ gram of protein
5–70-fold increase of blood capacity in oxygen (i.e. oxyphoric power)

*Hb should be adaptable and robust → can bind O2 in high PO2 environments, but release it in low PO2 environments and adapt to the needs of the organism (still be able to bind O2 in not so high PO2)

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4
Q

How many Hb molecules/RBC?
What is its moelcular weight?
What is its concentration in the blood in adults?

A

~280 million Hb molecules/RBC
- Molecular weight = 64,500 Da

Hb concentration in adults = 120-150g/L

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5
Q

What different subunits form a hemoglobin molecule (not talking about the chains)?

A
  1. Porphyrin ring + Fe2+ → Heme
  2. Heme + Globin chain → Hemoglobin subunit
  3. Hemoglobin subunit x4 → Hemoglobin tetramer

Total:
- 4 globin chains + 4 heme molecules + 4 Fe+ molecule → 4 O2 binding sites

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6
Q

What are the 2 families of globin chains?

A

a-chains

Non a-chains, mainly:
- b-chains > 95% of hemoglobin in adult
- g-chain, 1.5-3.5% of hemoglobin in adult
- y0chain in foetus and newborn

1 Hemoglobin tetramer = 2x a-chains + 2x non-a-chains
*Hb heterotetramer = more homodimer of 2 heterodimers
- Strong interaction between a1 and b1 chains (and a2 and b2 chains)
- Weak interaction between a1 and b2 chains (and a2 and b1 chains)

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7
Q

What is the chain composition of Hemoglobin A, Hemoglobin A2 and Hemoglobin F?

A

Hemoglobin A (adult hemoglobin) = a2b2

Hemoglobin A2 = a2g2

Hemoglobin F (fetal hemoglobin) = a2y2

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8
Q

What is the structure of Heme like, more precisely?

A

Heme = Porphyrin ring + Fe2+

  • Porphyrin ring holds a central iron ion which role is to carry O2 (Fe interacts with the N residues)
  • Must be in Fe2+ state and not Fe3+ to carry O2
    → Hemoglobin with Fe3+ is called Methemoglobinemia, which is a disease state
  • O2 tends to oxydate iron onto Fe3+
  • Globin chain protects heme from oxydative stress
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9
Q

What is Hemoglobin with Fe3+ is called?

A

Methemoglobinemia, which is a disease state

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10
Q

How does O2 binding change the conformation of hemoglobin?

A

O2 binding pulls iron and flattens the heme → ultimately changes globin conformation

*The globin chain is still sticking out (opposit side from the O2 sticking out) and is pushed in a small angle when O2 binds

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11
Q

How is Hemoglobin allosterically modulated by O2?

A

O2 binding modifies Hb conformation from the T (tense, deoxygenated) → R (relaxed, oxygenated) state

R state (compared to T state):
1. Altered globin conformation
2. Smaller central cavity → no 2,3-BPG binding
- Distance between iron atoms changes when going from T → R state
3. High affinity to O2 compare to T state

*T state = inter-alpha and inter-beta interactions not seen in R state

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12
Q

How is cooperativity a characteristic of hemoglobin?

A

O2 binding at one Hb subunit increases the affinity of other Hb subunits
*By allosteric modulation

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13
Q

What are the different allosteric regulators of Hb?

A

Homotropic (ligand is also a substrate for the enzyme):
- O2 binding

Heterotropic (ligand is not a substrate for the enzyme):
- 2,3-Bisphosphoglycerate (or diphosphoglycerate/2,3-DPG)
- H+
- CO2
- Nitric Oxide

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14
Q

How is the percentage of Hb bount to O2 (oxyhemoglobin) measured?

A

Measured using pulse oximetry
Relies on spectrophotometry
- Emits 2 lights of different wavelength (red/660nm and infrared/910nm)
- Absorbance of each light differ between Hb and HbO2
→ Hb absorbs Red light most
→ HbO2 absorbs Infrared most

*Similar to measure of BOLD signal

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15
Q

What explains the sigmoid shape of the Oxygen-Hemoglobin Dissociation Curve?

