Haemoglobin and Myoglobin Flashcards
What are globular haemeproteins?
Group of specialised proteins that contain haeme as a tightly bound prosthetic group
What is the role of the haeme group in myoglobin and haemoglobin?
Oxygen binding
What is the function of the haeme group in soluble guanylyl cyclase?
Binding of the vasodilator - nitric oxide
What is the haeme group?
Complex of protoporphyrin IX and ferrous iron (Fe++)
What additional bonds may the ferrous iron form in myoglobin and haemoglobin?
Histidine amino acid in the associated protein
Oxygen
What is myoglobin?
Monomeric 17.8kDa haemeprotein
What is the physiological function of myoglobin ?
Reservoir of oxygen within muscle cells to drive muscle contraction during arterial hypoxaemia
What kind of animals have high concentrations of myoglobin?
Diving mammals
What structure is found in 80% of myoglobin?
8 alpha helices
Where is haeme found in the protein?
Tethered into a hydrophobic cleft formed by E & F helices which contain a histidine residue
Proximal H (F8) binds Fe++ in haeme
Distal H (E7) helps stabilise ferrous iron allowing reversible binding of oxygen to Fe++
How many molecules of oxygen may a myoglobin bind to?
1 as it contains just 1 haeme group
Where is haemoglobin found?
Erythrocytes
What is the structure of the haemoglobin molecule?
4 protein subunits with associated haeme group, each structurally similar to myoglobin
2 alpha and 2 beta subunits
One molecule may transport 4 molecules of O2
What 2 forms of haemoglobin exist?
Oxyhaemoglobin and Deoxyhaemoglobin
What form does the haeme group take in deoxyhaemoglobin?
Non-planar
How far does Fe++ lie outside of the porphyrin plane is deoxyhaemoglobin?
0.4 armstrongs
What configuration is found in oxyhaemoglobin?
Planar due to Fe++ pulled into plane of porphyrin ring
What other name is given to deoxyhaemoglobin?
T form
What other name is given to Oxyhaemoglobin?
R form
Why is deoxyhaemoglobin taut?
Hydrophobic and ionic bonds constrain relative movement of four subunits
What does the taut form mean for deoxyhaemoglobin?
It has a low affinity for oxygen
Why is oxyhaemoglobin relaxed?
Movement of ferrous iron into plane of the haeme group causes changes in the quaternary structure of haemoglobin
Hydrophobic and ionic bonds are broken
Increased relative movement of subunits
What is a cooperative system in relation to O2 binding to Haemoglobin?
Binding of oxygen to one subunit of the haemoglobin tetramer influence the oxygen binding properties of the other subunits
What is a T-R conformational change caused by?
Oxygen binding to one subunit is transmitted to the other 3 monomers in the tetramer… Binding of oxygen to one subunit induces increased binding to the other 3 subunits
Define the partial pressure of O2(Po2).
Units of O2 concentration in Blood plasma
What is the Oxyhaemoglobin Dissociation Curve?
% Saturation of haemoglobin vs O2 concentration in blood
What shape is the curve in the oxyhaemoglobin dissociation curve and why?
Sigmoidal curve due to the cooperative nature ofO2 binding to haemoglobin
What shape is the myoglobin dissociation curve?
hyperbolic
What is the PO2 and PCO2 in the pulmonary artery?
PO2 = 40
PCO2 = 46
What is the PO2 and PCO2 in the pulmonary vein?
PO2 = 100
PCO2 = 40
How many oxygen molecules are released on average at rest from haemoglobin?
1
What is the oxygen concentration where hypoxia begins?
PO2«40mm Hg
What is reverse cooperativity?
R-T transitions reduce the affinity of other Hb subunits for O2
How should one think about oxygen release from haemoglobin?
Postage stamp analogy
At what tension does the first release of oxygen occur?
40 mm Hg
What other factors modulate the affinity of haemoglobin for oxygen?
pH of Blood
PCO2
2,3 diphosphoglycerate
With the other factors, how are they increased?
