Eicosanoids: Formation and function
Are you able to name the three subclasses of eicosanoids? Well, don't worry if you can't;
we'll be addressing this question and much more in this Chalk Talk episode.
Eicosanoids are a group of hormones belonging to the local hormones, which are sometimes
called tissue hormones. In contrast to classical hormones, local hormones aren’t synthesized
in endocrine glands and transported to the target site but are produced directly within
the tissue. This is facilitated by a fatty acid that is present in almost all cell membranes
called arachidonic acid. Arachidonic acid gives rise to three major classes of eicosanoids:
prostaglandins, thromboxanes, and leukotrienes. The advantage of these local hormones is that
they’re rapidly produced in various tissue types, depending on demand and cell type.
However, although eicosanoids constitute a large number of similar hormones, they can
exert different effects depending on the organ they’re produced in.
So, in this Chalk Talk episode, we’ll give you a step-by-step guide on the formation
and function of eicosanoids.
Eicosanoid synthesis begins with fatty acids from the cell membrane. The most important
of these fatty acids is arachidonic acid. On the one hand, prostaglandin H2 is synthesized
from arachidonic acid, which is the starting point for the synthesis of other prostaglandins
and thromboxanes.
On the other hand, arachidonic acid also gives rise to leukotriene A4, from which additional
leukotrienes are formed. Let’s go more in-depth and look at some examples of important eicosanoids.
In this episode, we won’t be including prostaglandins A, C, D, and F but will focus on prostaglandin
E2.
In addition to the previously mentioned prostaglandins, there’s also prostaglandin I2. Since prostaglandin
I2 acts as thromboxane’s antagonist, a substance counteracting the effects of another substance,
it’s often differentiated from the other prostaglandins and has even been assigned
a different name: prostacyclin. So, that’s why we’ve assigned it with a box of its
own in this image. The most important compound in the thromboxane family is thromboxane A2,
shown here on the right. Leukotriene A4 gives rise to leukotrienes B4 to E4.
OK, that completes our summary chart of the eicosanoids. Let’s now take a closer look
at the enzymes involved in their formation. We’ll start again with arachidonic acid.
Arachidonic acid is released on demand from the cell membrane. The most important enzyme
involved in this process is phospholipase A2, in short PLA2.
Let’s have a detailed look at its function. You can see a schematic representation of
a phospholipid at the top, whereas the bottom image shows the molecular structure of a phospholipid.
PLA2 cleaves arachidonic acid from the phospholipid in the biomembrane, setting it free for other
reactions.
Actually, stating that eicosanoids are synthesized from arachidonic acid, as we’ve done so
far, is merely an example. It would be more precise to say that eicosanoids are formed
from fatty acids that are 20 carbon atoms in length. By the way, this explains the origin
of their name: ‘Eikos’ is a Greek word and means 20. In addition, the fatty acid
must be unsaturated. Unsaturated means that not all carbon atoms carry the maximum number
of hydrogen atoms, but form double bonds. Three to five such double bonds are required
to synthesize eicosanoids. The most common and, therefore, important representative of
this type of fatty acid is arachidonic acid, which has four double bonds.
OK, let's go back to eicosanoid synthesis. The released arachidonic acid is converted
to prostaglandin H2. The key enzyme involved in this conversion is cyclooxygenase.
Let’s explore the reaction in more detail to understand the origin of the name cyclooxygenase.
The prefix “cyclo” indicates that the enzyme cyclizes arachidonic acid, that is,
it converts part of the molecule to a closed-ring. In its function as an oxygenase, it incorporates
oxygen into the molecule.
There are two isoforms of cyclooxygenase, cyclooxygenase 1 and cyclooxygenase 2, also
termed COX-1 and COX-2. So, why is this important to remember? Isoenzymes catalyze the same
reaction but differ slightly in their structure. These minor structural differences enable
some drugs to selectively influence COX-2, but not COX-1. This may be desirable as COX-1
and COX-2 have different biological functions. COX-1 is present in almost all cell types
and is constantly active, whereas COX-2 is only expressed under certain conditions such
as an inflammatory response.
In analogy to the left side of this image, there’s also an oxygenase present on the
right side of the image that uses arachidonic acid as a substrate. The enzyme is lipoxygenase,
in short LOX.
Let’s also look at this reaction in detail. Lipoxygenase catalyzes the reaction of arachidonic
acid to leukotriene A4. The name lipoxygenase indicates that the enzyme is capable of oxygenating
fatty acids or lipids. In contrast to COX, oxygen is incorporated into the molecule,
without forming a cyclic structure.