A

Cooperativity of Hb (due to allosteric regulators)

Concentration of allosteric regulators swiftly modify the sigmoid shape

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16
Q

What explains left and right shift of the O-Hb dissociation curve?

A

x-axis = PO2 (mm Hg) // y-axis = % saturation

Left shift (higher saturation ate lower PO2):
increased pH, decreased T˚, decrease CO2, decrease 2,3-BPG

Right shift (decreased O2 affinity):
decrease pH, increase T˚, increase CO2, increase 2,3-BPG

*Concentration of allosteric regulators swiftly modify the sigmoid shape of the curve

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17
Q

What is P50?

A

PO2 required to saturates 50% of Hb

P50 is an PO2 (mm Hg)
The higher the P50 is, the lower the affinity is
Allosteric modulators modify the P50 of Hb

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18
Q

How does exercise affect the O2-Hb dissociation curve?

A
  1. T˚ increasing and acid lactic production (decrease pH) → reduces Hb-O2 affinity
  2. Increased O2 utilization, so lower PO2 in tissue

→ Combination of both allow more O2 to be delivered to muscle

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19
Q

How does 2,3-BPG regulate Hb affinity to O2?

A

2,3-BPG is found in RBCs of mammals and some other vertebrates → located in the center of deoxygenated hemoglobin tetramer

2,3-BPG decreases the HbO2 affinity of human Hb dramatically compared to the effects of other allosteric ligands.
- No 2,3-DPG = high affinity to O2 (shifts the curve to the left)

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20
Q

How does the Hb-O2 dissociation curve shift in hypoxia?
What is an example of hypoxia at sea level?

A

Chronic anemia → increases 2,3-BPG

→ Reduces Hb-O2 affinity (increases P50)
→ Allow more O2 to be delivered

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21
Q

What is the major difference between hemoglobin and myoglobin?

A

Myoglobin is the hemoglobin of the muscles
- Higher affinity than Hb
- Stores the O2

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22
Q

What is the difference between Fetal Hemoglobin and adult Hemoglobin?

A
  • Main form of intra-uterine Hb
  • Higher affinity than adult Hb
  • Facilitates the trans-plancental O2 exchange
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23
Q

What are the main hemoglobin disorders?

A

Acquired:
- Carbon monoxide (CO) intoxication
- Methemoglobinemia (only treated in bonus slides
Example: Carboxyhemoglobin

Constitutional/genetic: quantitative and qualitative defects

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24
Q

What is Carboxyhemoglobin?

A

Acquired Hb abnormality:

Hb has ~200 fold more affinity for CO than for O2 Allosteric effect of CO = increasing O2 affinity
=> Not enough O2 release to tissue, leading to hypoxia

In non-smoker, COHb is < 3%
In smoker, up to 15%
Toxicity is also due to direct CO toxicity, notably to mitochondria

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25
Q

What are different constitutional (genetic) hemoglobin disorders?

A

Globin genes variants are extremely frequent (about 7% of the world’s population) The severity associated to is extremely variable

They may lead to:
1. Quantitative production defect:
- thalassemia (cf Hb synthesis regulation lecture)

  1. Qualitative defect leading to:
    -Modifying Hb function: high- and low-affinity variants, HbM
    -Hemolytic anemia: unstable hemoglobins (not treated in this course)
    -Hemoglobin sickling: (cf Hb synthesis regulation lecture)
  2. Nothing…
26
Q

What is the effect of a High-O2 affinity hemoglobin variants?

A

Decreased O2 release to tissue
Compensatory stimulation of erythropoiesis
→ Associated to erythrocytosis (high Hb)

*Red hands/feet

27
Q

What is the effect of a Low-O2 affinity hemoglobin variants?

A

Decreased O2 bound to Hb
→ Associated to cyanosis (high deoxygenated Hb)

*Blue hands

Excepted a few exceptions, does not require any treatment as individuals are adapted to this chronic and steady state

Hb-Hope, a low-O2 affinity variant, has even been associated to greater exercise performance

28
Q

What makes Hb a robust mechanism?

