>>Dr. Ketchum: Now we are going to be moving into the chemical classification which we’ve
been discussing, but we’re going to go ahead and look at the synthesis and release of your
chemical messengers. And so this is going to rely on you remembering those major classes
of chemical messengers. Here we are on our outline. And so on the outline as you kind
of progress, we’ve already talked about or we’ve already discussed chemical properties
of the chemical messengers and the five classes. Now what we’re going to go into next is
how are they synthesized? How are these chemical messengers synthesized and how do they get
secreted or released, in other words, from your secretory cell? So this is an overview
slide that will give you an idea of, of what we’re talking about. And you’re going
to be seeing this image several times now; you’ve seen it at least once now. So in
this section of the notes we’re looking at how the ligands are produced by the—by
the secretory cell. So again, here is my secretory cell. It’s going to synthesize and secrete
my ligand. And then once it gets synthesized, it can be secreted from the cell. So the secretory
cell synthesizes and secretes the ligand, and we want to look at how that is done.
So we return to this table, and what I would suggest doing with this table is adding in
another column for synthesis and secretion of the ligand. So this is all based on the
chemical class. And furthermore, it’s based on whether or not your—your ligand is lipophobic
or whether or not your ligand is lipophilic. So synthesis and secretion is dependent upon
that chemical property. Go ahead and commit to memory that your amino acids, your amines,
and your proteins and your peptides are all lipophobic. Steroids, any eicosanoids are
all lipophilic. Steroids you probably already know since they’re derived from cholesterol
and cholesterol is a fat, so they would be lipophilic. But you may not yet be familiar
with the eicosanoids, which are a type of lipid. So they are lipophilic. So in terms
of whether or not they’re lipophilic or whether or not they lipophobic, their method
for synthesis and secretion is a little bit different. If it’s a lipophilic ligand,
it’s synthesized on demand. In other words: When the body needs it, it’s going to make
it. So if it’s a steroid hormone for example, if the body needs the steroid hormone, it’s
going to make it on demand. When it’s made on demand it’s not going to be stored, right?
It’s made when it’s needed, so there’s no point in storing it. And the release rate
is dependent upon the synthesis of it. So the faster it’s synthesized, the faster
it’s released. Then, in terms of lipophobic ligands, it’s completely different now.
Lipophobic ligands, so for example your amino acids, your amines, your proteins, and your
peptides are all synthesized independent of the demand. So they’re just continually
made whether or not they’re needed or not. Then they get stored in secretory vesicles
of the secretory cell until they’re needed. So they just hang out in the secretory vesicle
until the body needs them. When the body needs them, they get released by exocytosis. So
they’re secreted by—or they’re secreted from the secretory cell via exocytosis, and
the release rate is determined by exocytosis. So it’s based on how quickly or the, the
rate at which exocytosis can occur.
Now looking at each of the chemical classes individually, we want to look at whether or
not or how—how these are actually synthesized and secreted. Okay, so the amine ligands,
their production is—or their synthesis, in other words, is dependent upon enzyme-catalyzed
reactions. And so we’ve spent quite a bit of time talking about enzymes and what an
enzyme-catalyzed reaction is, so what I would like to do is give you an example. Now this
is only an example. It is not for you to memorize, but it is for you to understand what I mean
by how amines are synthesized; they’re synthesized by using these enzyme-catalyzed reactions.
So first off, remember that amines are all derived from amino acids. In this case, we’re
going to use tyrosine as our amino acid that’s going to be deriving these ligands. So if
we had tyrosine, tyrosine can get converted into L-dopa via an enzyme called tyrosine
beta-hydroxylase. So this is an enzyme catalyzed reaction to produce L-dopa. From L-dopa, another
enzyme-catalyzed reaction has to occur that utilizes the enzyme dopa decarboxylase, and
then we can produce the ligand called dopamine. Then another enzyme-catalyzed reaction will
occur using dopamine beta-hydroxylase and that produces another ligand, which is norepinephrine.
And lastly another enzyme-catalyzed reaction occurs using an enzyme called PNMT, which
produces the ligand epinephrine.
