0:08 all right engineerd in this video we're
0:10 going to talk about the synthesis of
0:12 thyroid hormone all right so when we're
0:14 talking about the syn synthesis of
0:15 thyroid hormone what we're actually
0:17 doing in this video here is we're
0:18 actually taking the thyroid gland so you
0:19 know where the thyroid gland is actually
0:21 located it's located in the anterior
0:24 neck just inferior to the laryn or your
0:26 voice box and it's a butterfly shaped
0:28 gland and it consists of these things
0:30 called thyroid follicles those are the
0:32 structural and functional unit of the
0:34 thyroid gland what I'm doing is is I'm
0:36 taking a thyroid follicle and I'm
0:38 zooming in on it and taking a very deep
0:41 look into it okay so imagine this is the
0:42 thyroid follicle with these things
0:44 called follicular cells these simple
0:46 cuboidal epithelial cells I'm going to
0:48 zoom in on all of these cells and look
0:50 at the mechanism and the synthesis of
0:53 thyroid hormone okay all right so first
0:55 off we're going to go over the steps
0:57 afterwards we're going to have a quick
0:59 review and recap of everything we're
1:00 going to do first thing we're going to
1:02 start with is where is all of this whole
1:05 hormone producing action starting with
1:06 it's starting with the
1:09 hypothalamus so I like to remember it
1:12 like this I like to think about HPT axis
1:15 so hypothalamic
1:18 right because this is the
1:20 hypothalamus this is your anterior
1:22 pituitary right so we're going to put
1:24 anterior pituitary and then we're
1:27 zooming in on the thyroid gland right so
1:28 we're actually looking
1:32 specifically at the thyroid gland so I
1:33 like to think about this whole thing
1:35 we're going to talk about is the
1:40 hypothalamic pituitary thyroid axis okay
1:41 so let's go ahead and start about this
1:43 whole axis there's some neurons or
1:47 nuclei that's located in the actual
1:49 hypothalamus and these neurons are
1:52 secreting the actual a specific chemical
1:53 that's going to stimulate the anterior
1:56 pituitary what is those neurons these
1:59 neurons that are situated up here
2:00 that're going to be secreting this chemical
2:02 chemical called
2:04 called
2:07 thyrotropin releasing hormone TR these
2:10 nuclei are called the par
2:13 par ventricular
2:15 ventricular
2:18 nucleus okay so the PA of ventricular
2:19 nucleus is responsible for actually secreting
2:21 secreting
2:24 TR and if you know from the hypothalamic
2:27 anti pituitary video that the TR comes
2:30 down and stimulates these cells here in
2:32 the anterior pituitary what are those
2:35 cells there called these blue cells are called
2:36 called thyro
2:39 thyro
2:42 tropes and what happens is the TR
2:43 actually circulates down through that
2:44 blood connection that vascular
2:46 connection which is called the hypo
2:50 fisal portal system it circulates down
2:52 and goes into the anterior
2:56 pituitary stimulates these thyrotropes
2:58 and as a result these thyrotropes start
3:01 pumping out a specific type of hormone
3:03 that we're going to focus on a lot
3:07 called thyroid stimulating hormone
3:08 hormone
3:11 okay so the first hormone that was
3:13 produced was called thyrotropin
3:15 releasing hormone
3:18 TR the second hormone that was produced is
3:18 is
3:22 TSH what does TSH do it comes over here
3:25 to the thyroid gland in these thyroid
3:28 follicles so now look what TSH does it
3:30 actually circulates through the
3:34 blood and it comes over and it binds
3:37 onto this receptor that's present on the
3:40 external face of the cell membrane
3:41 because you know TSH is actually a
3:43 peptide hormone so it doesn't have
3:44 receptors inside the cell it has
3:48 receptors outside the cell when this TSH
3:50 binds onto this
3:53 receptor it activates an intracellular
3:57 pathway it activates specifically a g
4:00 stimulatory protein that that g
4:03 stimulatory protein is normally bound to
4:06 GDP which keeps it off but then it's
4:09 bound to GTP which turns it on so then
4:14 it's bound to GTP and it becomes
4:16 active the G stimulatory protein then
4:20 goes and activates a eector enzyme and
4:26 enzyme is going to react with the G
4:28 stimulatory protein and this enzyme is
4:30 called a denate
4:33 cyclas and what does AD denate cyclas do
4:37 this G stimulatory protein activates the
4:41 adate cyclace and aenl cyclas converts ATP
4:42 ATP
4:46 into cyclic
