Copper metabolism
Are you curious about how copper is transported in the body?
In this Chalk Talk episode, we’ll be taking a look at how copper is absorbed by liver
cells and further transported in the body.
Knowing these steps makes it easier to understand the different copper transport disorders.
The most important example is Wilson disease.
This disorder is caused by a defective copper-transporting protein, resulting in the release of large
amounts of free copper from the liver and eventually accumulation in the liver and other
organs.
We’ll be taking a detailed look at the processes involved in Wilson disease in the next Chalk
Talk episode.
But first, let's take a look at the physiology of copper metabolism.
This schematic image shows a liver cell or hepatocyte.
The top and bottom of the hepatocyte are in close contact with the liver sinusoids, which
are large capillaries found in the liver.
On the left is a bile duct, which connects with the hepatocyte.
After food intake, copper is absorbed by the small intestine and transported to the hepatocyte
via the portal vein.
Although we keep on mentioning copper, we’re actually referring to copper ions.
These copper ions, which are en route from the intestine to the liver, are loosely bound
to albumin.
Copper is then absorbed from the portal venous blood by the hepatocyte.
The cell membrane of the hepatocyte contains special copper transport proteins known as
CTR1.
The abbreviation CTR stands for copper transporter.
The copper ions in the blood enter the hepatocytes through CTR1.
The role of the hepatocytes is to determine the amount of copper to be stored and excreted
by the body.
For copper to be transported from the liver to individual organs, it needs to bind to
a carrier protein.
This occurs in the Golgi apparatus of the hepatocyte.
The carrier protein that binds to copper is an enzyme called apoceruloplasmin.
Before we continue, let’s briefly touch base on the nomenclature.
If copper ions are not bound to a carrier protein, the protein is called apoceruloplasmin.
However, once a copper ion binds to the transporter, it’s termed ceruloplasmin.
By the way, this applies to all enzymes that contain both a protein and a non-protein part.
The protein part of the enzyme is called an apoenzyme, whereas the non-protein part is
termed cofactor.
Once the cofactor binds to the apoenzyme, then the enzyme is considered complete and
functional.
The complete enzyme is called a holoenzyme.
In our example, the holoenzyme is ceruloplasmin.
Now, let’s get back to copper transport.
To reach apoceruloplasmin, copper must be transported across the Golgi apparatus membrane.
This is made possible through ATP7B, which is located in the membrane of the Golgi apparatus.
The ATP7B protein is an enzyme with ATPase activity and binds to copper.
The breakdown of ATP results in the release of energy that is subsequently used to transport
copper across the membrane.
In the Golgi apparatus, copper ions attach to the binding sites of apoceruloplasmin,
which usually binds six copper ions.
Subsequently, ceruloplasmin exits the hepatocyte and can be transported to various organs by
the blood.
The majority of copper is transported to the rest of the body by the blood.
A significantly smaller amount of copper can pass directly through the hepatocyte and is
present in blood as free serum copper.
By the way, in the image, it looks as though the copper ions are wandering through the
cell.
Yet, copper ions are toxic to cells and are, therefore, bound and transported inside cells
by different proteins, which aren’t shown in the image.
Now, let’s compare the two forms of copper in blood: Free serum copper isn’t bound
as a complex to ceruloplasmin.
It’s loosely bound to other proteins, such as albumin.
However, as the copper is only loosely bound, it’s called free serum copper.
Together, free serum copper and ceruloplasmin form total serum copper.
These three laboratory parameters - free serum copper, ceruloplasmin, and total serum copper
- are important for the blood diagnostics of copper metabolism.
We’ll be taking a detailed look at these parameters in our Chalk Talk episode on Wilson
disease.
In addition to providing the body with copper, hepatocytes have the important task of eliminating
excess copper from the body.
The copper that’s no longer needed is transported from the Golgi apparatus to the bile ducts
in vesicles.
Subsequently, copper can be excreted into the bile and eliminated from the body.
OK.
Let’s briefly recap the role of hepatocytes in copper metabolism.
Hepatocytes absorb copper from the blood and release most either as ceruloplasmin into
the blood, if the body requires copper.
If copper isn’t required, excess amounts are excreted into the bile.
ATP7B plays a very crucial role in this process: It’s responsible for trafficking copper
into the Golgi apparatus.
However, if dysfunctional, it leads to Wilson disease.
To round things off, we’d like to explain why copper is essential for the body.
The short answer is that copper is important in the function of many enzymes.
Now, let’s look at it in more detail: As metal ions, copper ions can easily absorb
as well as release electrons by alternating between the two oxidation states positive
2 and positive one.
Therefore, they’re suitable partners in reactions that involve the transfer of electrons,
termed redox reactions.
Here are some examples of enzymes in which copper plays an important role:
Cytochrome C oxidase uses copper to catalyze electron transfer to oxygen in the final step
of the respiratory electron transfer chain.
It’s also known as complex IV.
Superoxide dismutase is a key enzyme in cellular detoxification.
It can neutralize oxygen radicals, namely the free radical superoxide, which has the
molecular formula O negative two.
Copper acts physiologically as an antioxidant and protects cells against damage from oxidative
stress.
Dopamine beta-hydroxylase also contains copper.
It catalyzes the conversion of dopamine to noradrenaline and, in an additional step,
to adrenaline.
Tyrosinase catalyzes the production of melanin, the pigment responsible for the color of skin.
Lysyl oxidase is a key enzyme involved in cross-linking collagen.
Now, onto the final example.
We previously mentioned that ceruloplasmin is a copper transport protein; however, it
also exhibits enzymatic activity.
Ceruloplasmin catalyzes the oxidation of iron from a divalent to trivalent state.
It can then bind to its transport protein transferrin.
As we previously mentioned, ceruloplasmin is a transport protein; however, because it
can oxidize iron, it also belongs to a class of enzymes termed ferroxidases.
The prefix ferro- means iron.
As a result of these diverse functions, copper is an essential trace element that enables
important metabolic functions.
Yet, it’s also considered toxic at high concentrations, which is why a normal copper
balance is very important for the body.
If there’s a copper imbalance, the result is cellular damage.
In the next Chalk Talk episode, we’ll be looking at how this occurs in Wilson disease,
a copper metabolism disorder.
But before we move on to the next episode, won’t don’t you try this exercise?
The image here shows an overview of copper metabolism.
Why don’t you try to find out what happens when there’s a defective ATP7B protein?
How do levels of free serum copper, ceruloplasmin, and total serum copper change?
The answers will be provided in the next Chalk Talk episode on Wilson disease.