This document includes a complete summary plus all known altfragen of the lecturers in SoSe 2020. The summary/information is already written in form of exam questions for improved learning.
Molecular Medicine 1
Summary and Altfragen
SoSe 2020
T. H.
Short explanation of the summary’s structure:
The document is organised by the SS2020 lecturers and includes all known altfragen (underlined).
This summary only includes all known altfragen and was elaborated by my own investigations together with
lectures of Molecular Medicine 1 in the summer semester 2020. This document is only for personal use and
disclosure to any third party is prohibited. I cannot guarantee that the information is exhaustive or accurate.
, Skern
What does haemoglobin do?
• Binds oxygen in lungs and releases it in the capillaries, binds dioxide in capillaries, regulates pH
o Binds oxygen when concentration is high and releases when conc. is low
Structure of haemoglobin?
• 4 protein chains and 4 haem groups with quaternary structure
o Haem group binds oxygen reversibly without oxidation of Fe2+ to Fe3+; oxidation of
haemoglobin is prevented by hydrophobic environment provided by globin chains
• HbA (adult) has 2 α and 2 β chains (all α, β and γ chains have similar fold)
• HbF (fetal) has 2 α and 2 γ chains
o HbF has higher affinity for O2 than HbA allowing maternal HbA to deliver O2 to fetus because
there is blood barrier and blood should not be exchanged between mother and child (or at least
a minimum)
Important haemoglobin mutants?
• Point mutants – single AA change very important in function
o HbS β chain Glu6 → Val (introduces hydrophobic residue)
o HbC β chain Glu6 → Lys (changes charge)
o HbE
• Missing chains → thalassemia
o Missing genes or gene defect
▪ The β chain: gene present but synthesis defective
▪ The α chain: gene deletion
What is important to know about HbS and HbC?
• Relation of sickle cell anaemia and malaria-parasite plasmodium falciparum, HbS and HbC give a
selective advantage
o HbS: protects as heterozygote (HbA/HbS) whereas homozygote (HbS/HbS) leads to severe
disease the sickle cell anaemia
o HbC: protects only as homozygote (HbC/HbC)
What is the origin of P. falciparum?
• Most closely related to a species in gorilla, the closer the genomes of 2 different species the more likely
it is that a pathogen/virus can cycle between those 2 or go from 1 to another
Why does the mutation HbS affect Hb structure?
• Mutation generates a hydrophobic patch which leads to a new interaction in desoxyHb
o Causes HbS to precipitates as fibers in the capillaries and thus red blood cells change their
formation
o Leads to sickle cell formation, requires critical cluster of 10 HbS molecules
Why do the erythrocytes sickle?
• Kinetic reasons
• Fiber formation depends on HbS concentration
• Concentration in heterozygote is half that of homozygote
o Rate of fiber formation: 30s in heterozygote, homozygote 30ms
o It takes 30s to form these fibers and also the the red blood cells to sickle, time the cells need to
get from capillaries to lungs and get reoxygenated
o So the erythrocytes in a heterozygote can return to lung and get reoxygenated before sickling
occurs
, o In homozygote, 30ms is a really short timing and sickling happens quickly and sickle cells start
to block capillaries
• Body recognizes wrong red blood cells and removes sickle cells which leads to anaemia (Blutarmut)
• Capillaries blocked, O2 conc sinks, even more cells sickle, blood vessels clog, kidney failure etc.;
homozygotes lethal before adult but can now be treated with hydroxyurea which encourages the synthesis
of HbF
Why are HbA/HbS heterozygotes protected against P. falciparum?
• Replication of R. falciparum lowers pH of RBC (red blood cells)
o Hb loses O2, starts to sickle, increased by 40% in HbA/HbS
• Sickled cells lose potassium which is required for P. falciparum development; therefore parasite dies in
K+ depleted cells
• Even if sickling does not kill parasite, sickled cells removed by body so reduced replication gives immune
system time to increase defence
• HbS frequency as high as 40% in Africa, in malaria area HbA/HbS has a 15% higher reproductive fitness
than HbA/HbA
• Parasite also reorganises actin cytoskeleton but the oxidation products of HbS and HbC prevent this,
affecting transport in infected RBC and export of disease-causing parasite adherins
Why is HbC not distributed more widely/why is HbS distributed more widely?