4:49 am then cyclic activates a specific
4:52 enzyme and this enzyme is called protein
4:56 kinas a here's where it gets good you
4:58 know there's transcription factors you
4:59 know transcription factors are
5:02 specifically proteins that have one
5:03 component so let's say I draw a
5:04 transcription Factor here let's say I
5:06 draw it in red here's a transcription
5:08 Factor here's a little pocket
5:12 here and here is going to be the part
5:16 that binds with the DNA protein cyas a
5:19 comes over and puts phosphates on this
5:21 transcription Factor so look what it
5:24 does it comes in here and puts
5:27 phosphates onto this transcription
5:29 Factor when it phosphor relates this
5:31 transcription factor that transcription
5:33 Factor starts stimulating the genes to
5:35 make a specific protein so you know
5:37 whenever there's transcription
5:40 transcription produces what's called
5:43 mRNA and then that mRNA will actually go
5:45 to the ribosomes on the rough ER right
5:48 and produce proteins those proteins when
5:50 they're actually made they via
5:52 translation those proteins are modified
5:54 and and changed here and actually have
5:56 different types of actions that are
5:58 occurring here in the rough VR then
5:59 after that they're actually sent to to
6:01 the gii and then they're packaged and
6:05 modified within the GGI and then what
6:07 the gii is going to pack those this
6:10 protein inside of a vesicle and then
6:11 these vesicles that you're actually
6:13 going to make so out of this GOI you're
6:16 going to pack that actual that protein
6:18 right there into this vesicle so now I'm
6:20 going to pack that protein into this
6:23 vesicle so there's my protein and then
6:24 what's going to happen is I'm going to
6:26 take this protein and I'm going to fuse
6:28 this vesicle with the cell membrane so
6:30 now look this vesicle here is going to
6:32 fuse with the cell membrane because this
6:34 vesicle is a lipid bil layer this is a
6:37 lipid by layer they can come together
6:39 and dissolve right so fuse one another
6:41 when that fuses look what happens here
6:44 after the fusion of that vesicle so now
6:47 you get this little inward bubble and
6:48 what are you going to start releasing
6:51 out of here you're going to release out
6:53 into this luminal space here this
6:55 protein so then you're going to release
7:00 out this protein Okay so
7:02 that was the step there that was the
7:04 step of synthesizing this basic unit of
7:07 thyroid hormone okay stimulates a
7:09 receptor activates protein KY a
7:11 intracellularly phosphor transcription
7:13 factors stimulates the genes to make a
7:16 specific protein transcribes it
7:19 translates it packages it and excretes
7:22 it out or exocytosis it into the Lumen
7:23 now what we're going to do is we're
7:24 going to zoom in on this protein we're
7:25 going to take this protein and zoom in
7:29 on it what is this protein called this
7:31 protein is
7:34 called thyroglobulin thyro
7:37 thyro
7:39 globulin so what did we synthesize
7:42 essentially we we synthesized this
7:44 thyroglobulin colloid because it's like a
7:45 a
7:48 colloid here's where we have the basic
7:50 unit of our thyroid hormone what do I
7:51 mean by that you see these I drew
7:54 circular amino acids I'm going to
7:56 represent the the circular amino acids
7:58 in this case are going to
8:02 represent a specific amino acid and this
8:04 amino acid that I want it to be is called
8:05 called
8:08 tyrosine if we're talking about tyrosine
8:09 we could we could show its structure
8:10 let's say here's its structure right
8:14 here uh you have an AM Amino
8:16 Terminus carbon with a hydrogen and then
8:20 a carboxy Terminus and then you got
8:23 this phenol group coming off of it okay
8:26 that's the basic structure of tyrosine
8:27 but we're going to denote it by these
8:30 circles okay
8:32 now we have the basic unit here now we
8:35 need to do some other things so what
8:37 else do we need for this reaction to
8:41 occur we actually need iodine okay but
8:43 where's iodine coming from it's going to
8:44 come from certain types of nutrient
8:46 sources now generally here in America we
8:47 usually put it in the salt right it's
8:49 like iodized salt but it's in a lot of
8:51 other food sources but generally it's
8:53 circulating here in the blood so let's
8:55 show it here circulating in the
8:59 bloodstream let's do that in Black
9:01 so let's say here is our