A

It allows to adapt to:
- PO2 environment (lungs/tissues)
- Metabolic requirement (exercise…)
- Pathological states (lung disease…)

*By shifting the curve

29
Q

Which are the 2 main transcription factors responsible for initiation the regulation of Hemoglobin Synthesis?

A

EPO:
- Activate erythropoiesis
- Activate ferrochelatase through phosphorylation → allows incorporation of rion into Heme (final step of Heme synthesis)

GATA1:
- Promotes Heme synthesis
- Promotes Globin transcription → binds to LCR and to promotor making DNA loop

30
Q

Which are the 2 positive feedback loops regulating Hemoglobin synthesis?

A

COMPLETE

31
Q

Which 3 elements are needed in the proper balance for proper Hemoglobin synthesis?

A
  1. Iron
  2. Porphyrin
  3. Globin
32
Q

What are some important features of the Iron Cycle?
How much is in the body at homeostasis?
How much is absorbed? Where is it stored?

A

It is a CLOSED loop with very few inputs/outputs

  • Bulk iron is used in hemoblogin moleculares withing erythrocytes
  • Bulk iron is stored as ferritin molecules in the liver (all cell types, mainly hepatocytes)

Overall iron quantity in the body = 4-5g
1-2mg of iron absorbed daily through duodenum

33
Q

What is the role of Hepcidin in iron homeostasis?

A

Negative feedback of iron stock on iron absorption through hepcidin

High iron stores → hepcidin secretion by the liver → redcues iron absorption (enterocytes), recycling and release (by macrophages and hepatocytes) → to reduce circulating levels

Hepcidin levels can be altered in various hematological conditions (thalassemia)

34
Q

How does Iron regulate protein levels at the translation step?

A
  • Low iron state, IRP binds to IRE
  • High iron state, IRP binds to iron instead of IRE

IRE hairpin structure in mRNA 5’ UTR → IRP prevents translation

IRE hairpin structure in mRNA 5’ UTR → IRP favours translation
- Stabilizes mRNA by preventing RNase to degrade at the 3’ UTR

35
Q

What specific protein is regulated by iron at the translaitonal level?

A

IRE in the 5’ UTR of the ALAS2 gene → Heme synthesis

*Iron overload → more ALAS2 translation → allows 1st step of prophyrin synthesis → use up the iron:
Prophyrin + Iron = Heme

36
Q

What are the 2 main reasons iron would be lacking for erythropoiesis?
*Low levels of circulating iron

A
  1. “Real” Iron deficiency
    - Insufficient intake
    - Chronic/recurrent bleeding
  2. Functional deficiency
    Chronic inflammation → sequestrates iron into macrophages → no release to make it available for erythropoiesis
37
Q

What are the consequences of too much iron?

A

Iron overload leads to hemochromatosis → accumulation of iron in tissue (as ferritin)
- Mainly in liver, heart and endocrine tissues

Can be:
-Constitutional, due to genetic variants: hereditary hemochromatosis
-Acquired, due to high number of red cell transfusions: anemia requiring chronic transfusions

38
Q

What are the 2 main sites of Heme synthesis?
And starting material?

A

Erythrocytes precursors (for hemoglobin)
- Starts in the mitochondria from Succinylcholine-CoA (Krebs cycle) + Glycine (AA)
- Uses ALAS2 (2 genes)

Liver (for cytochrome P450)
- ALAS1 in hepatocytes

*Same Heme molecule

39
Q

What are the 2 main limiting factors for Heme Synthesis in erythrocytes precursors?

A
  1. ALA synthase activity (first step)
    Glycine + Sunccinyl-CoA → ALA
  2. Fe2+ quantity to incorporate to protoporphyrin IX (last step)
    Protoporphyrin IX + Fe2+ → Heme
40
Q

How are ALAS1 and ALAS2 regulated?

