hello and welcome to the review of chapter three of lippincott's biochemistry textbook in this chapter we're gonna go over globular proteins if you enjoyed the video please don't forget to give it a like and subscribe to the channel and if you want to support the channel you can do so via the patreon link within the description so starting off we're going to talk about heme proteins which are a particular type of globular proteins that contain this heme group this heme group has various roles depending on the environment that the protein is within but it is essentially just an ion or a ferrous ion which means iron with a two plus complex with proto-porphyrin nine so you can see this ion over here in this figure 3.1 where it forms six bonds four of them are two nitrogen molecules or nitrogen atoms i should say and then the other two are left free one of them is usually taken up by a histidine residue which is an amino acid and then the other one is left open which usually is used for binding of oxygen for example with myoglobin which is going to be the first globular heme protein that we're going to talk about in addition to hemoglobin a little bit later on so myoglobin is used in the heart and skeletal muscle to function more as an oxygen reservoir and then some functions as a oxygen carrier now it's important to know that myoglobin is a simplified version of a hemoglobin protein molecule meaning that it's just one polypeptide with an alpha helical content so it has alpha helixes within it and then within those alpha helixes we have this crevice which is where the heme group is actually found and it's lined with nonpolar amino acids and these hydrophobic interactions keep that heme group in that location within that crevice and then on the outer surface of the myoglobin once again we have the polar amino acids so that helps to actually interact with water so that can be somewhat soluble so that is myoglobin it is more the single polypeptide nice and simple whereas hemoglobin is a little bit more complex because it contains four of these polypeptides all complex together it contains two alpha groups and two beta groups now the alpha ones and the beta ones group together as one single dimer and then the alpha two and the beta twos group together as its own dimer so there's two identical dimers within the quaternary structure of a hemoglobin protein which is labeled alpha beta 1 and then alpha beta 2. now the difference between the hemoglobin and myoglobin is important because you will notice that hemoglobin with its four polypeptides has four heme groups which means it can carry four oxygens compared to just the one oxygen with myoglobin hemoglobin is also a little bit more complex because it can also transport hydrogen ions and carbon dioxide now that is a simplified version of a hemoglobin protein but here's it gets a little bit more complex where we have these two states depending on the positions of the two different dimers the simple way to remember this is that we have the t or taut structure and this is when it is deoxygenated so there is no oxygen bound to this hemoglobin and then there is also the r or relaxed structure of hemoglobin when there is oxygen bound to it so oxygen bound to hemoglobin creates the relaxed state you can think that you're nice and relaxed when you have plenty of oxygen but then when you don't have any oxygen then you're in the tort structure or t state so that is the deoxyhemoglobin state now the r form or the relaxed state obviously has a higher affinity for oxygen whereas the t state has a lower affinity for oxygen and it will go back and forth between these states depending on the partial pressure of oxygen in the environment which we'll get to next so we can describe that a little better looking at this oxygen dissociation curve which you can see over here in figure 3.6 now this is describing that on the x-axis we have the partial pressure of oxygen so this is how much oxygen is within the environment around the hemoglobin and then we have percentage of saturation with oxygen so that's how much oxygen is actually within the hemoglobin itself or the myoglobin if we're going to talk about myoglobin so as you can see if we talk about myoglobin first we only need a very small partial pressure of oxygen in order to be highly saturated with oxygen so myoglobin has a high affinity for oxygen which gives it the role of having a very good oxygen storage capability because you only need a small partial pressure of oxygen to completely saturate its levels but on the flip side in order for that myoglobin to release the oxygen you need the partial pressure of oxygen to reduce to pretty low levels for it to actually let go of that oxygen molecule and that's the major difference for hemoglobin which gives it more of a role as a transport protein for oxygen because you'll see the hemoglobin has the sigmoidal shape to it so that means that at the higher partial pressure of oxygen we have a very high saturation with oxygen for the hemoglobin but then as the partial pressure reduces our affinity for oxygen actually reduces so we get a greater reduction in the saturation of the