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Biosci 203- First 2 topics > Tom Brittain > Flashcards

Tom Brittain Flashcards

1
Q

What is the diffusion limit?

A

3-4mm

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2
Q

What makes gas exchange possible in humans, and why is an oxygen carrier molecule necessary?

A

The large surface area of the lung and its mucous layer (surfactant) makes gas diffusion across the lung efficient
The circulatory system can then be used to spread these gases from the lungs to the rest of the body, however as oxygen as low solubility, in order for this transport to be sufficient there must be a molecule (hemoglobin) which increases solubility of oxygen

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3
Q

What are the unique features of a red blood cell?

A 
A short lifespan of only 120 days
No nucleus or mitochondria
Biconcave disk
Essentially only performs glycolysis
Highly elastic due to a network of proteins
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4
Q

Why must erythrocytes exist, and free floating hemoglobin not used?

A

If just free floating Hb were used then in order to provide sufficient oxygen solubility the blood would become very viscous and too hard to pump around the body
Hemoglobin can also be toxic at high concentrations

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5
Q

Why must the red blood cell have its biconcave shape?

A

It is a balance between a flat disk which is used for rapid diffusion and a sphere for strength for when the red blood cell passes through capillaries inly half of its diameter

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6
Q

What is the concentration of hemaglobin in a red blood cell?

A

5mM, which is approximately the max concentration of hemaglobin possible without having crystallisation occuring

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7
Q

Why does a red blood cell have a limited lifespan of 120 days?

A

The lack of a nucleus means that the cell has no self repair mechanisms
The pressure placed on the red blood cell means that over the course of 120 days it will eventually become damaged enough to be degraded

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8
Q

What happens to red blood cells at the end of their lifespan?

A

When they are sufficiently damaged then they are recognised and broken down in the spleen while the components are recycled

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9
Q

How are red blood cells produced?

A

From hemopoietic cells in the pelvis and ribs which become reticulocyte which produces hemoglobin and then after synthesis is complete the nucleus is destroyed which creates a red blood cell which enters the circulation

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10
Q

Why do people have different types of haemoglobins?

A

To cope with different oxygen uses and demands at different lifestages

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11
Q

What is haemoglobin made of?

A

2 alpha and 2 beta subunits each of which has a heme group and are all alpha helical structures

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12
Q

Where are the alpha type globins coded?

A

Chromosome 16

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13
Q

Where are the beta chains coded?

A

Chromosome 11

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14
Q

What is the common gene structure of globin genes?

A

Approx. 1500 base pairs, 3 exons and 2 large introns

Alpha gene has 141 amino acids while beta gene has 146 amino acid

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15
Q

How is expression of the globin genes controlled?

A

Gene expression is controlled the locus control regions and promoters 5’ to the genes and the RNA stability controlled by nontranslated 3’ structures

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16
Q

How does haem synthesis control globin gene expression?

A

The haem group interacts with globin protein elongation factors to match the synthesis of the protein and its prosthetic group, alpha and beta gene transcription is matched by CHANCE not by any known biological mechanism

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17
Q

What are the different types of globin gene?

A

Embryonic where oxygen is obtained from surrounding fluid, Gower I,II and Portland in cells in the yolk sac
Fetal where HbF (two alpha units, two gamma units), are synthesized in liver red blood cells where oxygen is taken from the mother from the placenta
Adult hemoglobin synthesized in flat bones where oxygen is taken from air in the lungs

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18
Q

When is the alpha subunit used?

A

All stages of development

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19
Q

When is the beta chain activated?

A

A few weeks before birth in order to obtain a 50:50 ratio of fetal to adult hemoglobin at birth so the child is able to breathe when it is born

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20
Q

Why is it crucial that oxygen is bound to haemoglobin at the right tightness?

A

As if oxygen was bound too tightly then it would not be released and given up to the tissues but if it bound oxygen too loosely then it would not be able to pick up enough oxygen to supply the tissues

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21
Q

How does the haem group function?

A

Connected to the globin structure by binding to a proximal histidine
The Fe is kept in the 2+ form rather than the more stable 3+ through 4 bonds co-ordinate bonds with Nitrogens, therefore there is space for 2 co-ordinate bonds with oxygen where there are no amino acids available to make these bonds up

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22
Q

What is the role of distal haemoglobin?

A

It prevents the O2 molecule bound to the iron in haemoglobin from moving to its preferred vertical conformation by steric hindrance preventing the oxidation of the ferrous (2+) iron to Fe3+

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23
Q

How do the four subunits come together to make the quaternary structure in haemoglobin?