A

ALAS1 (hepatocytes) → negatively regulated by heme

ALAS2 (erythrocytes) → insensitive to heme concentration, positively regulated by iron concentration (5’ UTR IRE)
- This allows synthesis of large amount of heme in erythrocytes as long as there is enough iron
- If iron stores are low, heme synthesis is reduced

*Too much or too little ALAS2 activity leads to pathologies:
- Too much activity for the iron content → Accumulation of heme precursors (porphyrins), which are toxic
- Too little activity → Anemia because of insufficient red cell production

41
Q

What are the 2 groups of heme-related pathologies?

A

Porphyria → accumulation of heme precursors (porphyrins)
- Porphyrin accumulation is toxic
- (Very) rare diseases

Sideroblastic anemia → accumulation of iron in erythrocytes precursors

42
Q

What are symptoms of Porphyria?

A

Constitutional variant in one of the heme synthesis enzyme leading to accumulation of porphyrin in the liver (hepatic porphyria) and sometimes erythrocytes (erythropoietic porphyria)

Symptoms depends on the site(s) of accumulation:
- Acute attacks (hepatic) Abdominal pain, vomiting,
hypertension
- Cutaneous lesions (circulating precursors)
- Anemia (erythropoietic)

*Phosphyrins are photosensitive → Urine color changes with light (yellow → red)

43
Q

What is Sideroblastic anemias?

A

heme-related pathology: Accumulation of unused iron in erythrocytes precursors (ring erythroblasts)
- Defect in the incorporation of iron into heme or iron-sulfur cluster

Can be acquired
- Somatic variant (myelodysplastic syndrome)
- Toxic: alcohol, copper deficiency, lead poisoning

Congenital variant

*Very rare diseases
Some variants are also associated with
other clinical features (neurological, myopathy, endocrinologic) as the dysfunctional enzymes can be involved in other pathways (Kreb cycle, etc.)

NB: iron-sulfur cluster are mainly involved in oxido-reduction reactions

44
Q

What are the “structures” of the a-like chains and non-a chains at the DNA level?

A

Two different α-like chains (two genes coding for α) → chromosome 16
MCS - HbZ - Hba1 - Hba1

Four different non-α chains (two genes coding for γ) → chromosome 11
LCR - HbE - Hbg2 - Hbg1 - Hb delta - Hb beta

Gene expression changes throughout development:
COME BACK (slide 27 L6)

45
Q

What are the 4 possibilities of globin chain combinations in embryo?

A
  • delta/epsilon
  • alpha/epsilon
  • delta/gamma
  • delta/beta
    *Always x2 of each to have 4 globin chains
46
Q

What are the 2 possibilities of globin chain combinations in fetus?

A

alpha/delta (hemoglobin F) → largest amount
alpha/beta (hemoglobin A)

47
Q

What are the 3 possibilities of globin chain combinations in adult?

A

alpha/beta (Hemoglobin A) >= 95%
alpha/delta (emoglobin A2) ~ 2.5-3.5%
alpha/gamma (Hemoglobin F) < 1.5% (often undetectable)

48
Q

What are clinical methods to identifiy and often quantifiy the different hemoglobins?

A
  • High-performance liquid chromatography
  • Gel electrophoresis
  • Capillary electrophoresis
49
Q

What regulates Globin expression?

A

LCR (locus control region) drives ß-globin expression
MCS is the equivalent in α locus

LCR is guided by several transcription factors (TF) and coactivators (complex regulation)

GATA1 is a major TF up-regulating globin expression
- Expressed during erythropoiesis

50
Q

How is the switch from y to b globin orchestrated?

A

Switch from γ to ß globin is orchestrated by BCL11A which is synthetized in adults

BCL11A inhibits LCR binding to 5’ γ-chain promoter => increases ß-chain synthesis (can’t transcribe y-chain)

*Fetus don’t have BCL11A, so they have transcription y-chain transcription

51
Q

What does BACH1 regulate? How is it regulated itself?

A

BACH1 binds to LCR → represses b-globin expression

GATA1 promotes Heme synthesis → Heme inhibits BACH1’s binding to LCR → increases b-globin expression

52
Q

How is globin synthesis regulated and the translation level?