hemoglobin so basically meaning as the environment around the hemoglobin reduces in partial pressure it starts to offload its oxygen and get rid of its oxygen because its saturation reduces so the reason behind this is because oxygen has an allosteric effect to hemoglobin so as the partial pressure reduces the affinity for hemoglobin with oxygen also reduces and vice versa so the more oxygen molecules that bind to hemoglobin the greater affinity that it has for oxygen so this is very helpful for when we are breathing in oxygen from our lungs we have a high partial pressure of oxygen and so we obviously want to load up our hemoglobin with oxygen so then it can transport it around the body and it will eventually reach the tissues which are metabolically active and they're using all the oxygen so there is a low oxygen content in the tissues which mean that we are operating at this lower partial pressure and that will lower the affinity of hemoglobin with oxygen so then it actually wants to release its oxygen to the tissues so then now the tissues are being supplied with more oxygen and the hemoglobin isn't holding on to it which would be detrimental so that's why hemoglobin is better as a transport protein for oxygen because it's able to increase its affinity when it needs to actually store up with oxygen in the lungs and it's able to reduce its affinity when it needs to get rid of its oxygen in the tissues whereas myoglobin is more of a storage protein it just wants to hold on to oxygen to be used during anaerobic environments when there's very very low oxygen so myoglobin is just going to hold on to oxygen and will not release it until the partial pressure of oxygen reduces to pretty low levels so that describes how oxygen affects the affinity for hemoglobin there are other factors as well and they all relate to metabolism so the three main ones include hydrogen ions carbon dioxide and a molecule called 2 3 bpg now all of these states are going to be higher when we have higher metabolism you're going to have higher carbon dioxide when your tissues are using more oxygen you're going to have higher acid whenever you have higher metabolism just from breakdown products from metabolism and because carbon dioxide via the carbonic anhydrase equation gets turned into bicarbonate and hydrogen ions and then you're going to have high 2 3 bpg because it is a byproduct of the glycolytic pathway so that's breaking down glucose for energy within the red blood cells so if you have high metabolism you're going to have higher 2-3 bpg because you are actually using more energy you need to produce more energy from your glucose so all of these states high acid high carbon dioxide and high 2 3 bpg have an influence on hemoglobin's affinity for oxygen it will shift this entire oxygen dissociation curve to the right so that means hemoglobin is going to have a lower saturation of oxygen for a given partial pressure or said differently you will offload oxygen a lot easier at higher partial pressures of oxygen which is obviously going to be beneficial if you're a tissue that's highly metabolically active you're going to have a lot of acid carbon dioxide and 2 3 bpg around which is basically telling the hemoglobin to let go of its oxygen because there is a demand for oxygen in the tissues so shifts to the right reduces the affinity of hemoglobin to oxygen for a given partial pressure of oxygen which helps to unload that oxygen to the tissues so we are able to create those environments using acid and carbon dioxide and this is called the bohr effect and then also 2 3 bpg so that is the basics of our oxygen dissociation curve and how hemoglobin's affinity for oxygen is able to change now it does go into a little bit more details about 2-3 bpg and how it actually stabilizes the t conformation of the hemoglobin molecule remember that's the tort conformation or the deoxyhemoglobin so that's how it's able to reduce its affinity and more specifically you're going to have higher 2 3bpg whenever we have hypoxia or anemia since the red blood cells are now going to use more of that glycolytic pathway and produce more 2-3 bpg as a by-product now interestingly about 2-3 bpg is that in blood that is stored the red blood cells actually reduce their levels of 2-3 bpg so that means that the red blood cell within that stored blood actually has an extremely high affinity for oxygen because we don't have any 2 3 bpg that's keeping it in that deoxy state so that means that transfused red blood cells from old blood is going to hold on to its oxygen a lot better and not give it up to the tissues which is obviously bad we want our hemoglobin to give up oxygen to the tissues so in order to correct for this there is a treatment called rejuvenation which is a solution that actually restores the 2 3 bpg in stored blood one quick little paragraph on carbon dioxide the majority of carbon dioxide is actually carried in the blood as bicarbonate and h plus ions because it's a major buffer within the blood but some of the carbon dioxide is actually carried as carbamenoglobin so it's bound to hemoglobin in this state which stabilizes the deoxy form of hemoglobin