Hemoglobin structure and function Flashcards
What is a hemeprotein?
They are a group of specialized proteins that contain a heme group as a tightly bound prosthetic group (a non-protein compound that is permanently associated with a protein)
- The role of the heme group is dependent on the environment created by the 3D structure of the protein, heme in:
1) Cytochrome: electron carrier
2) Enzyme catalase: Active site
3) Myoglobin & Hemoglobin: Oxygen carrier
Describe the hemoglobin of RBC
- Hemoglobin has two parts:
1) Protein part (globin)
- Four parts, thus hemoglobin is a tetramer structure, heteromultimeric (different hemoglobin subunits “2-a, and 2-b)
2) Non-protein part (haem = porphyrin + iron)
- A pyrrole ring is a cyclic structure whose ring is formed of four carbon atoms with one nitrogen atom as the fifth atom
- When it binds to O2 in the lungs the RBC turns into the oxidized ferric form Fe3+, and once it gets reduced it turns into Fe2+
- Hemoglobin’s environment is hydrophobic and within this environment is the heme group
What is the function of myoglobin?
It is a single subunit that transfers oxygen from hemoglobin to the muscle mitochondria for oxidative cellular respiration (including oxidative phosphorylation)
What are the similarities between the structure of hemoglobin and myoglobin?
1) They both contain 8 alpha-helices
2) They both contain a heme group
- But myoglobin is a monomeric protein while Hb is a heterotetramer (a2b2)
Describe the structure of hemoglobin
1) Composed of two identical dimers (ab1, & ab2)
2) The two dimers are held together by polar bonds
3) The weaker interactions between the
2 dimers (ionic, hydrogen, and van der Waals)allow them to move with respect to each other, enabling the Hb to occupy different positions (oxy and deoxyhemoglobin)
What are the different configurations of the hemoglobin?
1) T form: The deoxy form of hemoglobin, or taut (tense) form. In
the T form, the two αβ dimers interact through a network of ionic bonds and hydrogen bonds that constrain the movement of the polypeptide chains, characterized by a lower affinity to oxygen
2) R/relaxed form: The binding of O2 to hemoglobin causes the rupture of some of the polar bonds between the αβ dimers, high affinity to oxygen
describe the oxygen binding curve to both hemoglobin and myoglobin
1) Hemoglobin:
At sites where oxygen partial pressure is high Hb will bind to it, while at sites where the oxygen partial pressure is low like in the respiring tissues, the Hb will unload the oxygen
2) Myoglobin:
- It has a high binding affinity to oxygen in both high and low oxygen partial pressure, which enables it to deliver any available oxygen to the mitochondria of the muscles, and this is why in a graph it has a hyperbolic curve
What is meant by allosteric stimulators of Hb?
Substances that binds to the hemoglobin at sites other than the active site and influence its binding strength
What are the allosteric substances that bind to Hb?
1) Increases oxygen affinity:
1. Decreased temp
2. Decreased 2,3-DGP
3. Decreased H+ (decreases acidity = increases pH)
- Causes a left shift in the oxygen dissociation curve and thus makes the curve more hyperbolic as opposed to its sigmoidal curve at the default oxygen binding strength of hemoglobin
2) Decreases oxygen affinity:
1. Increased temp
2. Increased 2,3-DGP
3. Increased H+
4. Increased CO2 (increases H+ ions, decreased pH)
What is meant by the Bohr effect?
