lecture 1 - baker study notes.odt

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University of Toronto St. George
Michael Baker

Lecture 1 Hemoglobin - Oxygen transporter - If you are a large animal you need the circulatory system to distribute oxygen evenly - Oxidation = loss of electrons - Here we are talking about oxygenation (O2 coming in)– want to promote it (avoid oxidation -would kill hemoglobin) - Hemoglobin has a quaternary structure (alpha 1 , alpha 2, beta 1, beta 2) - ****(4 subunits of monomers) o Two types of subunits – alpha and beta and two of each - These subunits are not covalently linked- largely ionic and non-covalent bonds - Black part = the heme group - Myoglobin = oxygen transporting in muscles - Myoglobin quite different from hemoglobin Heme prosthetic group - Organic molecule – not an amino acid - It’s attached to the amino acid – hemoglobin - It’s not ferric ion(otherwise it would burn upone binding of oxygen)– it’s ferrous (to allow oxygen to bind ) - Know that there are number of pyrolle rings fused together to give highly unsaturated structure with the iron sitting in the middle - Don’t worry about drawing the entire structure - Metals has coordinate links (not covalent) Myoglobin - Similar to one of the subunits of hemoglobin - Iron not only has four nitrogens around it- but one n on the bottom that allows the binding to imidiazole ring to stabilize it? - Oxygen on the top is stabilized by h- bonding - Hemogoblin carrys o and drops it where needed - If heme wasn’t in the middle- protected by proteins- then it would be oxidized to fe 3+ and start binding water instead of oxygen o So you can’t inject a patient with soluble heme to allow it to carry more oxygen – it needs to be surrounded by proteins - Carbon monoxide binds to the heme – it’s very toxic Myoglobin - Kind of like your cousin stays the same - Stays in the muscle cells - Unless you have a heart attack (myoglobin is lost)- muscle cells die- myoglobin released to the blood- o thus one marker for heart attack = myoglobin released in the blood – monomeric- one single protein- no subunits – binds oxygen very efficiently - Beat chain of hemoglobin structure is similar to myoglobin structure – largely alpha- helical o There are some beta turns to help with turning and folding How mygolbin – a simple single protein binds to oxygen?- the graph - myoglobin shoots up like a rocket (the percent the molecule is bound to oxygen) - Fractional saturation = y axis = what percent of the protein bound to oxygen - As you increase the pressure of oxygen (higher concentration of oxygen)- you would increase binding of oxygen - Hemoglobin also increases – but more and s shape - Lungs have a higher oxygen pressure than tissues - Both myoglobin and hemoglobin will eventually be saturated because there is muscle in the lungs and with myoglobin inside will be fully saturated**** what? - Hemoglobin loses pressure more quickly than myoglobin o myoglobin is very efficient and hyperbolic curve o hyperbolic curve similar to enzyme saturatioin – as you increase substrate (oxygen) concentration – the curve goes up hyperbolic Why not use myoglobin in redblood cells? - It is very efficient and binds oxygen quickly - Bus example- where you are sitting on the myoglobin bus seat but you can’t get off at your stop - 90% efficiency at the tissue level- will never let go of oxygen - Myoglobin binds so tightly – won’t let oxygen get off - it works well in a muscle cell because the pressure is a lot lower - S – sigmoid sign for hemoglobin = cooperativity o Hemoglobin graph starts slowly but as you bind more oxygen it goes really quickly o One subunit increases the affinity for oxygen for another subunit o it starts slowly but once it gets going – it shoots up like a rocket – as you bind oxygen they start influencing each other - A bit of resistance in the beginning because they don’t know what’s coming - But like chocolate once it has a little bit – it will want more - Other subunits bound to it realizes how good the chocolate is so will want it - The progression is an allosteric efffect where one subunit affects the another - The iron in the heme ring is attached to the rest of the protein- it actually changes its geometry the structure of protein - As a result of oxygen binding – it affects the interface structure – all the subunits shift a little bit loosening and opening up the structure - the cooperativity indicates t-state and r-state; You go from t4 state(deoxy state) to t3r to tr3 to r4 state (all relaxed)- The actual mechanism- How does this happen? - When O2 binds at one subunit → a change in conformation of that subunit - Binding of O 2 at heme→ a shift of Fe 2+ into plane of the porphyrin rin - This pulls the attached His F-8 towards the porphyrin ring - Position of the α-helix with His F-8 also shifts - This leads to an opening up of the structure of this subunit - The open conformation is also known as the R or relaxed conformation - This change influences other subunits in the Hb tetramer - Thus T 4tight deoxyHb changes to R
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