reducing its infinity for oxygen once again and then we do have some carbon dioxide also just dissolved directly into blood but only a small proportion and then lastly here before we go into some other minor hemoglobins it talks about carbon monoxide bonding carbon monoxide is horrible because it does two things one it takes up one of the slots that oxygen would use in the heme group within the hemoglobin so that actually reduces the carrying capability of hemoglobin because now one of those four slots is taken up by carbon monoxide and sometimes even half of it is taken up by carbon monoxide as you can see over here in figure 3.13 here with carbon monoxide 50 has taken up this hemoglobin in this example so now we can only have an oxygen carrying capability or content half of what was available without any carbon monoxide because half of the hemoglobin cannot actually bind to oxygen now it not only takes the slot of oxygen but it also increases the affinity of the other heme groups to oxygen so that means that not only is it taking up an extra slot it's telling those other heme groups to not let go of the oxygen so now you have hemoglobin that's carrying half your oxygen and it's not letting go of it so now getting to our minor hemoglobins there's some other hemoglobins within the body which obviously as the title explains are relatively minor we have hemoglobin a which is our main hemoglobin 90 of our hemoglobin made out of alpha and beta chains then we've got this hemoglobin a2 which is made out of alpha and delta chains which comprises a tiny proportion of our hemoglobin and then there's also hemoglobin f which is our fetal hemoglobin so this is only present within the fetus and this is two alpha chains and then two delta chains as well now these delta chains are part of the globin family and this hemoglobin if is found mainly just after birth and quickly depletes as hemoglobin a starts to get produced by the bone marrow now hemoglobin f does have a higher affinity for oxygen because in the fetus that hemoglobin needs to have a higher affinity than your mother so then it's able to take the oxygen from your mother's hemoglobin to then transport around the fetus so there's a higher affinity of hemoglobin if to be able to take oxygen from hemoglobin a from your mother and transport it around the fetal body but once you're born you no longer need that and you want to produce more hemoglobin and then lastly we've got this hemoglobin a1c which just means that it's a glycated meaning that it's condensed with hexose or a sugar type of hemoglobin pretty small percentages like that and you have an increased number of hemoglobin a1c when you have states with high blood sugar like diabetes as shown over here now before getting into disorders of our hemoglobins it's important to know just the basics of the genes that comprise the production of alpha and beta hemoglobin polypeptides so the alpha gene contains these two areas that can produce your alpha chains which are located on chromosome 16 whereas our beta globulins they are produced from chromosome 11 and we only have one site that's able to produce that you can also see on this diagram which you can pause if you need to memorize these other types of hemoglobin that are also produced on these two chromosomes but the main point is chromosome 16 is used for your alpha globins and there's two sites so two genes to produce your alpha globins and then our beta globulins they are produced from chromosome 11 and there's only one site when it comes to the actual dna transcription and translation this text doesn't go into too much about genetics but essentially you have your gene that gets transcribed into mrna so that's just reading the gene producing this one strand of mrna which is then spliced meaning that you remove the introns and just leave the exons the exons then have the codes to produce the polypeptide via translation which involves ribosomes so getting to our disorders the main ones that we're going to talk about here is sickle cell anemia because this is quite an important one this is a more common hemoglobin disease or hemoglobin s disease this is a single nucleotide substitution in the beta globin and it's an all those normal recessive disorder essentially where glutamate is replaced with valine within the actual primary protein structure so that switch results in a disorder in that hemoglobin or the beta globin so then it's able to produce the sickle like shape and the sickle-like shape means that the red blood cell cannot transport through capillaries very well and gets clogged so you can clog up your capillaries quite easily which results in pain and results in anemia since it gets broken down quicker and also because the red blood cells of sickle cells have a shorter lifespan of less than 20 days compared to 120 days of your red blood cell and then you're also susceptible to infections as well so sickle cell anemia or sickle cell disease is a disorder of a single base mutation or single nucleotide substitution i should say glutamate for valine produces a red blood cell that forms the sickle shape which will show on the other side but that