9:04 iodine but usually
9:07 iodine in the blood is in an ion form
9:09 meaning that it has a negative charge so
9:12 it's not really iodine this is actually
9:15 called iodide so we have to be specific about
9:16 about
9:18 this this is
9:21 iodide now iodide is extremely
9:23 concentrated in this area so we can say
9:26 that this is high concentration right so
9:29 high concentration of iodine over here
9:30 and I can just instead of putting high I
9:33 can put high like that up arrow and over
9:37 here there's a very low concentration of
9:39 iodine so to pump something from areas
9:43 of low to high requires energy
9:45 thankfully we have sodium sodium is so
9:48 good to us look what sodium says he's like
9:49 like
9:53 hey iodide I got you I'll help you out
9:56 so what sodium does is he moves you know
9:58 sodium he's an actually lower
10:00 concentration ins inside the cell and
10:03 then he's actually in high concentration
10:04 outside the
10:07 cell so you know what he does he moves
10:10 from areas of high to low that's a
10:11 passive transport when you're moving
10:13 from high to low well guess who else
10:17 moves with him co-transporting iodide so
10:21 iodide moves with him okay so there's a
10:24 sorter or co-transporter where you're
10:27 removing sodium and iodide it doesn't
10:30 directly use ATP it's an indirect use of
10:32 ATP what is it called when there's an
10:34 indirect use of ATP this right here is called
10:36 called secondary
10:38 secondary active
10:40 active
10:44 transport okay so now we got the iodide
10:47 in here why do we need the iodide okay
10:50 this iodide is going to come through the
10:53 cell let's keep following it here let's
10:55 see what it does and look what happens
10:57 here there's a specific protein here on the
10:57 the
11:02 membrane let's say here's this protein
11:04 here and look what this Pro this protein
11:06 it might seem like it's not it's
11:07 insignificant but this protein is very
11:10 important because obviously any mutation
11:12 it can alter the the function of the
11:14 thyroid hormone production so let's say
11:19 here in red we draw this protein
11:21 here okay what is this here protein
11:24 called this protein is called pendrin
11:26 it's called pendrin so what is it called
11:27 again it's called
11:30 pen dren
11:34 and what it does is it pumps the iodide
11:38 out here into this vicinity okay so now
11:40 the iodide is going to get pumped out
11:43 here into this actual luminal space so
11:45 now look iodide is going to get
11:48 pumped out but here's the next thing
11:50 that has to
11:52 happen this is reactive okay because
11:54 it's got all this charge we want to be
11:56 able to you know prevent it from having
11:57 all these problems so that we can put it
11:59 on this uh amino acid
12:01 so look what this enzyme here look at
12:03 this little sneaky Frenchman enzyme
12:05 looks like right so look at this guy
12:06 with the you know the whole like little
12:08 mustache right this enzyme is a really
12:12 cool enzyme this enzyme is called
12:15 thyroid peroxidase I'm going to denote
12:16 as TPO but again I'll write it here it's called
12:18 called thyroid
12:23 peroxidase what this enzyme does is
12:26 Imagine here's his foot imagine here's
12:33 this guy is g to kick the iodide he's
12:35 going to kick him and what he's going to
12:37 do is he's going to kick him so hard
12:39 that he converts this
12:43 guy into what's called
12:44 iodine so you know what uh you know
12:46 whenever you go from iodine which is a
12:48 negative charge to a zero charge that's
12:51 called oxidation so what is this this
12:52 reaction here this is oxidation
12:55 oxidation is the loss of electrons he
12:57 kicks him so hard he knocks electrons
12:59 off of them okay so look at this here he
13:01 kicks them so hard knocks electrons off
13:03 of them what is this step right here
13:07 called this step is called iodide
13:09 iodide
13:12 oxidation okay then he's got this other
13:14 enzyme he's
13:17 got he's only got four toes and then
13:19 look what he does he takes let's say
13:21 there's a whole bunch of iodines here he
13:23 takes these iodines and he has them on
13:25 his toes here and look what he does he
13:28 comes over and he puts boop boop boop
13:30 onto these little tires amino acids so
13:32 look what he does he takes these iodines
13:35 and he puts them onto these tyrosine
13:37 amino acids so what does he do then
13:38 let's say that he puts let's say he puts