Now again, don’t memorize this diagram; understand this diagram. So if a secretory
cell has only dopa decarboxylase and it has dopamine beta-hydroxylase, can epinephrine
be produced? So these are the only two enzymes present in this cell. So can epinephrine be
made? Hopefully when looking at this diagram, you answered no. The reason that epinephrine
cannot be produced is that if you lack tyrosine beta-hydroxylase—and in this case we do—if
you don’t have tyrosine beta-hydroxylase, you cannot make L-dopa. If you cannot make
L-dopa, you cannot make dopamine, and therefore cannot make norepinephrine, and therefore
cannot make epinephrine. Not to mention we’re also missing the enzyme PMNT. So we’re missing
two enzymes that are vital to making epinephrine in this example. So again, don’t memorize
the names; don’t memorize the flow of this. Understand that you have to have the enzyme
in order to produce the ligand or the chemical messenger of interest. So then we move into
synthesis and secretion of our peptides and our proteins. And this is where we had a pre-pro-peptide,
a pro-peptide, and a peptide. And to go from one to the next, they were cleaving amino
acids. Some hormones are peptide hormones, so this works the same way, except we change
the terminology just a little bit.
So we start with a pre-pro-hormone that’s made by the rough endoplasmic reticulum. We
cleave off some amino acids in the smooth endoplasmic reticulum. And when we do that
in the smooth endoplasmic reticulum, that gives us a pro-hormone. We cleave off some
more amino acids in the Golgi apparatus, and that gives us our final or our functioning
hormone. So these are the steps on how we synthesize a peptide or a protein hormone.
And so this is the diagram. And by looking at this diagram and using the next slide,
it’ll help explain each of the steps in this if you’re shu—if you’re still unfamiliar
with this process.
Steroids then, as we mentioned before are all derived from cholesterol, and hence, they
are lipophilic. And so there’s a whole series of enzyme-catalyzed reactions in the smooth
endoplasmic reticulum or the mitochondria that have to occur in order for these steroid
ligands to be made. And so let’s take a look again at another pathway. Again, this
is only an example of how steroid ligands are produced or they’re synthesized. Do
not memorize this. On this diagram, it’s important for you to understand that every
arrow represents an enzyme, and that enzyme is needed to produce or to facilitate that
reaction. For example, when we start with cholesterol, there has to be some sort of enzyme present
that produces a non-active intermediate. Then there has to be some sort of enzyme present
in the system to produce our ligand progesterone; that’s a steroid hormone.
Now continuing through this, going back to our non-active intermediate here. We have
to have an enzyme that produces another non-active intermediate, okay, which has a particular
name, but we’re not worrying about those names here. Then we know that we need an enzyme-catalyzed
reaction to occur to convert that to another non-active intermediate. And then you need
another enzyme, and another enzyme, and ultimately you’ll get cortisol, which is also a ligand—a
steroid hormone. Okay? So I’m not going to take you through each step in this pathway,
but you should understand that these are all enzyme-catalyzed reactions and that they’re—as,
as the result of these enzyme-catalyzed reactions, we’re synthesizing steroid ligands. And
then we have the eicosanoids. So there are two major pathways to producing your eicosanoids.
You have the cyclooxygenase pathway and the lipoxygenase pathway. This is something that’s
very important for you to understand and that—and for you to know. So here we’re going to
begin with the pathway for synthesis of our eicosanoids. Remember that eicosanoids are
lipophilic, so they are made when the body needs them; they’re synthesized and released
when the body demands them.
Okay, so we’re going to begin with a membrane phospholipid. And the membrane phospholipid
contains phospholipase A2. Now this is an enzyme, correct, because it ends in a-s-e.
What this enzyme does is it causes the release of arachidonic acid from the bilayer. So as
we said earlier that all eicosanoids are derived from arachidonic acids—now you know that
you have to have some sort of enzyme, you have to have phospholipase A2, to make arachidonic
acid. Once arachidonic acid is produced, then either the—or cyclooxygenase pathway—or
lipoxygenase pathway will occur. The pathway that occurs is completely dependent upon what
enzymes are present in the cell. So if the cyclooxygenase pathway takes place, then we
will produce prostaglandins, prostacyclins, and thromboxanes; these are all types of eicosanoids.
Two of them (prostacyclins and thromboxanes) are important in blood clotting. Now if the
lipoxygenase pathway occurs, then…and we have the enzymes that are present to do—to
produce the leukotrienes—leukotrienes are a type of ligand that are in the class eicosanoids.
Leukotrienes, you’ll find out later, are important in the inflammatory response.