reduces your lifespan by these red blood cells not functioning very well they get clogged in capillaries and then they also have a shorter lifespan now it's important to note that we only have one beta gene on our chromosome 11 but remember we have two chromosomes one from your mum one from your dad so if you are heterozygous which means that you only have one abnormal mutation and one gene then you may have a completely normal life span and produce some sickle cells in some normal cells but if you're homozygous that means both your chromosome 11's have this mutation so you have full blown circle cell disease and that's when you have your reduced life expectancy now that's important to note because heterozygous people who have one abnormal gene so then you produce some sickle cells actually have a protection against plasmodium falciparum which is the parasite that causes malaria so sickle cells are quite hard for malaria to actually get into and reproduce so they actually end up dying so you have this protection against a infectious disease which is quite prevalent in africa which is where sickle cell disease is also prevalent because the heterozygous people are protected from malaria but then the homozygous people obviously suffer from sickle cell disease and you can see a sickle cell over here you can see that it forms this circle shape versus a red blood cell which is more like a donut with a little filling in the middle now another hemoglobin disease is hemoglobin c which is once again glutamate being replaced but this time for lysine and usually it's only homozygous people who have an issue but it's usually a mild chronic hemolytic anemia and they don't suffer from the same crisis as sickle cell disease as well so no therapy is really required so then we also have hemoglobin sc disease which is a mix of sickle cell and hemoglobin c disease so you have one gene on chromosome 11 that has your sickle cell gene mutation and then your other chromosome has the hemoglobin c gene mutation once again this crises are less frequent but there are more significant clinical variability with those two changes now meth hemoglobin is this is when the ion in the two plus state or the ferrous state gets oxidized into the fe3 plus state or the ferric state this ferric states cannot bind with oxygen at all so it's important that our hemoglobin that contains this ion that this ion is in the ferrous state not the ferric state so it can actually bind to oxygen this oxygenation of iron occurs due to certain drugs like nitrates and then some other oxidative drugs or toxins it can also sometimes be a congenital defect now this results in chocolate cyanosis because your blood can no longer carry oxygen which gives it that red color so you have this brown colored blood and the treatment is methylene blue which is able to convert the fe3 plus back to the fe2 plus now the last diseases to talk about are thalassemias this is when we have an improper production of either our alpha or our beta chains so beta thalassemias this is when we have reduced beta globin production so then we get increased alpha globins compared to our beta globins remember we need one of each or two of each to form a hemoglobin so what happens is that you actually start to produce more hemoglobin a2 which is our alpha and our delta since we're producing alpha still we just start to produce more delta or hemoglobin f which is alpha and gamma so these patients can do relatively okay just need regular transfusions of blood just to keep up with our hemoglobin production and usually these signs don't actually become apparent until shortly after birth once that hemoglobin a is meant to start to be heavily produced but it's not because of the beta globins issue now alpha thalassemias is just the opposite so now alpha isn't being produced but this is much more important because alpha is in every single other hemoglobin so you're basically just not producing hemoglobin anymore instead you're just producing hemoglobin but which is just all gamma globins and that's extremely fatal now it's important to note once again that we have two genes on one chromosome for the production of alpha globins so that means you have two chromosomes with two genes each so you have four different alpha genes to produce your alpha globins so that means you need all four of them to be knocked out in order for you to only produce non-alpha hemoglobins so you do have states where you only have one knocked out so you're a silent carrier maybe you've got two knocked out so then you're just carrying the trait or if you have three genes knocked out then you're going to have variable clinical severity because you can still produce some but then if you have all four knocked out that's when there's a big issue since the alpha globins are used in every hemoglobin so that is a more fatal disease so that brings us to these chapter reviews here so feel free to pause it here there's the first part of our study question over here with the answer and then the second part of the study questions over here with the answers on the side so feel free to drop a comment otherwise we'll see in the next video