haemoglobin and molecular medicine Flashcards
Describe the structure of haemoglobin.
Haemoglobin a tetramer with an2β2 structure, where the αunit contains 141 amino acids and the βunit contains 146 amino acids.
What is the primary difference the α and β subunits of haemoglobin?
The primary sequences of α and β subunits differ, but their tertiary structure is the same.
How does foetal haemoglobin differ from adult haemoglobin?
Foetal haemoglobin (α2γ2) has a different subunit composition compared to adult haemoglobin, and it allows for efficient oxygen exchange in the foetal circulation.
Define cooperative binding of oxygen in haemoglobin.
Cooperative binding of oxygen in haemoglobin refers to the phenomenon where the binding of one oxygen molecule enhances the affinity for subsequent oxygen molecules.
Who determined that sickle cell disease was caused by an abnormality in haemoglobin?
Linus Pauling, from CalTech, Pasadena, determined that sickle cell disease was caused by an abnormality in haemoglobin.
What was the contribution of Vernon Ingram in the study of sickle cell disease?
Vernon Ingram, from MIT, Boston, determined the mutation responsible for sickle cell disease.
Describe the role of Max Perutz in understanding sickle cell disease.
Max Perutz, from Cambridge, provided a structural explanation for the effect of mutation in sickle cell disease.
Who was the first person to clearly describe a link between molecular and clinical defects in human disease?
David Weatherall, from Oxford, was the first person to clearly describe a link between molecular and clinical defects in human disease.
What technique did Maud Menten and colleagues use to distinguish between haemoglobin variants in 1944?
Maud Menten and colleagues used sedimentation and electrophoresis to distinguish between haemoglobin variants in 1944.
Describe the contribution of Linus Pauling in the study of sickle cell disease.
Linus Pauling determined that sickle cell disease was caused by an abnormality in hemoglobin
What did Vernon Ingram determine regarding sickle cell disease?
Vernon Ingram determined the mutation in sickle cell disease.
Define the significance of Max Perutz’s work in relation to sickle cell disease.
Max Perutz provided a structural explanation for the effect of mutation in sickle cell disease.
How did David Weatherall contribute to the understanding of human diseases?
David Weatherall was the first person to clearly describe a link between molecular and clinical defects in human disease.
What was the key finding regarding the electrophoretic mobility of hemoglobin in sickle cell patients?
The sickle cell hemoglobin was more positively charged compared to normal hemoglobin.
Describe the observation made about the hemoglobin of healthy individuals of Caucasian and African descent.
Healthy individuals of Caucasian and African descent were shown to have ‘indistinguishable’ hemoglobin.
What was the significance of the difference observed in the globins of hemoglobin from normal and sickle cell patients?
It was the first demonstration that a disease could be caused by an abnormality in a protein.
Describe the experiment conducted by Vernon Ingram involving haemoglobin and trypsin digestion.
Vernon Ingram digested haemoglobin into fragments using trypsin and analyzed them through 2-dimensional electrophoresis.
Define the small change observed by Vernon Ingram in sickle cell haemoglobin.
The change consisted of the replacement of one glutamic acid by valine in nearly 300 amino acids.
How did Vernon Ingram demonstrate the difference between haemoglobin A and haemoglobin S at the peptide level?
He found one peptide that was positively charged in haemoglobin S but uncharged in haemoglobin A.
Do you know the error Vernon Ingram made in the N-terminus sequence of haemoglobin?
He mistakenly listed Valine instead of Glutamic acid in the sequence.
Describe the genetic code changes identified by Vernon Ingram related to sickle cell mutation.
In sickle cell mutation, Glutamic acid (GAG) is replaced by Valine (GTG) in the genetic code.
What contribution did Vernon Ingram make to the field of molecular medicine?
He is considered the Father of Molecular Medicine for his groundbreaking work on sickle cell mutation.
Explain the significance of Vernon Ingram’s discovery regarding the sickle cell mutation in the β-globin chain.
He demonstrated that the sickle cell mutation was specific to the β-globin chain and not the α-globin chain.
What hypothesis did Vernon Ingram contribute to with his work?
He contributed to the ‘one gene – one protein’ hypothesis, providing the first real proof.
Describe Vernon Ingram’s findings regarding the effect of sickle cell mutation on foetuses and neonates.
He explained why sickle cell doesn’t affect foetuses or neonates due to the presence of α2γ2.
What other inherited defect in haemoglobin did Vernon Ingram work on?
He also worked on thalassaemia, another inherited defect in haemoglobin.
Explain the two proposed reasons by Vernon Ingram for the reduction in globin chain synthesis.
He proposed that the reduction could result from a silent mutation in the structural gene or a defect in neighboring DNA regulating gene expression.
Describe the contribution of Max Perutz to molecular biology and.
Max Perutz determined the 3-dimensional structure of haemoglobin using X-ray crystallography, explained the molecular mechanism for oxygen binding, and provided insights into how mutations lead to disease.
What is the function of myoglobin in mammalian muscle tissue?
Myoglobin is a simple O2 binding protein with a single binding site for oxygen.
Define the term ‘globins’ and their common structural feature.
Globins are a protein family found in all Kingdoms of Life, based on eight alpha helices.
How does the haemoglobin tetramer exist in two states and what are the characteristics of each state?
The haemoglobin tetramer can exist in a low affinity state (deoxyhaemoglobin) and a high affinity state (oxyhaemoglobin), with a P50 value indicating the oxygen affinity of each state.
Describe the significance of Glu-6 in haemoglobin tetramers.
Glu-6 is present in the 2 beta subunits of the haemoglobin tetramer.
What is the role of Val-6 in haemoglobin tetramers when deoxygenated?
Val-6 can bind to a hydrophobic patch formed by Phe-85 and Leu-88 on a beta chain of another haemoglobin tetramer when deoxygenated.
Who is known as the ‘Father of Molecular Medicine’ and why?
Vernon Ingram is considered the Father of Molecular Medicine for his work using DNA restriction enzymes to study mutations affecting transcription/translation.
Define thalassaemia and its association with specific populations.
Thalassaemia is a blood disorder, more widespread than sickle cell disease, common in Mediterranean populations and the ‘malaria belt’.
What achievement is Professor Sir David Weatherall known for in the field of medical research?
David Weatherall received the 2010 Lasker-Koshland Special Achievement Award for advances in thalassaemia research.
What method did David Weatherall develop at Johns Hopkins related to globin chains?
David Weatherall developed a method to separate alpha and beta globin chains and quantitatively measure the rate of synthesis of each chain.
How did Max Perutz contribute to the understanding of haemoglobin structure and function?
Max Perutz used X-ray crystallography to determine the 3-dimensional structure of haemoglobin, explaining its oxygen binding mechanism and the impact of mutations on disease.
Describe the distribution of sickle-cell anaemia haplotypes among nations with high prevalence of the disease.
Sickle-cell anaemia haplotypes are distributed globally, with specific prevalence in regions known as the ‘malaria belt’ and Mediterranean populations.