A

the alpha and beta chains make contacts with both similar and dis-similar chains but the connections with the dissimilar chains are stronger than the connections with the similar chains

24
Q

How is oxygen binding to hemoglobin characterized?

A

The binding is co-operative/allosteric
The curve is sigmoidal
the p50 is used to measure the concentration at which there is 50% oxygen saturation, typically 26-28mmHg
The hill coefficient is the slope of the curve and relates to hos strongly the subunits interact, its typically 2.8 for haemoglobin

25
Q

What are the three models for the homotropic effect of oxygen binding?

A

The monod-Wyman-Changeaux two state, concerted model
The Koshland-Nemethy-Filemr sequential model
The stereochemical Perutz model

26
Q

What is the two state, concerted model?

A

Haemoglobin can exist in two possible structures one of which is high affinity (R), the other is low affinity (T) regardless of whether oxygen is bound or not, during the process of oxygenation the protein undergoes a concerted switch from mainly T to mainly R and all the subunits on each structure are the same

27
Q

What is the sequential model?

A

The subunits of haemoglobin gradually change structure during the process of haemoglobin in a sequential manner

28
Q

What is the stereochemical model?

A

Based of X ray crystallography of both oxy and deoxy structures there are more ionic bonds in the deoxy structure, when oxygen binds a pocket which holds a tyrosine residue shrinks leading to tyrosine being pushed our breaking an ionic bond to cause the observed structural change

29
Q

What is the heterotropic allosteric control of oxygen affinity?

A

Oxygen is affected by substances other than oxygen (effectors) ALL of which lower oxygen affinity
These bind to haemoglobin to change function but NOT to the haem group

30
Q

What is the Bohr effect?

A

As the pH is lowered the oxygen affinity for haemoglobin is reduced, this can often be from a proton released by the haemoglobin (as the pKa of sidechains can change driving H+ release) itself or from substances such as lactic acid produced during exercise causing a local acidity of the blood

31
Q

How is the Bohr effect useful to muscles in exercise?

A

The lactic acid produced by anaerobic respiration can result in a pH change inducing the haemoglobin to release more oxygen, while the muscles myoglobin which is a single subunit protein is unaffected by this pH and therefore can still bind oxygen with high affinity increasing the oxygen available to muscles to under go oxidative phosphorylation and gai large amounts of energy

32
Q

What is the root effect?

A

An ‘extreme’ version of the Bohr effect which occurs in fish, which have a different haemoglobin, a gland secretes acid which drives haemoglobin to dramatically lower its affinity for oxygen which allows a gas pocket to build up which moves the fish upwards

33
Q

How does 2,3 Diphosphoglycerate (2,3 DPG) affect haemoglobin?

A

Typically binds between two sets of positive charges (as it is negatively charged on both sides) on beta subunits when in the deoxy state,stabilizing this low oxygen affinity state this is the most important allosteric effector for haemoglobin

34
Q

How is 2,3-DPG used in red blood cells?

A

Produced by a mutase and phosphatase from 1,3 DPG which is a product of glycolysis within the red blood cell, typically there is one 2,3-DPG per haemoglobin

35
Q

Why is the relationship between fetal haemoglobin and 2,3-DPG significant?

A

Fetal haemoglobin has a mutation which causes the beta chain to switch one of its histidines to a serine in the site that 2,3-DPG usually binds thus changing the charge and preventing binding
This gives fetal haemoglobin a much higher affinity for oxygen than adult haemoglobin under physiological conditions resulting in its ability to steal oxygen from the mother across the placenta

36
Q

How does temperature affect haemoglobin?

A

Within the physiological range, in humans an increase in temperature results in a lower oxygen affinity of haemoglobin
While some animals which live in cold environments can have the inverse of this relationship

37
Q

How does chloride affect haemoglobin?

A

Bind preferentially to the deoxy form of haemoglobin and lower its oxygen affinity, also plays a role in CO2 transport

38
Q

What are the two ways in which CO2 can affect haemoglobin?

A

CO2 can react with amino side chains on deoxy haemoglobin which lowers oxygen affinity
Inside the red blood cell CO2 can be converted to bicarbonate through the carbonic anhydrase enzyme,this reaction produces an H+ which results in the bohr effect to lower haemoglobin affinity for oxygen

39
Q

What are the different locations on the haemoglobin protein that mutations can occur and what are their effects?