• Hetero and homozygotes do highly reduce in risk of clinical malaria but limited pathology compared to
HbS
o Does not disturb the haemoglobin that much, not that effective sickling and protects mainly
homozygotes, so it also requires longer time to spread out whereas for HbS heterozygosity is
already enough
Describe life-cycle of malaria parasite!
What is a future attempt to understand process of this disease?
• Proteomics can play a key role here because each proteome
defines the respective organism, the three organisms
interact together and also have evolved and are evolving
together
• So looking at 1 of them or a change in proteome of 1 of
them can tell you something new or maybe upcoming of the
other organisms’ proteome
New options to fight malaria?
• One vaccine with limited efficiency
• Anti-malarials best line of defence
o Artemisinin in collaboration with piperaquine which is a protease inhibitor prevents parasite
eating haemoglobin (ACT, artemisinin combination therapy)
• Resistance to therapies already shortly after their introduction
What are the resistance mechanisms?
• Chloroquine: normally binds heme, preserving its toxicity; resistance: blocked transporter or efflux thus
it cannot reach heme
• Mefloquine: active in cytosol targeting parasites ribosomes; resistance: upregulation of transporters
pumping mefloquine into digestive vacuole and then destroyed
• Piperaquine: targets plasmepsins which are required to digest haemoglobin; resistance: upregulation of
plasmepsin
• Lumefantrine: like chloroquine
, What about artemisinin?
• P. falciparum evolving and having new mutations in specific proteins like Kelch 13 (K13) and thus lead
to resistance to artemisinin
• Resistance started to establish in south east asia and the spread to Arabic world, Africa and south America
New targets in sight?
• K13 mutations discovered or present when artemisinin is present, also tested with other drugs, many other
genes and variants for resitances
• 1 gene (either target or resistance) was identified for each compound
How does A. Gambiae find a human?
• Odour (Geruch) recognised via odorant receptor (OR), to test this they expressed the ORs of a malaria
receptor in fruit flies
o Eg AgOR2 (A. gambiae odorant receptor) recognises indole which is main constituent of human
sweat
o AgOR10 similar to indole, phenol and 3-methyl indole (induces females of other species to lay
eggs; also mosquito repellent (abweisend) produced by cows depending on conc.)
o ORs can act differently, some are activated by specific odours and another OR is deactivated by
the same substance or could activate another OR
• Looking at the distribution of the odours of A. gambiae compared to drosophila revealed these results, it
showed that fruit flies are not interested at all in aromatics like indole, phenol etc., and vice versa, A.
gambiae not that much interested in the odours the fruit flies are looking for
If you compare human- and animal specific A. aegypti what was found out?
• Domestic A. aegypti attracted to humans associated with affinity of AaegOr4 (A. aegypti odorant receptor
4) to sulcatone, forest A.a. not attracted
• Sulcatone is a volatile compound unique to human odour, low conc. attracts high conc. repells
HbA, HbS und HbC beschreiben, warum hat HbA/HbS bei Malaria einen Vorteil?
Define the unit Angström. Why are HbA molecules never less than 10A apart? Is fiber formation in HbS
enthalphic or entropic? Justify your answer. How can mosquitoes sense humans?
• 1 Å is 1/10 of a nanometer (0.1 nm) and commonly used in structure biology
Who was John Dalton?
• British chemist, could not see colours as others and wanted to find out why he was lacking these colours
• Achromatopsia sort of colour blindness, complete colour blindness, which is inherited autosomal
recessive
o Small group of people stranded on island due to typhoon (1 male and 19 female), male started
to repopulate and had this mutation for colour blindness, it was a limited gene pool and therefore
this high frequency of achromatopsia exists and this gene is so wide spread
How are the cells arranged in the retina?
• Retina is light receptive part, consists of cones (daylight and colour vision) and rods (night vision)
• Cones: cell membrane snake like, in membrane there is photopigment which are 7 helical transmembrane
domains where is the binding site for retinal is
o Around the retinal there is a hydrophobic pocket, arrangement of different AAs like having
tyrosine or serine affects wave length
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