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Introductory Biochemistry > Ligand Binding Proteins - Hemoglobin and Myoglobin > Flashcards

Ligand Binding Proteins - Hemoglobin and Myoglobin Flashcards

1
Q

Are there any functional groups within a protein that can bind to oxygen?

A

No

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2
Q

Why can’t Mb and Hb only use iron (II) to transport oxygen?

A

The oxygen will react with it and produce ROS, which damage DNA, lipids, and proteins

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3
Q

How is the reactivity of Fe (II) regulated?

A

It is coordinated to a porphyrin ring and then bound to a protein to completely control it’s activity

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4
Q

What are the components of the prosthetic group heme?

A

Fe (II) coordinated to the porphyrin

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5
Q

Where in the protein does the heme bind?

A

In a globin fold

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6
Q

What is the structure of the globin fold?

A

8 alpha helices and a few loops and turns

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7
Q

Which helices in the globin fold does heme bind to?

A

E and F

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8
Q

What is a ligand?

A

Molecule that binds reversibly and specifically to a protein

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9
Q

What is the ligand and binding site for myoglobin?

A

Ligand is oxygen, binding site is the Fe in the heme group

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10
Q

What is Kd? What does it tell us?

A

The dissociation constant, the concentration of ligand that gives 50% fractional saturation. Tells us how well a protein binds to its ligand. A lower Kd means higher affinity

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11
Q

What sort of curve do we get if we plot Y vs [L] for myoglobin?

A

Hyperbolic

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12
Q

Why does ligand binding plateau after a while?

A

All the protein sites are occupied, doesn’t even matter if more gets added

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13
Q

What does a lower Kd mean?

A

It takes less ligand around to fill up half of the binding sites

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14
Q

Is the Kd for Mb low or high?

A

Low, so high affinity

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15
Q

How does the colour of Mb and Hb change when bound to oxygen?

A

They are bright red when bound to oxygen and more purple when not

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16
Q

What are the two amino acid side chains directly involved in oxygen binding? What are their positions?

A

HisF8 - histidine at position 8 on helix F

HisE7 - histidine at position 7 on helix E

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17
Q

What does HisF8 do?

A

It is bound to the Fe and tethers the heme to the protein with a covalent bond in position 5 on the iron

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18
Q

What does HisE7 do?

A

Hydrogen bonds to the oxygen when it is bound in position 6 on the iron

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19
Q

How does being bound to a protein reduce the affinity of the heme for CO?

A

CO likes to bind in a straight line, while oxygen likes to bind at an angle. When the CO binds when heme is in a protein, it isn’t at an optimal angle so affinity is weaker

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20
Q

What is the main structural difference between Mb and Hb?

A

Hb has a quaternary structure

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21
Q

What are the subunits that make up Hb?

A

Two alpha globin and two beta globin. Both are all alpha helices

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22
Q

How many oxygen molecules can Hb be bound to at a time?

A
  1. Each subunit has a heme
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23
Q

What shape is the ligand binding curve for Hb?

A

Sigmoidal

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24
Q

What are the two states of Hb?

A

T - tense

R - relaxed

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25
Q

What is the oxygen affinity when Hb is in the T state? What is stabilizing this state?

A

Low oxygen affinity, is deoxyHb. Extra salt bridges stabilize the T state

26
Q

What is the oxygen affinity when Hb is in the R state? What is stabilizing this state?

A

High oxygen affinity, is OxyHb. Oxygen binding stabilizes it

27
Q

What is the difference between the T and R states of Hb?

A

Subunit arrangement and the size of the central cavity (larger in the T state)

28
Q

What is allostery?

A

Conformation changes in response to ligand binding

29
Q

What are allosteric effectors?

A

Molecules that cause allosteric changes

30
Q

What do allosteric activators do?

A

Change conformation so ligand binding increases

31
Q

What do allosteric inhibitors do?

A

Change conformation so ligand binding decreases

32
Q

What is a homoallosteric effector?

A

The effector is the same molecule as the ligand

33
Q

What is a heteroallosteric effector?

A

The effector is a different molecule than the ligand

34
Q

What is cooperativity?

A

Conformational changes in one subunit facilitates changes in the others

35
Q

What type of ligand binding curve do structures that show cooperativity have?

A

Sigmoidal

36
Q

What type of allosteric effector is oxygen? Which Hb state does it favour?