13:42 an iodine here and an iodine there an
13:45 iodine there an iodine there he put four
13:48 iodines on these guys this right here is
13:50 called iodination so when the thyroid
13:52 peroxidase puts the iodines on the
13:53 tyrosine amino acids of the
13:57 thyroglobulin colloid this is called
14:04 dination all right but then he can do
14:05 that to other ones too so let's say that
14:08 he does it also to this guy here so
14:10 let's say he puts on one there and let's
14:12 say he puts two onto this
14:14 one okay you see what he did there this
14:16 is where it gets really cool now let's
14:19 apply a concept when you're naming
14:20 things generally you use the term like
14:25 mono to say one die to say two right so
14:27 how many amino acids are on that
14:30 tyrosine two we don't say say two we say
14:34 d but what is d d
14:38 iodo tyrosine amino acid what about this
14:41 one same thing it has two of them so di
14:44 ioto tyrosine amino acid what about this
14:48 one he has one so that's mono so this is
14:51 mono ioto tyrosine amino acid this one
14:55 has two so this is D ioto tyrosine amino
14:58 acid look what this guy does he has a
15:00 handle over
15:03 here he's so cool that he can actually
15:05 split his hand in half look at this he
15:07 splits it in half he goes over here and
15:09 splits this guy in half and then he
15:11 takes his little fingers and he fuses
15:13 these guys together so then look what he
15:16 can do he can couple the dit and the dit
15:20 and couple the MIT and the dit if he
15:22 couples these guys together he fuses
15:24 them together what are you going to get
15:27 let's see if I take a
15:31 dit a diot thyrosine and I add it to a
15:33 diot thyrosine I'm going to get four
15:36 iodines on one on these two tyrosine
15:40 amino acids we're going to call that
15:45 T4 T4 is another word for
15:49 thyroxine okay but what if I take an
15:52 MIT and a dit and fuse these together
15:54 well then I get three iodines on two
15:56 tyrosine amino acids so we're going to
15:57 call that
15:59 T3 T3
16:01 is also called trodo
16:03 trodo thyronine
16:05 thyronine
16:10 okay thyroxine and triot thyronine so T3
16:14 and T4 collectively are thyroid
16:17 thyroid
16:20 hormone okay that should make sense now
16:24 right so iodide oxidation iodination
16:27 coupling now there's other enzymes in
16:29 this area that will try to be able to to
16:32 help in this cutting and re uh uh moving
16:34 these different types of dits and mits
16:36 around thyroid globula but in general
16:38 thyroid peroxides is helping to be able
16:40 to kind of put these dits and mits
16:41 together but there will be other
16:44 cleavage processes and
16:46 rearrangements but we've basically in a
16:49 nutshell have t T4 and T3 in our
16:52 thyroglobulin colloid but we can't just
16:54 secrete that out into the blood we have
16:58 to get these chunks and these chunks out
16:59 of this
17:01 so now look guys we have this guy here
17:03 here's our thyroid globulin with the T4
17:06 and T3 in it our thyroid hormone what
17:09 we're going to do is we're going to take
17:11 this whole thyroglobulin choid with the
17:13 T4 and T3 and bring it into the cell you
17:14 see these guys right here these
17:17 lysosomes they're going to help us to
17:19 get this thyroid hormone out of the
17:22 colloid so how does it do this how does
17:24 it get in you know there's a process
17:25 where you take substances into the cell
17:27 it's called
17:29 endocytosis so what do this guy going to
17:30 do he's going to bring so it's going to
17:33 actually endocytose this whole protein
17:35 and put it into this vesicle so what is
17:36 this this reaction right here called
17:38 whenever you bring this protein
17:41 substance into the cell and pack it into
17:44 this vesicle this is going to be called Endo
17:46 Endo
17:49 cytosis okay now we've brought it into
17:52 the cell and we have our T4 T3 right
17:55 there so this is T4 this is T3 but the
17:57 whole thing is the thyroglobulin colloid
18:00 right and our T4 and T3 are part of that
18:03 we have to isolate that T4 and T3 out of
18:06 that so that we only secrete that how do
18:10 we do that these Lal enzymes the lomes will
18:11 will
18:15 fuse with this vesicle here so look it
18:17 fuses with the vesicle and then these
18:20 enzymes are ready to start cutting
18:22 things up they're ready what are they
18:23 going to
18:26 do they're going to cut all around this
