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2. MCBG > 10 Protein Function - Oxygen Transport > Flashcards

10 Protein Function - Oxygen Transport Flashcards

1
Q

Briefly, what do haemoglobin and myoglobin do?

A

Pick up oxygen at lungs, transport to tissues, release, pick up waste carbon dioxide, transport to lungs, release, pick up oxygen

Note myoglobin does not transport carbon dioxide, only hb

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2
Q

Describe the structure of haem in myo/haemoglobin

A

Fe2+ atom bound to 4 Nitogen atoms of a protoporphyrin ring

Has two sites free, so one is occupied by histidine residue in haemoglobin/myoglobin and other site picks up oxygen

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3
Q

Describe structure of myoglobin

A
  1. Single polypeptide chain is
  2. Haem in middle makes interactions with histadines -93 His in 8th alpha helix covalently linked to Fe
  3. Mainly alpha helical
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4
Q

How does the conformation of myoglobin change when an oxygen molecule binds?

A
  1. Originally, the Fe in deoxymyoglobin is slightly below plane of ring
  2. When Oxygen binds, Fe moves into the plane of the ring
  3. Therefore the histidine also moves and a change in conformation of the protein occurs
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5
Q

Describe the myoglobin haemoglobin graph

A
  1. Fractional saturation vs partial pressure of oxygen
  2. Myoglobin has a higher affinity for oxygen than haemoglobin. So myoglobin saturates quickly at low pressures of oxygen and shows rectangular hyperbola shape. Haemoglobin slow saturation but then quickly picks up and then plateaus -sigmoidal curve underneath myoglobins
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6
Q

Describe the structure of haemoglobin

A
  1. Four polypeptide chains - a1, a2, B1, B2
  2. Each chain contains a haem group
  3. Conformation of each chain/subunit similar to myoglobin
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7
Q

What two states can haemoglobin exist in?

A
  1. Low affinity T state
    - positively charged residues aligned with negatively charged aspartate on another subunit
    - these interactions stabilise the structure so more difficult for O2 to bind
  2. High affinity R state
    - 15 degree rotation so interactions do not occur anymore
    - oxygen binds more easily as haem units are more exposed
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8
Q

What is cooperative binding? Give example.

A
  1. Oxygen binds to T state, haemoglobin has very low affinity for it
  2. Conformation change occurs
  3. Haemoglobin changes to R state and affinity for oxygen increases as more and more oxygen attach
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9
Q

Why is haemoglobin on the curve of fractional saturation vs partial pressure of oxygen, sigmoidal?

A
  1. At low pp, most molecules in T state so low affinity for oxygen
  2. Cooperative binding of oxygen causes affinity to increase as more molecules bind to subunits
  3. Affinity gets higher and higher explaining curve shape
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10
Q

Which direction does the curve shift if affinity for o2 increases?

A

Left (remember where myoglobin is)

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11
Q

Which direction does the curve shift if affinity for o2 decreases?

A

Right

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12
Q

Why is the shape of the sigmoidal curve helpful for efficient take up of Oxygen in the lungs and release into the tissues?

A

Lungs - high partial pressure of oxygen so pick up O2 efficiently as lots of oxygen encourages R states
Tissues - low partial pressure of oxygen so encourages T state and release of oxygen

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13
Q

What is BPG?

A

2,3 bisphosphoglycerate - byproduct formed in RBCs with multiple negatively charged molecules

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14
Q

how does BPG regulate oxygen binding? Where is it useful?

A
  1. Negatively charged groups want to bind positively charged groups (histidine) and so it sits in the middle of the subunits (one per tetramer)
  2. Decreases affinity for oxygen (shifts curve to right) hence promotes release of it near tissues
  3. People at higher altitudes have higher BPG as partial pressure of oxygen is lower there, but still get same amt to tissues as BPG just allows it to release more
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15
Q

How much BPG in blood for people that live at sea level and at higher altitudes?

A

Sea level = approx. 5mM

Higher altitudes = approx. 8mM

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16
Q

How do carbon dioxide (Waste from tissues)and hydrogen ions (pH) regulate oxygen binding

A

Bohr effect

  1. Active muscle produces CO2 and lactic acid
    - CO2 binds to N terminus covalently
    - H+ protonate AA residues
  2. Lowers affinity of haemoglobin for oxygen
  3. Shifts curve to right
  4. Enhanced unloading of bound oxygen as haem mol moves from R=>T state
17
Q

Why is carbon monoxide poisonous?

A
  1. CO binds 250x more tightly than O2 and hence blocks binding of O2
  2. Each subunit can bind 1 CO mol, when all four bound, haem is dead
  3. Fatal when COHb is >50%
18
Q

Does CO increase or decrease affinity for oxygen?

A

Increases affinity for unaffected subunits (shifts curve to left)

19
Q

Those with >50% COHb results in fatality, but those who are anaemic can live with 50% Hb. Why?

A

What makes it fatal is the curve shifting to the left (the increase in affinity for oxygen) making it more difficult for oxygen to be released at tissues

20
Q

What chains make up foetal haemoglobin? HbF

A

Alpha2 gamma2

21
Q

Explain the changes between alpha, beta and gamma globin chains from conception, before birth, after birth and onward

A

conception onward to birth lots of alpha globin chains
Conception onward to birth lots of gamma chains
Conception onward to birth hardly any beta chains
After birth, still lots of alpha chains
After birth to 6 months, gamma chains decrease
After birth, beta chains increase

22
Q

Describe foetal haemoglobin its function

A
  1. 2alpha, 2gamma
  2. Higher affinity for oxygen than maternal HbA
  3. Foetus gets oxygen from mothers blood so without high affinity, this wouldn’t be possible
  4. Shifts curve to left
23
Q

Describe sickle cell anemia

A
  1. Single base pair mutation of glu (-vely charged) to val (hydrophobic, uncharged)
  2. Val doesnt like being on the outside so RBCs hide them by joining another tetramer forming a stick hydrophobic tetramer
  3. Sickles cells more prone to lyse
  4. More rigid - block microvasculature, making them prone to burst
24
Q

What is thalassaemia?

A

Inbalance of no of alpha and beta globin chains

25
Q

What are the different types?

A
  1. Alpha
    - decreased/absent alpha chains
    - beta can form tetramers
    - but increased affinity for oxygen
    - different severities as multiple copies of alpha chains present (2 alpha1 and 2 alpha2) (1 lost =silent carrier, 2 lost = heterozygous form, 3 lost = severe HbH disease, 4 lost=usually fatal)
  2. Beta
    - decreased/absent beta chains
    - alpha cant form tetramers
    - 2 beta genes, if 1 lost - minor, if 2 lost - major

2. MCBG (18 decks)

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