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Protein structure and function > myoglobin and haemoglobin > Flashcards

myoglobin and haemoglobin Flashcards

1
Q

What is Myoglobin?

A

An O2 binding protein in the muscle and acts like a store/sponge

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2
Q

what is the structure of myoglobin?

A

not fixed. helicies can move. has a globin polypeptide + haem prosthetic group. Globin is 153AA made up of 8 alpha helices and has the Haem Fe2+ in a protoporphyrin IX ring.

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3
Q

Describe the structure of the Protoporphyrin IX ring.

A

a flat multi ring structure. is cooridnated by 4 nitrogens that interact with a Fe2+ arond it and below it at position 5 there is another nitrogen atom in the His93 side chain. above at postion 6 is where oxygen binds.

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4
Q

What occurs when oxygen binds to prevent production of superoxides?

A

the distal his64 stabalises the oxygen to prevent the release of superoxide radical 02-

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5
Q

During intense exersise what happens to the oxygen?

A

myoglobin remains bound at most tissue pO2 but during intense exerises they release the O2

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6
Q

What is the structure of Haemoglobin?

A

Tetremer of 4 subunits so can bind to 4 Oxygens.

Alpha 1 and 2 and beta 1 and 2 which forms a quaternary structure.

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7
Q

What are the small and large scale changes for Oxygen binding on Hameoglobin?

A

small scale change - puls on helix F which alters bonds in the dimer dimer interface

large scale change - rotation of alphaBeta dimers by 15 degrees. (quaternary shift)

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8
Q

What are the two forms of Hb

A

Tense low affinity form. deoxy

Relaxed high affinity form. Oxy. salt bridges are broken allowing the Q shift.

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9
Q

What are the changes in affintity when oxygen starts to bind?

A

Hb with 1 oxygen tends to be mostly tense.

takes 2 oxygens to cause a Q shift to all Relaxed form.

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10
Q

why is there changes in affinity?

A

Alpha and beta subunits arent the same. Alpha can bid to O2 in tense and relaxed states.

Beta can only bind in the R state.

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11
Q

Why is blood less sigmoidal than pure Hb?

A

Alosteric regulators bind to Hb and alter affinity for Oxygen.

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12
Q

What does BPG (2,3 bisphosphoglycerate) do that has allosteric reguation?

A

binds to cavity in Hb. holds the tetramer in a low affinty tense form.

2 oxygens are required to dislodge BPG.

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13
Q

What metabolic diseases alter BPG levels affecting Hb affinity to oxygen.

A

Hexokinase deficency. leads to decreased BPG. shift to left.

Pyruvate kinase deficicency casues increased BPG so causes a shift to right.

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14
Q

What is the Bohr shift?

A

When there is increaseWhen ↑[H+ ] and ↑[CO2 ] the saturation curves shifts to the right

O2 affinity is reduced → more released to tissues

↑[H+ ] and ↑[CO2 ] = ↑ activity and ↑ requirement for O2

At the same pO2 less is bound to Hb

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15
Q

how does His146 interact with Asp94 in the same Beta subunit? in Hb

A

In tense form it forms a salt bridge with the Asp94.
In R form His146 is unprotonated at pH 7.4 so no salt bridge. O2 can bind

Drop in pH leads to protonation of His146. (can be caused by CO2) causing salt bridge formation causing release of O2 in the shift to the T form.

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16
Q

what is the equation for how CO2 contributes to the Bohr shift?

A

CO2 + H2O ↔ H2CO3 ↔ HCO3 - + H+

catalysed by Carbonic anhydrase

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17
Q

How do Chloride ions stabilise the T form?

A

Coat the +ve residues lining the 2,3-BPG cavity reducing the destabalising repulsion

Cross link of Val1 alpha 2 and arg141 Alpha 1

Protonation enhanced in bohr shift. leads to T form shift.

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18
Q

How do you treat methaemoglobinaemia?