18:30 thyroglobulin CID and isolate just the
18:34 T4 and just the T3 so now what are we
18:37 going to get out of this afterwards all
18:40 we're going to have left in this vesicle
18:41 so now what we're going to do is we're
18:44 going to isolate out of this these
18:48 two things here the T3 and the T4 so
18:50 let's say this one up top is the T4 so
18:54 it'll have four iodines coming off of
18:57 it okay then over here let's say this is
18:59 T3 so I'll have
19:03 three iodines coming off of it right so
19:06 we isolated the T4 and the T3 out of the
19:08 thyroglobulin colloid through the action
19:15 losal
19:18 enzymes then we have our functional T3
19:21 and T4 now we're going to fuse this
19:23 vesicle with the cell membrane of the
19:26 follicular cell when this fuses look
19:29 what we can do we can release
19:32 out this T3 and T4 out into the
19:35 bloodstream but you know T3 and T4 are
19:37 kind of interesting they're kind of um
19:39 they act like steroid hormones so
19:42 because of that these are actually
19:44 because of those Benzene Rings the
19:46 phenol rings they're not really good at
19:48 being water soluble so we have to
19:50 transport them in the blood through some
19:53 type of transport protein so the liver
19:56 actually synthesizes a specific protein
19:58 here to transport
20:01 this actual thyroid hormone through the
20:03 actual blood what is this protein here
20:06 called that it actually secretes this
20:09 protein here is called
20:12 thyroxine binding
20:15 globulin okay so this protein right here is
20:15 is called
20:17 called thyroxine
20:19 thyroxine binding
20:21 binding
20:23 globulin and what happens is look now
20:25 I'm going to draw over here I'm just
20:29 going to write it in T4
20:33 and T3 are transported by this protein
20:37 called thyroxine binding globulins
20:39 okay all right so now that we've done
20:41 that we have almost everything that we
20:44 need here to make the functional thyroid
20:45 hormone now we're going to do is is
20:47 we're going to recap everything and
20:48 we're going to finish this video off
20:50 okay guys so let's recap in an order
20:52 here so the first thing that had to
20:56 happen was TR had to be released so
21:03 from
21:05 hypothalamus and specifically you could
21:08 say the paraventricular
21:11 nucleus TR then stimulates the anter
21:14 pituitary so the thyrotropes but we're
21:21 release
21:23 TSH then TSH
21:29 stimulates the pH cells right so our
21:31 thyroid gland so specifically the
21:33 follicular cells that make up that
21:42 synthesize thyroglobulin so I'm going to
21:44 put here
21:46 thyroglobulin so tgb
21:50 thyroglobulin okay then what the fourth
21:53 step was is that we had to get that
21:55 iodide inside so we had to do what's called
21:57 called
22:04 okay that was the fourth step the fifth
22:07 step was that we had to oxidize we had
22:10 to oxidize the iodide right so we have
22:17 oxidation of
22:19 iodide through the thyroid peroxidase enzyme
22:20 enzyme
22:23 right after it gets transported through
22:25 the pendrin protein into the actual
22:27 Lumen then the sixth step is we have to
22:32 iodinate the tyrosine amino acids so
22:35 iodination of
22:39 tyrosine amino acids okay seventh step
22:42 is coupling so then you have to couple
22:43 so then you have to
22:45 couple what the
22:49 dits and
22:53 mits respectively dit with MIT is T3 dit
22:54 with dit is
22:58 T4 then what the eighth step is I have
23:01 to take that thyroglobulin coll my T3
23:04 and T4 and bring it into the cell so I
23:07 have to mediate what's called Indo
23:09 Indo
23:15 cytosis okay of T what
23:18 thyroglobulin and with well with the T3
23:21 and the T4 so in other words we have to
23:24 endocytose of the thyro globulin
23:32 with T3 and T4 in it then losal enzymes lysosomal
23:35 lysosomal
23:38 enzymes cleave
23:41 T3 and T4 out of
23:47 thyroglobulin and what is the 10th and
23:49 final step the 10th and final step is
23:51 actually going to be the EXO
23:53 EXO
23:59 cytosis of T3 and T4 into blood
24:03 plasma which is bound to the actual thy
24:07 thyroxine binding globulins which is
24:08 then going to be transported to the
24:11 Target tissues all right guys in this
24:12 video we covered the synthesis of
24:14 thyroid hormone I hope it made sense I
24:16 hope you guys enjoyed it in the next
24:18 video we're going to talk about the
24:20 effect of thyroid hormone on its Target organs