Increased metabolic activity
What does acidity and carbon dioxide do to the oxyhaemoglobin curve?
Increase in metabolic activity
What is the Bohr Effect?
Reduction in pH causes protonation of histidine residues on Hb
This allows additional ionic bonds to form between the Hb subunits which stabilises the T form
CO2 group may directly bind to free amino groups on Hb
Does a lower pH increase or decrease haemoglobin’s affinity for O2?
Decrease
Where is the glycolytic pathway the only source of ATP?
Hypoxic tissues
Where does 2,3 diphosphoglycerate bind to haemoglobin?
Pocket of positively charged amino acids formed by the beta subunits which stabilises the T form
What does high oxygen concentrations in the lungs do to 2,3-dpg
Expels it
What does haemoglobin stripped of 2,3 - DPG do to its affinity for oxygen binding?
Curve shifts leftwards causing a greater affinity
Why is carbon monoxide so dangerous?
Haemoglobin has a 200 fold affinity for CO than for O2
It binds to the haeme group and may displace O2 forming carbon monoxyhaemoglobin
What are the toxic effects of carbon monoxide?
Reduces the overall oxygen transported in blood
At sub-lethal concentrations, binding of CO shifts conformation of other subunits to R form which causes tissue hypoxia
What is the major form of haemoglobin in adults?
Haemoglobin A
What is the minor form of haemoglobin in adults?
Haemoglobin A2
What is the difference between Haemoglobin A and Haemoglobin A2?
Beta subunits in A replaced by closely related delta subunits in A2
What form of Haemoglobin is produced during early embryonic development and what subunits are present?
Haemoglobin Gower 1
2 teslas and 2 epsilons
What form of Haemoglobin is synthesised during foetal development and what subunits are present?
Haemoglobin F
2 alphas and 2 gammas
Does foetal haemoglobin have a higher or lower affinity to oxygen than Haemoglobin A and why?
Higher due to very weak binding of 2,3-DPG which facilitates transfer of O2 across placenta from maternal erythrocytes
What is the name of the family of genetic diseases that result in insufficient quantities of haemoglobin molecules and structurally abnormal haemoglobin molecules?
Haemoglobinopathies
What usually results from haemoglobinopathies?
Anaemia
Where are the genes for the haemoglobin subunits located?
Chromosome 11 and chromosome 16
What subunits are produced by Chromosome 11?
beta subunits
What subunits are produced by chromosome 16?
alpha subunits
What is sickle cell anaemia caused by?
A point mutation in the beta globin gene (valine inserted instead of glutamine)
What symbol is given to haemoglobin in a sickle cell anaemia patient?
HbS
What differs in deoxy-HgS
Val6 interacts with Phe85 and Val88 of beta chain of neighbouring molecules resulting in clumping of HbS molecules
What happens in Oxy-HgS?
Phe85 and Val88 is internalised in the molecule causing no change in the R form
What are the signs and symptoms of sickle cell anaemia?
Lower PO2 levels in systemic capillaries - aggregation of HgS, RBCs are sickle-shaped, Localised tissue hypoxia, haemolysis
Anaemia
Pain and fever (sickle cell crisis)
Organ damage
severe infections
What kind of condition of is Sickle Cell Anaemia?
Autosomal Recessive Disorder - Homozygous
What is the demographic with the highest rate of sickle cell anaemia?
People of African origin
Why did sickle cell anaemia evolve?
Heterozygous individuals are more resistant to malaria in regions where it is endemic
What are Thalassaemias?
No production or greatly reduced production of the alpha or beta globin subunits
What happens in an individual who is has a homozygous form of beta thalassaemia?
Precipitation of “unpaired” alpha subunits leading to death of progenitor RBCs
Ineffective erythropoiesis and severe anaemia
What is the progression of alpha thalassaemia?
1 defective gene = asymptomatic
3 defective genes = severe haemolytic anaemia
4 defective genes = foetal death