A

treat with reducing agent methlene blue. turns the Fe3+ back into Fe2+. It is a conditiion that comes from the inheritance of deficieny of Methaemoglobin reductase that converts teh Fe3+ to Fe2+

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19
Q

What is Haemoblobin M?

A

HbM is all locked in T form. single AA change that stabalises the Fe3+ form.

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20
Q

What is Iwate?

A

an Alpha subunit mutation where His87 > Tyr87

cant move F helix closer to Haem which leads to loss of Q shift,

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21
Q

What condition does Hameoglobin S mutation cause?

A

sickle cell anemia. Abnormal HbS distorts the RBC and only effects the deoxy T form. its a point mutatipn in the beta subunits.

glu6 to val6

22
Q

what does a sigmoidal saturation curve show in respect to Haemoglobin subunits?

A

Shows their cooperative nature.

23
Q

at high and low pO2 what happens to the oxygen on Hb

A

at tissue pO2 which is lower the oxygen gets released but at high pO2 at areas like the lungs the Oxygen is bound so the Haemoglobin becomes saturated.

24
Q

What is the structure of Haemoglobin?

A

A tetremer. 4 subunits that can bind 4 oxygens. has a quaternary strucutre with 2 differnt globin chains alpha and beta which means Hameoglobin is made of 2alphaBeta dimers.

25
Q

how can deoxy and oxygenated haemoglobin be distingused?

A

oxyHb is bright red and deoxyHb is dark red. they can be distingused using spectroscopy at 660nm.

26
Q

What is the globin fold?

A

it is where the globin superfamily share a common 3D fold. even though globin sequence is quite different from globin to globin their helice structure ends up the same.

27
Q

When oxygenated what happens structurally to the haemoglobin?

A

salt bridges break and there is a rotation of the dimers that changes the quaternary structure.

electron rearrangements shrink the Fe ion allowing it to move further into the ring and this causes the proximal His to be pulled with it.

the proximal His in turn pulls on helix F.

28
Q

what states can the alpha and beta subunits bind to oxygen in Hameoglobin?

A

alpha can bind in the Tense and relaxed state.

beta can only bind in the relaxed state.

29
Q

describe the order in which oxygen binds to Haemoglobin.

A

oxygen first binds to one of the alpha subunits. this puts strain on both of the alpha subunits.
a second oxygen binds to the free alpha subunit and this provides enough strain to flip the beta subunits into the relaxed state which allows for oxygen to bind to the two beta subunits sequentially.

30
Q

What are allosteric regulators that alter affinity for O2 in Haemoglobin.

A

2,3-Bisphosphoglycerate (2,3-BPG)
H+
CO2

H+ and CO2 increase during exercise.

31
Q

How does 2,3-BPG affect affinity?

A

Binds to the cavity in Hb and it causes the teteramer to be held in its low affinity T form as it forms salt bridges keeping in place.

2,3-BPG cannot bind to the R form. can only bind when in the T form and oxygen is released from the R state.

32
Q

How many oxygens are needed to dislodge 2,3-BPG

A

2 oxygens.

33
Q

What are some metabolic diseases that affect 2,3-BPG levels

A

hexokinase deficiency which lowers BPG levels. causes a shift to the left so increases Hb affinity.

pyruvate kinase deficiency that increases BPG levels. causes a right shift deceasing affinity.

34
Q

What is the bohr shift?

A

When ↑[H+ ] and ↑[CO2 ] the saturation curves shifts to the right
O2 affinity is reduced → more released to tissues

↑[H+ ] and ↑[CO2 ] = ↑ activity and ↑ requirement for O2

means at same PO2 levels there is an increased release of O2 which is required during increased activity.

35
Q

What salt bridges form in the T form?

A

His146 to Asp94 in same beta subunit. (histidine to aspartic acid)

36
Q

What happens to His146 in the relaxed form?

A

His146 is unprotonated at the relaxed form pH of 7.4 so no salt bridge forms allowing oxygen binding.

37
Q

When there is a drop in pH what occurs to His146?

A

His146 becomes protonated and a salt bridge forms with the release of Oxygen in the shift to the T form.