OK, so that should wrap things up on the most important enzymes involved in eicosanoid formation.
Before we move on to the physiological roles of the different eicosanoids, we should address
one last aspect regarding terminology: Have you ever asked yourself what the letters and
numbers in the names of the eicosanoids symbolize? The letters indicate different functional
groups in the ring. The subscript at the end of the name stands for the number of carbon
double bonds in the molecule. Prostaglandins and thromboxanes, which are metabolites of
arachidonic acid, have two double bonds. Therefore, they’re easily identified by the subscript
2.
In contrast, leukotrienes, which are also formed from arachidonic acid, have four double
bonds, as indicated by the subscript 4 on the name leukotriene. Three of these four
double bonds are conjugated, which means they’re separated by a single bond. This gives rise
to the suffix “-triene” in leukotriene. By the way, the prefix “leuko-” implies
that they’re formed by leukocytes, or in other words white blood cells.
Don’t worry if these structural forms appear complex. The most important thing to remember
is that the compounds are quite similar.
Let’s use the prostaglandins E2 and F2 as an example. They differ in the functional
groups on the ring, shown here in red. Prostaglandin E2 has a ketone on its ring, which is an oxygen
atom forming a double bond to a carbon atom. In prostaglandin F2, this oxygen atom is part
of a hydroxyl group and forms a single bond to a carbon atom. These subtle differences
between the various prostaglandins result in the frequent overlap in their effects,
which has been widely discussed in the literature.
In the next slide, we’ll summarize the most important functions of eicosanoids.
As eicosanoids are local hormones, it’s important to consider their physiological
effect depending on the organ they’re formed in.
Let’s start with prostaglandin E2 and a selection of its effects. One very important
function is the involvement of prostaglandin E2 as a mediator of pain and the inflammatory
response. This effect is due to the binding of prostaglandin E2 to free nerve endings
called nociceptors, which register pain signals.
Prostaglandin E2 is also produced in the hypothalamus in response to chemical messengers released
during an inflammatory response. Therefore, prostaglandins increase the body’s core
temperature, inducing fever.
However, prostaglandins are also important for the function of several organs. In the
stomach, prostaglandin E2 has a protective effect by facilitating mucus production.
In the kidney, it causes vasodilation, leading to increased renal blood flow, abbreviated
here as RBF.
Prostaglandin E2 is also formed in the uterus and stimulates uterine smooth muscle contraction
with increasing gestational age.
Furthermore, prostaglandin E2 is also formed in the prostate and released in seminal fluid,
where it increases sperm motility. This actually gave rise to the name prostaglandin, as these
hormones were first isolated from seminal fluid, which is produced in the prostate gland.
Now, let’s move on to prostacyclin. One of the sites of prostacyclin synthesis is
in the epithelium of blood vessels, where they have a vasodilatory effect and inhibit
platelet aggregation. Therefore, both functions are important in regulating coagulation, in
which prostacyclin has an important antagonist: thromboxane A2.
Thromboxane A2 is released by activated platelets, resulting in vasoconstriction and platelet
aggregation. Accordingly, the origin of the name thromboxane can be traced back to its
synthesis in platelets, which are also termed thrombocytes.
Leukotrienes also have various effects on the body. Leukotriene B4, for example, is
synthesized by immune cells, especially neutrophils to attract other immune cells, indicating
that it has a chemotactic effect.
Leukotrienes C4, D4, and E4 are also synthesized in immune cells, especially by eosinophils.
In the lung, they lead to airway narrowing or bronchoconstriction. This is clinically
relevant because excess production of leukotrienes can result in an asthma attack.
Yet, the bronchoconstrictive effect of leukotrienes can be reduced by blocking the receptors of
leukotrienes C4, D4, and E4 on target cells. The drug montelukast and other leukotriene
antagonists ending with -lukast are used to block the actions of leukotrienes.
OK. Up to this point, we’ve introduced you to the most important eicosanoids and explained
their functions.
The exciting thing about this subject is that eicosanoids are also used in daily clinical
practice. For example, in gynecology during labor induction and in to keep the ductus
arteriosus open. Further information can be found in our library. But first, let’s go
to the quiz.
In this episode, we looked at arachidonic acid metabolism. Were you able to remember
all of the different substances? Arrange the arachidonic acid metabolites on the left side
to the boxes in the pedigree chart. Good luck!