all right engineerd in this video we're going to talk about the synthesis of thyroid hormone all right so when we're talking about the syn synthesis of thyroid hormone what we're actually doing in this video here is we're actually taking the thyroid gland so you know where the thyroid gland is actually located it's located in the anterior neck just inferior to the laryn or your voice box and it's a butterfly shaped gland and it consists of these things called thyroid follicles those are the structural and functional unit of the thyroid gland what I'm doing is is I'm taking a thyroid follicle and I'm zooming in on it and taking a very deep look into it okay so imagine this is the thyroid follicle with these things called follicular cells these simple cuboidal epithelial cells I'm going to zoom in on all of these cells and look at the mechanism and the synthesis of thyroid hormone okay all right so first off we're going to go over the steps afterwards we're going to have a quick review and recap of everything we're going to do first thing we're going to start with is where is all of this whole hormone producing action starting with it's starting with the hypothalamus so I like to remember it like this I like to think about HPT axis so hypothalamic right because this is the hypothalamus this is your anterior pituitary right so we're going to put anterior pituitary and then we're zooming in on the thyroid gland right so we're actually looking specifically at the thyroid gland so I like to think about this whole thing we're going to talk about is the hypothalamic pituitary thyroid axis okay so let's go ahead and start about this whole axis there's some neurons or nuclei that's located in the actual hypothalamus and these neurons are secreting the actual a specific chemical that's going to stimulate the anterior pituitary what is those neurons these neurons that are situated up here that're going to be secreting this chemical called thyrotropin releasing hormone TR these nuclei are called the par ventricular nucleus okay so the PA of ventricular nucleus is responsible for actually secreting TR and if you know from the hypothalamic anti pituitary video that the TR comes down and stimulates these cells here in the anterior pituitary what are those cells there called these blue cells are called thyro tropes and what happens is the TR actually circulates down through that blood connection that vascular connection which is called the hypo fisal portal system it circulates down and goes into the anterior pituitary stimulates these thyrotropes and as a result these thyrotropes start pumping out a specific type of hormone that we're going to focus on a lot called thyroid stimulating hormone okay so the first hormone that was produced was called thyrotropin releasing hormone TR the second hormone that was produced is TSH what does TSH do it comes over here to the thyroid gland in these thyroid follicles so now look what TSH does it actually circulates through the blood and it comes over and it binds onto this receptor that's present on the external face of the cell membrane because you know TSH is actually a peptide hormone so it doesn't have receptors inside the cell it has receptors outside the cell when this TSH binds onto this receptor it activates an intracellular pathway it activates specifically a g stimulatory protein that that g stimulatory protein is normally bound to GDP which keeps it off but then it's bound to GTP which turns it on so then it's bound to GTP and it becomes active the G stimulatory protein then goes and activates a eector enzyme and that eector enzyme is going to react with the G stimulatory protein and this enzyme is called a denate cyclas and what does AD denate cyclas do this G stimulatory protein activates the adate cyclace and aenl cyclas converts ATP into cyclic am then cyclic activates a specific enzyme and this enzyme is called protein kinas a here's where it gets good you know there's transcription factors you know transcription factors are specifically proteins that have one component so let's say I draw a transcription Factor here let's say I draw it in red here's a transcription Factor here's a little pocket here and here is going to be the part that binds with the DNA protein cyas a comes over and puts phosphates on this transcription Factor so look what it does it comes in here and puts phosphates onto this transcription Factor when it phosphor relates this transcription factor that transcription Factor starts stimulating the genes to make a specific protein so you know whenever there's transcription transcription produces what's called mRNA and then that mRNA will actually go to the ribosomes on the rough ER right and produce proteins those proteins when they're actually made they via translation those proteins are modified and and changed here and actually have different types of actions that are occurring here in the rough VR then after that they're actually sent to to the gii and then they're packaged and modified within the GGI and then what the gii is going to pack those this protein inside of a vesicle and then these vesicles that you're actually going to make so out of this GOI you're going to pack that actual that protein right there into this vesicle so now I'm going to pack that protein into this vesicle so there's my protein and then what's going to happen is I'm going to take this protein and I'm going to fuse this vesicle with the cell membrane so now look this vesicle here is going to fuse with the cell membrane because this vesicle is a lipid bil layer this is a lipid by layer they can come together and dissolve right so fuse one another when that fuses look what happens here after the fusion of that vesicle so now you get this little inward bubble and what are you going to start releasing out of here you're going to release out into this luminal space here this protein so then you're going to release out this protein Okay so that was the step there that was the step of synthesizing this basic unit of thyroid hormone okay stimulates a receptor activates protein KY a intracellularly phosphor transcription factors stimulates the genes to make a specific protein transcribes it translates it packages it and excretes it out or exocytosis it into the Lumen now what we're going to do is we're going to zoom in on this protein we're going to take this protein and zoom in on