38
Q

How does CO2 contribute to the Bohr shift?

A

CO2 + H2O ↔ H2CO3 ↔ HCO3 - + H+
which is catalysed by carbonic anhydrase which leads to increased H+ concentration.
increases pH that causes a shift to the right decreasing affinity and thus causing increased release of O2.

ALSO carbonic acid binds to the N terminus of the alpha2 subunit creating a carbamate that allows salt bridge formation between there and the C terminus if the alpha1 subunit causing a T form shift.

39
Q

How do chloride ions stabalise the T form?

A

coat the positive residues lining the 2,3-BPG cavity reducing the destabilising repulsion.

Cross-link Val1α2 and Arg141α1

protonation gets enhanced in bohr shift causing T form shift. this is due to Cl- acting as a cotransporter with HCO3-

40
Q

C terminal salt bridges are essential for cooperativity. when happens to the hill constant when they are removed?

A

removal of Arg141 drops Hill constant to 1.7
removal of His146 drops hill constant to 1

hill constant also drops with removal of proximal His

41
Q

What other molecules bind to Hb? what are their differences with Oxygen binding affintiy?

A

Carbon monoxide. Has a bidnig affinity 250x greater than O2 but the distal His can weaken the interaction by 200x. One carbon monoxide puts all Hb in R form.

Nitric oxide. Binding affinity 10000x that of O2.

42
Q

What is methaemoglobinaemia?

A

inherited deficiency of methaemoglobin reductase.

methaemoglobin reductase is needed to convert Fe3 back to Fe2.

can be treated with methylene blue (reducing agent) and turns the Fe3+ back to Fe2+

43
Q

What is haemoglobin M

A

where all locked in T form. there is a single aa change that stabalises the Fe3+ form of haem. Oxygen in new sidechain interacts with iron.

44
Q

What is Iwate mutation?

A

is an alpha subunit mutation where the proximal his87 becomes Tyr87.

prevents helix F being moved closer to the Haem.

loss of Q shift.

45
Q

What is Boston Mutation?

A

is an alpha subunit mutation

distal His58 becomes Tyr58 pulls the Fe to otherside of the ring so proximal His cant bind to it.

loss of Q shift

46
Q

What is Milwaukee mutation?

A

a beta subunit mutation.

val67 to Glu67

COO- bind to Fe3+ which means beta subunit cannot bind to the oxygen but alpha still can.

47
Q

What is haemoglobin S?

A

Sickle cell anemia. the abnormal HbS distorts the RBC.

only affects the T form. (only see siclking in veins not arteries)

it is a point mutation in the beta subunit of Glu6 to Val6

HbS polymerises to form long fillaments.

48
Q

Why do HbS polymerise into long filaments?

A

the point mutation of Glu to Val changes charged to hydrophobic. hydrophobic interactions between the Val6 and Leu88/Phe85 on another Hb molecule causes aggregation. this cannot happen however during the R form due to subunit rotation hence why sickling only found in veins.

49
Q

What is thalessameia?

A

is where there is a lack of one or other subunit of Hb.

Alpha-thalassaemia is lack of alpha subunit. leads to no cooperativity and a high affinity. poor release of O2.

beta-thalassaemia is lack of beta subunit. alpha subunits aggregate. immature RBC are destroyed and leads to anaemia.

50
Q

What is different between adult and fetal Hb?

A

Fetal Hb has a higher affinity for O2 than adult. is needed from transfer from mother to foetus.

(Adult =HbA)
(Fetal = HbF)

51
Q

What are some adaptations of camelids that alter their Hb?

A

Camelids has Hb that becomes 100% saturated at pO2 of 0.08atm.
alpacas and lamas have a change in beta subunit.
His > Asn which causes the T form to remain for longer as there is a higher affinity/shift to the left.

Vicunas have an alpha subunit change of Ala > Thr
decreases Cl- binding and causes a shift to the left and higher O2 affinity.

Protein structure and function (7 decks)

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