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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
What is the oxygen affinity when Hb is in the T state? What is stabilizing this state?
Low oxygen affinity, is deoxyHb. Extra salt bridges stabilize the T state
26
What is the oxygen affinity when Hb is in the R state? What is stabilizing this state?
High oxygen affinity, is OxyHb. Oxygen binding stabilizes it
27
What is the difference between the T and R states of Hb?
Subunit arrangement and the size of the central cavity (larger in the T state)
28
What is allostery?
Conformation changes in response to ligand binding
29
What are allosteric effectors?
Molecules that cause allosteric changes
30
What do allosteric activators do?
Change conformation so ligand binding increases
31
What do allosteric inhibitors do?
Change conformation so ligand binding decreases
32
What is a homoallosteric effector?
The effector is the same molecule as the ligand
33
What is a heteroallosteric effector?
The effector is a different molecule than the ligand
34
What is cooperativity?
Conformational changes in one subunit facilitates changes in the others
35
What type of ligand binding curve do structures that show cooperativity have?
Sigmoidal
36
What type of allosteric effector is oxygen? Which Hb state does it favour?
Homoallosteric activator. It favours the R state
37
How does oxygen binding create cooperativity in the Hb subunits?
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
Which Hb state is favoured in the lungs?
High oxygen in the lungs favours the R state so oxygen binds
39
Which Hb state is favoured in the tissues?
Low oxygen in the tissues favours the T state so Hb releases the oxygen
40
How does oxygen dissociation create cooperativity in the Hb subunits?
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
What does the oxygen binding site look like in the T state?
The diameter of the iron is slightly too large to fit in the porphyrin ring, so the ring forms a puckered shape
42
What does the oxygen binding site look site in the R state?
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
How does the small movement of the iron create an entire conformational change?
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
What is BPG?
A molecule with a lot of negative charges that is essential for the formation of the T state
45
What type of allosteric effector is BPG?
Heteroallosteric inhibitor
46
Where does BPG bind? Why?
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
Which state does BPG favour?
T state. When it binds, more oxygen gets delivered to the tissues
48
What is the Bohr effect?
The response of Hb to pH changes. When pH drops, the T state is favoured
49
How is blood pH affected during muscle activity?
Metabolism increases, so more metabolism products are formed. CO2 and H+ are some of those products, and lowers the pH
50
What happens to the histidine and N-termini in the central cavity at low pH?
They get protonated. Forms new salt bridges and increases BPG binding, which stabilizes the T state
51
What happens to the sigmoidal binding curve at low pH or at high BPG concentrations?
It shifts to the right. More oxygen gets dropped off at the tissues
52
How does CO2 affect the state of Hb?
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
How does H+ and CO2 binding relate to oxygen binding?
They are inversely proportional to oxygen binding
54
What is the pO2 and pH in the lungs? Which Hb state is favoured?
High pO2, high pH. R state is favoured
55
What is the pO2 and pH in the tissues? Which Hb state is favoured?
Low pO2, low pH, BPG binding is favoured. T state is favoured, causing Hb to release its oxygen
56
What is the mutation that changes normal hemoglobin (HbA) to sickle-cell hemoglobin (HbS)?
A point mutation that changes E6 to a valine
57
Why is the valine of HbS a problem?
A normally charged amino acid on the surface is now hydrophobic, so it doesn't want to be interacting with all that water
58
What causes the sickle shape of the red blood cells?
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
What is difference between HbA and fetal hemoglobin (HbF)?
Instead of having the beta subunit, it has the gamma subunit instead. Gamma subunit has H143S in the central cavity
60
What state is favoured in HbF? Why?
R state. The central cavity loses two positive charges, so BPG doesn't bind as well
61
Why is having the R state persist longer advantageous for the fetus?
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
How does the sigmoidal binding curve change for HbF?
Shifts it to the left

Introductory Biochemistry (16 decks)

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