it what is this protein called this protein is called thyroglobulin thyro globulin so what did we synthesize essentially we we synthesized this thyroglobulin colloid because it's like a colloid here's where we have the basic unit of our thyroid hormone what do I mean by that you see these I drew circular amino acids I'm going to represent the the circular amino acids in this case are going to represent a specific amino acid and this amino acid that I want it to be is called tyrosine if we're talking about tyrosine we could we could show its structure let's say here's its structure right here uh you have an AM Amino Terminus carbon with a hydrogen and then a carboxy Terminus and then you got this phenol group coming off of it okay that's the basic structure of tyrosine but we're going to denote it by these circles okay now we have the basic unit here now we need to do some other things so what else do we need for this reaction to occur we actually need iodine okay but where's iodine coming from it's going to come from certain types of nutrient sources now generally here in America we usually put it in the salt right it's like iodized salt but it's in a lot of other food sources but generally it's circulating here in the blood so let's show it here circulating in the bloodstream let's do that in Black so let's say here is our iodine but usually iodine in the blood is in an ion form meaning that it has a negative charge so it's not really iodine this is actually called iodide so we have to be specific about this this is iodide now iodide is extremely concentrated in this area so we can say that this is high concentration right so high concentration of iodine over here and I can just instead of putting high I can put high like that up arrow and over here there's a very low concentration of iodine so to pump something from areas of low to high requires energy thankfully we have sodium sodium is so good to us look what sodium says he's like hey iodide I got you I'll help you out so what sodium does is he moves you know sodium he's an actually lower concentration ins inside the cell and then he's actually in high concentration outside the cell so you know what he does he moves from areas of high to low that's a passive transport when you're moving from high to low well guess who else moves with him co-transporting iodide so iodide moves with him okay so there's a sorter or co-transporter where you're removing sodium and iodide it doesn't directly use ATP it's an indirect use of ATP what is it called when there's an indirect use of ATP this right here is called secondary active transport okay so now we got the iodide in here why do we need the iodide okay this iodide is going to come through the cell let's keep following it here let's see what it does and look what happens here there's a specific protein here on the membrane let's say here's this protein here and look what this Pro this protein it might seem like it's not it's insignificant but this protein is very important because obviously any mutation it can alter the the function of the thyroid hormone production so let's say here in red we draw this protein here okay what is this here protein called this protein is called pendrin it's called pendrin so what is it called again it's called pen dren and what it does is it pumps the iodide out here into this vicinity okay so now the iodide is going to get pumped out here into this actual luminal space so now look iodide is going to get pumped out but here's the next thing that has to happen this is reactive okay because it's got all this charge we want to be able to you know prevent it from having all these problems so that we can put it on this uh amino acid so look what this enzyme here look at this little sneaky Frenchman enzyme looks like right so look at this guy with the you know the whole like little mustache right this enzyme is a really cool enzyme this enzyme is called thyroid peroxidase I'm going to denote as TPO but again I'll write it here it's called thyroid peroxidase what this enzyme does is Imagine here's his foot imagine here's his foot this guy is g to kick the iodide he's going to kick him and what he's going to do is he's going to kick him so hard that he converts this guy into what's called iodine so you know what uh you know whenever you go from iodine which is a negative charge to a zero charge that's called oxidation so what is this this reaction here this is oxidation oxidation is the loss of electrons he kicks him so hard he knocks electrons off of them okay so look at this here he kicks them so hard knocks electrons off of them what is this step right here called this step is called iodide oxidation okay then he's got this other enzyme he's got he's only got four toes and then look what he does he takes let's say there's a whole bunch of iodines here he takes these iodines and he has them on his toes here and look what he does he comes over and he puts boop boop boop onto these little tires amino acids so look what he does he takes these iodines and he puts them onto these tyrosine amino acids so what does he do then let's say that he puts let's say he puts an iodine here and an iodine there an iodine there an iodine there he put four iodines on these guys this right here is called iodination so when the thyroid peroxidase puts the iodines on the tyrosine amino acids of the thyroglobulin colloid this is called iodination okay so it's called IO dination all right but then he can do that to other ones too so let's say that he does it also to this guy here so let's say he puts on one there and let's say he puts two onto this one okay you see what he did there this is where it gets really cool now let's apply a concept when you're naming things generally you use the term like mono to say one die to say two right so how many amino acids are on that tyrosine two we don't say say two we say d but what is d d iodo tyrosine amino acid what about this one same thing it has two of them so di ioto tyrosine amino acid what about this one he has one so that's mono so this is mono ioto tyrosine amino acid this one has two so this is D ioto tyrosine amino acid look what this guy does he has a handle over here he's so cool that he can actually split his hand in half look at this he splits it in half he goes over here and splits this guy in half and then he takes his little fingers and he fuses these