- Most of the CO2 produced in metabolism is hydrated and transported as a bicarbonate ion, producing H+ ions and inducing the Bohr effect, The Bohr effect states that the release of oxygen is enhanced when there is low pH and when the partial pressure of CO2 is increased, shifting the graph towards the right and the hemoglobin becomes in the taut form
Describe the effect of 2,3-bisphosphoglycerate to hemoglobin
2,3-BPG is negatively charged due to the presence of a phosphate group, whereas on the contrary the hemoglobin is negatively charged due to the presence of positively charged amino acids (like arginine), it binds to deoxyhemoglobin via ionic interactions stabilizing the T conformation of Hb making reducing its affinity to oxygen, this reduced affinity helps the Hb to release O2 in tissues taking into consideration their partial pressure there
Describe the effect of CO on Hb
CO bonds tightly to Hb iron, forming a structure called carboxyhemoglobin, shifting the Hb to the R conformation as it stabilizes it, increasing the Hb oxygen binding affinity, but even tho CO binding affinity to Hb is much higher and thus O2 will not be able to displace it leading to a decreased O2 deliver to tissues, this can lead to hypoxia and eventually death
Describe the composition of hemoglobin
Heme consists of different porphyrins (like protoporphyrin IX), they are composed of four pyrrole rings (5-membered ring with 4 carbons and one nitrogen) which are linked together by methylene bridges, each pyrrole group has an acetyl and propionyl group in their side chains, the iron ion found at their center is normally reduced +2 and +3 when it is oxidized
What is the major site of heme biosynthesis?
Liver, they synthesize heme proteins and erythropoietic cells of the bone marrow, the initial and last three steps in the formation of porphyrins occurs in the mitochondria, where the intermediate steps occurs in the cytoplasm
What are the starting materials in the synthesis of heme?
1) Glycine (source of nitrogen)
2) Succinyl CoA
- Both of them are the source of carbon and nitrogen
What is the committed and rate-limiting step in the synthesis of heme?
It is the first reaction, mediated by the ALA synthase enzyme, involving the condensation of glycine and succinyl CoA to produce delta-aminolevulinic acid (porphyrin precursor)
- This reaction occurs in the matric of the mitochondria and requires vitamin B6 as a cofactor
What will happen if a mutation occurs in the ALA synthase 2?
X-linked sideroblastic anemia
What is a regulator of ALA function?
- When porphyrins levels are high
- F2+ gets oxidized to Fe3+
- This will convert haem to hemin
- Then hemin will decrease the transcription of ALA synthase
What is the second reaction in the formation of heme?
2 molecules of aminolevulinate condense forming porphobilinogen, which is catalyzed by porphobilinogen synthase/ALA dehydratase, this enzyme contains zinc as a cofactor
- In lead poisoning lead will replace zinc causing toxicity and anemia by inhibiting this pathway
What is the third reaction in the formation of heme?
It is the condensation of four pyrrole rings to form a tetrapyrrole hydroxymethylbilane via hydroxymethylbilane synthase
reaction 4:
Isomerization and cyclization via uroporphyrinogen III synthase to give uroporphyrinogen III
What is the fifth step in the synthesis of Heme?
The acetyl groups of uroporphyrinogen III decarboxylates producing coproporphyrinogen via the enzyme uroporphyrinogen decarboxylase
What is the sixth step in the synthesis of heme?
Coproporphyrinogen III enters the mitochondria and the propionyl groups are decarboxylated generating protoporphyrinogen IX via the enzyme coproporphyrinogen oxidase
Rxn 7:
protoporphyrinogen IX undergoes oxidation to produce protoporphyrin IX via the enzyme protoporphyrinogen oxidase, and iron is incorporated into it spontaneously via ferrochelatase to produce a heme which will inhibit the enzyme ALA synthase (the committed step)
What enhances the rate of iron cooperation with protoporphyrin?
Ferrochelatase enzyme, which is inhibited by lead and heavy metals also
What is meant by porphyrias?
They are rare inherited (acquired) defects in heme synthesis that result in the accumulation and increased excretion of porphyrins/porphyrin precursors, each porphyria accumulates different intermediates of the heme synthetic pathway
Classified into:
1) Erythropoietic
2) Hepatic
- Depending on whether the enzyme deficiency occurs in the erythropoietin cell of the bone marrow or in the liver (hepatic porphyrias can be classified into acute and chronic)
