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Synthesis of classical neurotransmitters from amino acids


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#1 LabRat84

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Posted 15 April 2010 - 04:30 AM


Dear forum members,

As you all know, amino acids are key in the synthesis of neurotransmitters. The following represents the culmination of the research I've done into the transport of amino acids across the blood-brain barrier and neurotransmitter synthesis. I decided not to add the receptors; that's another project. My main goal is to elucidate the function of TAAR1 (Trace Amino Acid Receptor) in neuropharmacology. TAAR1 appears to modulate the dopamine transporter. Both PEA and amphetamines are agonists of TAAR1. Search PubMed; the receptor was only discovered recently and there are not many publications on it. A review can be found here for those with Elsevier access.
T1AM (3-iodothyronamine) is derived from thyroid hormone and is an endogenous ligand for TAAR1. In mice, T1AM causes hypothermia and a switch to fat metabolism (much like a hibernation state). But those effects are not mediated through the TAAR1 receptor.

About my illustration: Each arrow represents a catalytic step. Above the arrow is the enzyme that catalyzes that step. In violet are cofactors of that enzyme, required for catalysis.
In red are the enzymes that degrade the designated neurotransmitter. A list of BBB transporters is provided, as are detailed synthetic and catabolic pathways for the monoamines. Note that methylfolate is a precursor to THB (BH4), a cofactor in several steps illustrated below.
This version contains the HPT (hypothalamic-pituitary-thyroid) and HPA (hypothalamic-pituitary-adrenal axes) and their effects on neurotransmitter synthesis.
A simpler version without the HPT and HPA axes can be found here.
A smaller file without the supporting charts (just my illustration) is here.
Enjoy for your reference! Let me know if there are any corrections to be made.

Posted Image

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Edited by LabRat84, 15 April 2010 - 04:39 AM.

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#2 chrono

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Posted 15 April 2010 - 06:59 AM

Wow, excellent contribution, and very nicely done! Extremely helpful for visualizing how these systems are interconnected. And also for visualizing the gaps in my knowledge from only studying the systems most relevant to my interests ;)

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#3 medievil

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Posted 15 April 2010 - 12:05 PM

Very good contribution, nicely done!

Edited by medievil, 15 April 2010 - 12:05 PM.


#4 LabRat84

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Posted 15 April 2010 - 05:19 PM

Attached is a nice illustration of the transsulfuration/methylation pathways (I forgot where it came from). A more detailed version can be found here.

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Edited by LabRat84, 15 April 2010 - 05:28 PM.


#5 LabRat84

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Posted 15 April 2010 - 05:23 PM

Thanks. Neuropharmacology tends to look at the receptor and transporter side of things (the things that lie on the cell membrane). Orthomolecular therapy (and other supplementation advocates) focus on the "supply side." An approach that incorporates knowledge of both is key to understanding and modifying the brain. Tryptophan and tyrosine use the same transporters to cross the BBB. A diet too high in tryptophan might lead to a catecholamine deficiency, or one without enough tryptophan might lead to a serotonin deficiency. Let's say that the major cause of depression is indeed serotonin deficiency. Psychiatrists treat with SSRIs, which are effective in many ways but don't actually treat the underlying problem; they just make serotonin more available temporarily. Lack of reuptake means more has to be synthesized. If the precursors aren't there, you'll deplete.
Loading up on direct agonists is not a good idea in many cases, because direct agonists often cause downregulation of the target receptors. (Sometimes treating with an antagonist to cause upregulation is desirable, like memantine and nAChRs. But that requires understanding which receptors upregulate in response to antagonism/reduced agonism, and which don't).

The "input" side (what this chart represents) is much simpler than the "output" side - interaction of different neuron types, the colocalization of transmitters, various receptor subtypes, autoreceptors, different pathways throughout the CNS, etc. There are also peripheral effects to worry about, as the same receptors are found in peripheral neurons and muscles (including the heart). That's why messing around with agonists and antagonists is more dangerous than supplementing with precursors (though precursors are not without risk).

My chart doesn't include the HPG (gonadal) axis, which is also important, because sex hormones modify the brain and affect mood and cognition. (E.g. the brain is rich in estrogen receptors. And there's a common phenomenon of "'roid rage.") The pathways are different in men and women. One abbreviation I forgot: PRL=Prolactin. Men have this too (and, incidentally, it's possible for men to lactate).

I also didn't include the synthesis actions of oxytocin and vasopressin, which also affect the brain. These are polypeptides, though, and are expressed through genetic mechanisms, not synthesized from simple catalytic reactions from precursors. There are also neuropeptides (YY, Substance P, and several others). Most neuropeptides are colocalized with classical neurotransmitters. But we have the most control over the monoamines and classical neurotransmitters through supplementation and psychoactive substances.

#6 Jurence

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Posted 15 April 2010 - 05:25 PM

Wow this is great! The third part (biochemical structures) was too technical for me, but I loved it all!

#7 chrono

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Posted 15 April 2010 - 07:02 PM

The "input" side (what this chart represents) is much simpler than the "output" side - interaction of different neuron types, the colocalization of transmitters, various receptor subtypes, autoreceptors, different pathways throughout the CNS, etc.

This is something I would love to see you do a similar chart of, if you decided to take up that project too. Though I'm sure the complexity would be daunting.

#8 LabRat84

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Posted 15 April 2010 - 09:54 PM

The "input" side (what this chart represents) is much simpler than the "output" side - interaction of different neuron types, the colocalization of transmitters, various receptor subtypes, autoreceptors, different pathways throughout the CNS, etc.

This is something I would love to see you do a similar chart of, if you decided to take up that project too. Though I'm sure the complexity would be daunting.

I initially set out with that goal, but realized how complex it was. The input side is basic biochemistry and some endocrinology. But the "output" side is Ph.D thesis material (and beyond).

A more modest goal would be a computer interface that shows the effects of various drugs on all known neurotransmitter receptors, transporters, synthesis enzymes, and metabolic enzymes.
The target proteins would be listed schematically, and different colors would appear over the names of the proteins based on the effect of a given compound. (Perhaps based on the PSDP database) You could then visualize how drugs would interact with various signaling systems.

#9 Nobility

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Posted 17 January 2014 - 05:01 PM

Good Post!!

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#10 golden1

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Posted 17 January 2014 - 06:03 PM

oh neat, I just posted in another thread wondering about TAAR1




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