guys together so then look what he can do he can couple the dit and the dit and couple the MIT and the dit if he couples these guys together he fuses them together what are you going to get let's see if I take a dit a diot thyrosine and I add it to a diot thyrosine I'm going to get four iodines on one on these two tyrosine amino acids we're going to call that T4 T4 is another word for thyroxine okay but what if I take an MIT and a dit and fuse these together well then I get three iodines on two tyrosine amino acids so we're going to call that T3 T3 is also called trodo thyronine okay thyroxine and triot thyronine so T3 and T4 collectively are thyroid hormone okay that should make sense now right so iodide oxidation iodination coupling now there's other enzymes in this area that will try to be able to to help in this cutting and re uh uh moving these different types of dits and mits around thyroid globula but in general thyroid peroxides is helping to be able to kind of put these dits and mits together but there will be other cleavage processes and rearrangements but we've basically in a nutshell have t T4 and T3 in our thyroglobulin colloid but we can't just secrete that out into the blood we have to get these chunks and these chunks out of this so now look guys we have this guy here here's our thyroid globulin with the T4 and T3 in it our thyroid hormone what we're going to do is we're going to take this whole thyroglobulin choid with the T4 and T3 and bring it into the cell you see these guys right here these lysosomes they're going to help us to get this thyroid hormone out of the colloid so how does it do this how does it get in you know there's a process where you take substances into the cell it's called endocytosis so what do this guy going to do he's going to bring so it's going to actually endocytose this whole protein and put it into this vesicle so what is this this reaction right here called whenever you bring this protein substance into the cell and pack it into this vesicle this is going to be called Endo cytosis okay now we've brought it into the cell and we have our T4 T3 right there so this is T4 this is T3 but the whole thing is the thyroglobulin colloid right and our T4 and T3 are part of that we have to isolate that T4 and T3 out of that so that we only secrete that how do we do that these Lal enzymes the lomes will fuse with this vesicle here so look it fuses with the vesicle and then these enzymes are ready to start cutting things up they're ready what are they going to do they're going to cut all around this thyroglobulin CID and isolate just the T4 and just the T3 so now what are we going to get out of this afterwards all we're going to have left in this vesicle so now what we're going to do is we're going to isolate out of this these two things here the T3 and the T4 so let's say this one up top is the T4 so it'll have four iodines coming off of it okay then over here let's say this is T3 so I'll have three iodines coming off of it right so we isolated the T4 and the T3 out of the thyroglobulin colloid through the action of who are these guys the losal enzymes then we have our functional T3 and T4 now we're going to fuse this vesicle with the cell membrane of the follicular cell when this fuses look what we can do we can release out this T3 and T4 out into the bloodstream but you know T3 and T4 are kind of interesting they're kind of um they act like steroid hormones so because of that these are actually because of those Benzene Rings the phenol rings they're not really good at being water soluble so we have to transport them in the blood through some type of transport protein so the liver actually synthesizes a specific protein here to transport this actual thyroid hormone through the actual blood what is this protein here called that it actually secretes this protein here is called thyroxine binding globulin okay so this protein right here is called thyroxine binding globulin and what happens is look now I'm going to draw over here I'm just going to write it in T4 and T3 are transported by this protein called thyroxine binding globulins okay all right so now that we've done that we have almost everything that we need here to make the functional thyroid hormone now we're going to do is is we're going to recap everything and we're going to finish this video off okay guys so let's recap in an order here so the first thing that had to happen was TR had to be released so TR release from hypothalamus and specifically you could say the paraventricular nucleus TR then stimulates the anter pituitary so the thyrotropes but we're just going to put anterior pituitary to release TSH then TSH stimulates the pH cells right so our thyroid gland so specifically the follicular cells that make up that thyroid follicle to synthesize thyroglobulin so I'm going to put here thyroglobulin so tgb thyroglobulin okay then what the fourth step was is that we had to get that iodide inside so we had to do what's called iodide trapping okay that was the fourth step the fifth step was that we had to oxidize we had to oxidize the iodide right so we have to oxidize the iodide so we'll say oxidation of iodide through the thyroid peroxidase enzyme right after it gets transported through the pendrin protein into the actual Lumen then the sixth step is we have to iodinate the tyrosine amino acids so iodination of tyrosine amino acids okay seventh step is coupling so then you have to couple so then you have to couple what the dits and mits respectively dit with MIT is T3 dit with dit is T4 then what the eighth step is I have to take that thyroglobulin coll my T3 and T4 and bring it into the cell so I have to mediate what's called Indo cytosis okay of T what thyroglobulin and with well with the T3 and the T4 so in other words we have to endocytose of the thyro globulin with T3 and T4 in it then losal enzymes lysosomal enzymes cleave T3 and T4 out of thyroglobulin and what is the 10th and final step the 10th and final step is actually going to be the EXO cytosis of T3 and T4 into blood plasma which is bound to the actual thy thyroxine binding globulins which is then going to be transported to the Target tissues all right guys in this video we covered the synthesis of thyroid hormone I hope it made sense I hope you guys enjoyed it in the next video we're going to talk about the effect of thyroid hormone on its Target organs