A

Surface residues which usually affect aggregation and can lead to polymerisation
The haem cavity which can affect oxygen affinity or iron oxidation
The subunit interface which usually affect dissociation or co-operativity

40
Q

What is polycythaemia and why does it occur?

A

More than normal numbers of red blood cells in the blood, typically caused by functional mutations for haemoglobin

41
Q

What is howick haemoglobin?

A

A mutation which changes a tryptophan to glycine which prevents the subunits from joining so only dimers form which have no co-operativity, high oxygen affinity, no Bohr effect and no 2,3 DPG effect

42
Q

What is HbS?

A

A mutation on a beta gene which changes a glutamine to valine
This results in a sticky hydrophobic patch on deoxy haemoglobin which leads to polymerisation of haemoglobin which can grow longer than the red blood cell causing sickle cells to form

43
Q

Why are sickle cells potentially damaging?

A

The sickle shape results in a loss of elasticity which means that the red blood cell cannot stretch through the microcapillaries

44
Q

What is balanced polymorphism and its role in both sickle cell and thalassaemia?

A

When a mutation that would typically be harmful is preserved as heterozygotes have a survival advantage, in the case of sickle cell and thalassaemia they can provide some protection to malaria

45
Q

Why do sickle cells provide resistance to malaria?

A

Malaria typically reproduces in red blood cells, which requires some use of oxygen resulting in the red blood cell being almost locked in the deoxy conformation leading to the sickle cell formation, this can be more easily damaged which results in them being recognised by the spleen and broken down before the parasite matures

46
Q

What is Hb M?

A

Methaemoglobin in which a mutation of the distal histidine to a tyrosine results in oxidation of the iron from Fe2+ (ferrous) to Fe3+ (ferric) which is no longer able to carry oxygen

47
Q

What is thalassaemia?

A

When there is an in balance in haemoglobin chain synthesis, this can be alpha thalassaemia where there is less than normal synthesis of alpha chains, typically due to gene deletions or it can be beta thalassaemia which is less than normal beta chain synthesis which is due to a processing defects rather than loss of genes

48
Q

What are the different situations that can arise from from alpha thalassaemia?

A

Because the genome contains four alpha gene copies 5 situations are possible
normal
alpha thalassaemia 1- 2 copies missing, some O2 transport defects, red blood cell defects
alpha thalassaemia 2- one copy missing mild effects with no major red blood cell effects
Haemoglobin H disease- 3 copys are missing resulting in serious blood defects and major oygen transport problems
Hydrops fetalis no genes are present resulting in death in utero

49
Q

What is the consequence of beta thalassemia?

A

Due to the fact that the condition is caused by processing defects rather than gene deletion, beta thalassaemia shows a wider, continuous range of effects

50
Q

Why do some organisms have polymorphism of haemoglobins?

A

It enables them to cope with a widely changing oxygen environment, or they can be used for special functions such as the root effect in fish

51
Q

What large animal does not have a haemoglobin and why?

A

The antarctic fish which has no hemoglobin as it lives at low temperatures which has a high dissolved O2 content, and the fish has a very low level of activity removing the need of an oxygen carrying molecule

52
Q

How is co-operativity is often achieved in primitive vertebrates such as hag fish and lamprey?

A

Through progressive dissociation of the tetramer, which increases affinity for oxygen

53
Q

What is erythrocruorin?

A

The oxygen carrying protein of earthworms which is extracellular, therefore not contained within a red blood cell, instead it forms large aggregates with high molecular weights, high oxygen affinity and high co-operativity

54
Q

What is chlorocruorin?

A

An extracellular, haem group protein which forms large aggregates with high molecular weights, green coloured, high affinity and low cooperativity used by sea worms

55
Q

What is hemerythrin?

A

A non haem protein in sea worms which is violet/pink when oxygenated and colourless when deoxygenated
intracellular protein which forms disulphide linked polymers with a low molecular weight, high affinity which has an oxygen binding site which contains two iron groups which become oxidised when oxygen is bound however only one iron binds oxygen directly carrying it as a peroxide

56
Q

What is hemocyanin?

A

Protein used by arthropods and molluscs which use 2 coppers instead of iron, colourless when deoxygenated, is extracellular with high molecular weight

57
Q

What are the general features of oxygen carrying molecules?

A

They all use a transition metal which has one less atom bound than it naturally wants so it can bind oxygen
Used by almost all larger organisms to increase oxygen solubility in the circulation
Can be affected by a range of allosteric effectors
Side chains can control colour

Biosci 203- First 2 topics (7 decks)

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