Mutations in an enzyme called cytochrome-b5 reductase cause a blood disorder cal

Question

Mutations in an enzyme called cytochrome-b5 reductase cause a blood disorder called Methemoglobinemia. (a) What is Methemoglobinemia and what are the physical symptoms?

Methemoglobinemia is disorder of the blood in which an abnormal amount of methemoglobin (a form of hemoglobin) is produced. With methemoglobinemia, the hemoglobin can carry oxygen but is unable to release it effectively to body tissues It can be inherited or caused by exposure to certain drugs, chemicals, or foods. Physical symptoms can include bluish colouring of the skin, developmental delay, failure to thrive, seizures, intellectual disability, headache, fatigue, shortness of breath, lack of energy depending on the type (https://www.nlm.nih.gov/medlineplus/ency/article/000562.htm, June 6, 2016)

(b) What is cytochrome-b5 reductase and how is it related to methemoglobinemia?

(c) Describe how does the oxidation state of the iron affect oxygen binding/transport?

(d) How would the hill coefficient be affected? Briefly explain.

Explanation / Answer

b) cytochrome-b5 reductase is an enzyme that converts methemoglobin to hemoglobin with the help of NADH.They are electron transport hemoproteind

its deficiency causes methemoglobinemia.

NADH + H+ + 2 ferricytochrome b5 (Fe3+)---->NAD+ +2 ferrocytochrome b5(Fe2)

c)iron lies in the centre of the porphyrin ring in haemoglobin in Fe2+ state,bonded to 4 -nitrogen atoms of pyrrole.The fifth coordination site is bonded to histidine residue of the constituent protein and Fe2+ is slightly out of the porphyrin ring plane because of its large size.When o2 is bonded to the 6th coordination site in oxyhaemoglobin, fe2+is simultaneously oxidized to Fe3+ and fits into the ring centre of the molecular plane.

hence.oxidation of Fe2+ of the heme groups causes binding of O2.

d)O2 binding to haemoglobin shows positive cooperative binding ,such that there occurs a structural change in hemoglobin that causes more oxygen to bind to hemoglobin if one molecule binds until all the binding sites in heme molecule are saturated with O2

As Fe3+ moves into the porphyrin ring ,histidine residue also moves along with it,which is the part of the alpha helix.As the histidine lies in the interface of alpha-beta dimer,consequently,the structural change is transmitted to other sub-units. from T-state to R-state.with the later having 20-fold more affinity for O2.

the hill equation,Y=k[X]^n/1+[X]^n

[n=hill coefficient

[X]=ligand concentration =O2

k=association constant

n>1 for positive cooperativity.

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