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BIOC192 2022 > lecture 8 - allostery & cooperativity in haemoglobin > Flashcards

lecture 8 - allostery & cooperativity in haemoglobin Flashcards

1
Q

What is a conformational change of a protein?

A

A change in the shape of secondary elements of a protein

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2
Q

What is the shape of the haem unit in deoxyhaemoglobin?

A

Dished

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3
Q

What is the shape of haem in oxyhemoglobin?

A

Flattened

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4
Q

How does O2 cause a conformational change in Haem binding to Hb?

A

O2 flattens the Haem, pulling Fe2+ into plane, and pulls His F8 of helix F towards the binding site.

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5
Q

How does proximity of haem and Helix F affect Hb O2 binding?

A

Anything that keeps helix F away from the haem unit weeks oxygen binding

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6
Q

What helices are involved in alternative side chain packing between the T and R states in Hb?

A

the F and C helices of adjacent subunits. (e.g. alpha1 and Beta2)

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7
Q

What is one of the key differences in bonding/side chain packing in the F and C helices of adjacent subunits between the oxygenated (R) and deoxygenated (T) states?

A

Tyrosine residue on C helix moves from being H-bonded to aspartic acid on F helix to being unbonded

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8
Q

What is the unabbreviated name for BPG?

A

2,3-biphosphoglycerate

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9
Q

Where does BPG originate, and what is its fucntion?

A

A molecule made during metabolism that stabilises the T-state of HB by binding to an allosteric site

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10
Q

What is the charge on BPG?

A

5 negative charges

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11
Q

What is the charge on the allosteric site of Hb that BPG binds to, and why?

A

Positive, due to BPG’s 5 negative charges, allowing for electrostatic interaction/binding

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12
Q

What is the physiological function of BPG?

A

Made during respiration, and binds to deoxy-Hb in T state, stabilising it and reducing oxygen affinity so O2 can be delivered to peripheral tissues.

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13
Q

What are the 3 key allosteric inhibitors that influence Hb binding and cooperativity?

A

BPG, CO2, H+

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14
Q

What is the effect of allosteric inhibitors on Hb?

A

Stabilise the T state, reducing oxygen affinity

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15
Q

In the absence of inhibitors, what state is Hb predominantly in?

A

The R-state, because the inhibitors stabilise the T-state

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16
Q

What are the 2 ways that CO2 reduced O2 affinity of Hb?

A

Directly, and via lowering the pH of blood

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17
Q

What is the Bohr effect?

A

Decrease in the affinity of Hb to oxygen due to increased CO2 levels and low pH of the blood.

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18
Q

Where does CO2 bind to to stabilise the deoxy-Hb conformation in the T state?

A

Extreme N-terminal amino groups

19
Q

Where does H+ bind to to stabilise the deoxy-Hb conformation in the T state?

A

H+ protonates certain amino side chains

20
Q

What is the reaction for the reversible binding of CO2 and H+ to Hb?

A

HbO2 + H+ + CO2 ⇌ O2 + Hb-CO2-H+ (CO2 and H+ bound to Hb)

21
Q

What binding reaction involving CO2 and H+ occurs in actively metabolising tissue, such as muscle?

A

Oxygen unloading - HbO2 + H+ + CO2 ⇌ O2 + Hb-CO2-H+

22
Q

What binding reaction involving CO2 and H+ occurs in the alveoli of the lungs?

A

Oxygen loading - O2 + Hb-CO2-H+ ⇌ HbO2 + H+ + CO2

23
Q

What happens to BPG concentration at high altitude?

A

BPG production increases

24
Q

What is the function of increased BPG concentration at high altitude?

A

Reduces Hb’s affinity to O2, allowing more oxygen to be delivered to tissues - a rightward shift of the binding curve

25
Q

Does foetal haemoglobin have a higher or lower affinity for oxygen?

A

Higher

26
Q

How does foetal haemoglobin differ to adult haemoglobin?

A

They have different isoforms/subunits with higher O2 affinity

27
Q

What are the alternative subunits that foetal haemoglobin has?

A

ε (epsilon), γ (gamma), ζ (zeta)

28
Q

What is the fucntion of the alternative subunits found in foetal Hb?

A

Increased affinity to O2 allows the foetus to capture O2 in the placenta

29
Q

What is the relative sensitivity of foetal Hb to BPG?

A

Low sensitivity to BPG, so binds O2 tightly

30
Q

What chain replaces the Beta chain of adult Hb in foetal Hb?

A

Gamma chain

31
Q

What is the oxidation state of Fe in deoxy-Hb?

A

Fe2+

32
Q

What is the oxidation state of Fe in oxy-Hb?

A

Fe2+

33
Q

What is the oxidation state of Fe in methaemoglobin?

A

Fe3+

34
Q

What happens to binding in methaemoglobin?

A

The oxidation of Fe2+ to Fe3+ shifts one subunit to the R-state conformation without O2 binding (as O2 cannot bid to Fe3+). Cooperativity means that the other subunits of the tetramer are shifted to the R state, so cannot release O2 to the tissues as they should

35
Q

What enzyme is used to converted methaemoglobin back to haemoglobin?

A

cytochrome b5 reductase

36
Q

How does cytochrome b5 reducatase regenerate methaemoglobin to haemoglobin?

A

Reduces the Fe3+ back to Fe2+, using electron transfer via the electron carrier NADH

37
Q

What is the symbol for Boston haemoglobin?

A

HbM

38
Q

What is the oxidation state of Fe in Boston Hb (HbM)?

A

Fe3+

39
Q

How does HbM/Boston Hb function?

A

All subunits of HbM remains in the T state due to the Fe3+ Haem units (methaemoglobin), and oxygen cannot bind

40
Q

What is the symbol for sickle cell haemoglobin?

A

HbS

41
Q

What is the affect of sickle cell haemoglobin on red blood cells?

A

Red blood cells have an abnormal shape and get stuck in blood capillaries

42
Q

What type of mutation causes sickle cell haemoglobin?

A

Gain of function mutation

43
Q

What occurs in a HbS mutation?

A

Protein mutation enables an abnormal hydrophobic interaction between Hb molecules, particularly in their deoxy- form, causing polymerisation of HB into chains that distort the red blood cells

44
Q

What part of haemoglobin does BPG bind to?

A

A positively charged pocket in the middle/core

BIOC192 2022 (37 decks)

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