A
  1. HRI (Heme-regulated eIF2α kinase) phosphorylates eIF2α
  2. When phosphorylated, eIF2α (P-eIF2α) inhibits globin translation

→ Heme inhibits HRI, thus prevents P-eIF2α-mediated inhibition of translation
*Heme promotes goblin translation

53
Q

What is associated with homozygous state and heterozygous/compound heterozygous state?

A

At heterozygous state, several hemoglobin variants have been associated to malaria protection
- Such as thalassemia variants, Hb S, Hb C, Hb E
→ Extremely prevalent in people whose ancestries are from some malaria-endemic area

At homozygous/compound heterozygous state, some variants are associated to severe diseases
At homozygous/compound heterozygous state, some variants are associated to severe diseases
- Balance skewed towards destruction of RBCs and malaria is already increased RBC death so makes it even worst
- The low prevalance of this phenotype does not counter-balance the advantage of the heterozygous state

54
Q

What is Thalassemia?

A

Constitutional (genetic) quantitative defect in globin synthesis
Genes can be non-functional because of mutations or deletions

2 main types:
- α-thalassemia: 1 to 4 of the 4 α-globin genes is non-functional (2 genes/chromosomes)
- β-thalassemia: 1 or 2 of the 2 β-globin genes is non-functional (1 gene/chromosome)
*The other type of chain is expressed in excess in erythrocyte precursor causing hemolysis in the bone marrow (counter-balance/imbalance)

*Severity proportionnal to the number of non-functional genes i.e. to the magnitude of the imbalance
- from asymptomatic to severe anemia

55
Q

What are clinical features and treatments for Thalassemia?

A

Clinical features:
- Anemia
- Extramedullary hematopoiesis (skull and bone deformations, liver and spleen size increase)

Treatments:
- Transfusion
- Bonne marrow transplant
- Gene therapy

56
Q

What is Sickle Cell Disease?

A

Homozygous/compound heterozygous state for HbS:
HbS/HbS or HbS/ß-thalassemia or HbS/HbC

HbS is a point mutation (Glu6Val) of b-globin

One of the most frequent monogenic disease worldwide (500 000 newborns/year)
HbS can polymerize leading to erythrocyte sickling than can:
- Occlude the vessels (vaso-occlusion)
- Self-destroy (hemolysis)

57
Q

What are treatment possibilities for Sickle Cell Disease?

A

Increase O2 affinity: (HbS polymerizes when deoxygenated)
- Voxelotor
- Pyruvate-kinase allosteric activators

Increase HbF: (To have less HbS)
- Hydroxyurea
- Gene therapy

Without infection prophylaxis, most of children die before 5 because of asplenia
Reduced life expectancy and pervasive complications even with optimal treatment

58
Q

How is Gene therapy used to treat Sickle Cell Disease?

A

Gene modification can be done using:
1) Adenoviruses: incorporation of new DNA material (e.g. γ-chain, normal ß-chain)
2) CRISPR/Cas9: deleting DNA material → deletion of erythroid-specific BCL11a enhancer increases HbF level
3) CRISPR/dCas9: directly modify DNA material

59
Q

What are 2 categories of pathologies associated with Globin synthesis?

A
  1. Imbalance between globin chains synthesis Thalassemia
  2. Abnormal hemoglobins
    High/low-affinity variants, HbM
    Unstable hemoglobins
    Sickle Cell Disease
60
Q

What is the main global regulator of hemoglobin synthesis? (except for GATA1)

A

Erythropoietin (EPO) secretion in kidney proportional to hypoxia

EPO stimulates and is required for erythropoiesis
Stimulates precursors that express the receptor for EPO (EpoR)

Epo receptor also activates Ferrochelatase by phosphorylation (stat5) → iron incorporation into heme

61
Q

What are the 3 main triggers of hemoglobin synthesis?

A
  1. EPO
  2. GATA1 expression during erythropoiesis
  3. Iron repletion

PHGY 313 (5 decks)

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