Hey everyone, in this lesson we're going to talk about catecholamine synthesis. So we're going to talk about what a catecholamine is, how the catecholamine synthesis pathway operates, including the enzymes required in the pathway, and then finally we're going to talk about different genetic diseases or disorders that actually affect this pathway. So to begin, what is a catecholamine?
Well a catecholamine is simply a catechol plus amine. So it's a monoamine and it's again a catechol group. So it's a a benzene ring with two hydroxyl groups attached plus one amine group. Now the catecholamines include dopamine, norepinephrine, and epinephrine.
So they're all variations on the same molecule and they all act as neurotransmitters and hormones and all are derived from phenylalanine and or tyrosine. So phenylalanine, as we know, is an essential amino acid. And phenylalanine and tyrosine both can actually be taken up by the diet. Phenylalanine is required from the diet.
Tyrosine is actually produced from phenylalanine. We'll get into that in a bit of detail in the next slide. So it all starts with phenylalanine. Phenylalanine is brought in into the body through dietary intake.
Now what happens is it actually undergoes a hydroxylation reaction on the benzene ring. to form tyrosine by the enzyme phenylalanine hydroxylase. And this step requires tetrahydrobioptrin and the hydroxyl group actually gets transferred from the tetrahydrobioptrin and gets actually gets transferred to the phenylalanine to produce tyrosine and the tetrahydrobioptrin becomes dihydrobioptrin. Now the dihydrobioptrin can actually be recycled back into tetrahydrobioptrin by the enzyme dihydrobiopterin reductase with the cofactor NADPH. Now, just a quick note, 50% of dietary phenylalanine is used for tyrosine synthesis.
So tyrosine can come from phenylalanine or it can actually come from the diet as well. Now, tyrosine can actually be shunted into a different pathway. It can actually undergo...
a transamination reaction via the enzyme tyrosine transaminase to form 4-hydroxyphenylpyruvic acid. Now, as you can see here, the amine group from tyrosine is actually removed and replaced with a ketone. And the 4-hydroxyphenylpyruvic acid can actually be used to form fumarate and acetoacetate for glycogenic or ketogenic reactions.
Now, the tyrosine can also be acted on by the enzyme tyrosine hydroxylase. Now, tyrosine hydroxylase, what it'll do is it'll actually take the tyrosine and actually hydroxylate it again. Now, this is when we actually have a catecholamine. And again, this is carried out with the help of tetrahydrobioptrin. So the hydroxyl group gets transferred from the tetrahydrobioptrin onto the tyrosine to form 3,4-dihydroxyphenylalanine.
or DOPA. Again, the tetrahydrobioptin becomes dihydroboctrin, and the dihydroboctrin can be, again, recycled back to tetrahydroboctrin by DHB reductase. Now, once we have DOPA, this can actually be decarboxylated by the enzyme aromatic amino acid decarboxylase. And again, what is decarboxylation?
Well, decarboxylation is just the removal of a CO2 group. and that's exactly what happens in this reaction. So as you can see here, you remove the carboxylic acid group from the dihydroxyphenylalanine, and you are left with dopamine. And one last thing about this enzyme, aromatic amino acid decarboxylase actually requires vitamin B6 or pyridoxal phosphate as a cofactor. Now once you have dopamine, dopamine can actually go through another...
hydroxylation reaction to produce norepinephrine. So the only difference here is you see there's a hydroxyl group on, another hydroxyl group on norepinephrine as opposed to dopamine. And again, this is actually carried out by ascorbate or vitamin C. And this is actually, ascorbate is actually processed into dehydroascorbate in this reaction. So once we have norepinephrine, norepinephrine can actually be methylated.
by the enzyme phenylethanolamine N-methyltransferase to form epinephrine. And this is actually carried out with the help of the cofactor S-adenosylmethionine, or SAM. And what happens is SAM will actually donate a methyl group to the norepinephrine to form epinephrine. And in doing so, SAM will actually become S-adenosylhomocysteine.
Now, S-adenosyl homocysteine can actually be recycled back into S-adenosylmethionine via the activated methyl cycle, and I'll show you that in another lesson. And as you can see, epinephrine is simply norepinephrine with an additional methyl group attached at the amine group. So here is the entire catecholamine synthesis pathway in a concise format. So I'm just going to go over what happens in each step once again for clarity. In the first step from phenylalanine to tyrosine, there's a hydroxylation step by the enzyme phenylalanine hydroxylase.
The next step from tyrosine to DOPA is also another hydroxylation reaction by the enzyme tyrosine hydroxylase. Then DOPA actually gets decarboxylated to dopamine, so this is actually a decarboxylation reaction. Dopamine goes through another hydroxylation to form norepinephrine, which is another hydroxylation reaction. And then the final reaction in the pathway. is norepinephrine to epinephrine via the enzyme phenylethanolamine and methyltransferase, which is a methylation step.
Now, when we look at these enzymes, there are actually a variety of genetic diseases that actually affect these enzymes in the pathway. So starting at the beginning of the pathway, if there's a mutation in phenylalanine hydroxylase enzyme, this can lead to a condition known as phenylketonuria. Now, phenylketonuria is due to a mutation in phenylalanine hydroxylase gene, which causes a reduction in this enzyme or a reduced activity of this enzyme, leading to toxically high levels of phenylalanine in the body. Now, in the next step, when we have tyrosine, tyrosine can actually be processed by something known as tyrosinase. Now, I didn't mention this before, but tyrosinase is an enzyme analog of tyrosine hydroxylase and tyrosinase is actually present in melanocytes.
Now in melanocytes, tyrosine gets processed by tyrosinase into DOPA, the same as we've learned before, and then DOPA can actually be processed into melanin. Now if there's a mutation in tyrosinase, what can happen is we get a condition known as albinism. So any mutation in tyrosinase gene can actually cause albinism.
If we go farther down the pathway, if we see that there's mutations in the gene encoding dopamine beta-hydroxylase, we actually get a condition known as dopamine beta-hydroxylase deficiency. And finally, when we look at the last enzyme in the pathway, phenylethanolamine and methyltransferase, there has been some evidence suggesting that reduced activity of this enzyme or reduced amount of this enzyme can lead to higher incidences of vitiligo and Alzheimer's disease. Anyways guys, that was catecholamine synthesis lesson. If you found this video helpful, please like and subscribe for more videos like this one.
And as always, thank you so much for watching and have a great day.