A

Homoallosteric activator. It favours the R state

37
Q

How does oxygen binding create cooperativity in the Hb subunits?

A

When oxygen binds to one subunit in the T state, it changes shape into the R state. This creates unfavourable interactions with the other subunits, so they also change into the R state to get rid of those unfavourable interactions

38
Q

Which Hb state is favoured in the lungs?

A

High oxygen in the lungs favours the R state so oxygen binds

39
Q

Which Hb state is favoured in the tissues?

A

Low oxygen in the tissues favours the T state so Hb releases the oxygen

40
Q

How does oxygen dissociation create cooperativity in the Hb subunits?

A

When one dissociates Hb goes into the T state. Unfavourable interactions make the other subunits change shape and release their oxygen and the entire Hb ends up in the T state

41
Q

What does the oxygen binding site look like in the T state?

A

The diameter of the iron is slightly too large to fit in the porphyrin ring, so the ring forms a puckered shape

42
Q

What does the oxygen binding site look site in the R state?

A

The diameter of the iron is slightly smaller than in the T state, so it can fit in the porphyrin. It physically moves down into the ring

43
Q

How does the small movement of the iron create an entire conformational change?

A

When the iron moves, it is still attached to HisF8, so it pulls on that too. That causes helix F to pivot and Hb undergoes a change into the R state to relieve the unfavourable interactions created by that pivot

44
Q

What is BPG?

A

A molecule with a lot of negative charges that is essential for the formation of the T state

45
Q

What type of allosteric effector is BPG?

A

Heteroallosteric inhibitor

46
Q

Where does BPG bind? Why?

A

In the central cavity of the T state. It is too small in the R state. It binds there because there are a lot of positive charges

47
Q

Which state does BPG favour?

A

T state. When it binds, more oxygen gets delivered to the tissues

48
Q

What is the Bohr effect?

A

The response of Hb to pH changes. When pH drops, the T state is favoured

49
Q

How is blood pH affected during muscle activity?

A

Metabolism increases, so more metabolism products are formed. CO2 and H+ are some of those products, and lowers the pH

50
Q

What happens to the histidine and N-termini in the central cavity at low pH?

A

They get protonated. Forms new salt bridges and increases BPG binding, which stabilizes the T state

51
Q

What happens to the sigmoidal binding curve at low pH or at high BPG concentrations?

A

It shifts to the right. More oxygen gets dropped off at the tissues

52
Q

How does CO2 affect the state of Hb?

A

It can bind directly to Hb as a carbamate, which forms new salt bridges and produces H+ that lowers the pH. Hb will release the CO2 at the lungs

53
Q

How does H+ and CO2 binding relate to oxygen binding?

A

They are inversely proportional to oxygen binding

54
Q

What is the pO2 and pH in the lungs? Which Hb state is favoured?

A

High pO2, high pH. R state is favoured

55
Q

What is the pO2 and pH in the tissues? Which Hb state is favoured?

A

Low pO2, low pH, BPG binding is favoured. T state is favoured, causing Hb to release its oxygen

56
Q

What is the mutation that changes normal hemoglobin (HbA) to sickle-cell hemoglobin (HbS)?

A

A point mutation that changes E6 to a valine

57
Q

Why is the valine of HbS a problem?

A

A normally charged amino acid on the surface is now hydrophobic, so it doesn’t want to be interacting with all that water

58
Q

What causes the sickle shape of the red blood cells?

A

The valine sticks to the hydrophobic patch on the surface of the T state Hb. Causes HbS to aggregate into insoluble fibres and distorts the shape of the red blood cell. Hb also can’t carry very much oxygen

59
Q

What is difference between HbA and fetal hemoglobin (HbF)?

A

Instead of having the beta subunit, it has the gamma subunit instead. Gamma subunit has H143S in the central cavity

60
Q

What state is favoured in HbF? Why?

A

R state. The central cavity loses two positive charges, so BPG doesn’t bind as well

61
Q

Why is having the R state persist longer advantageous for the fetus?

A

The mother’s Hb reaches saturation sooner, so it releases the oxygen it is carrying. HbF is still in the R state at this pO2, so it is able to pick it up because of high affinity

62
Q

How does the sigmoidal binding curve change for HbF?

A

Shifts it to the left

Introductory Biochemistry (16 decks)

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