to possibly clarify this discussion:

1. TH, tyrosine hydroxylase (TH) is the enzyme (a protein catalyst, produced inside the cells) which converts L-tyrosine (an amino acid, which may be made inside the cells from its precursor L-phenylalanine, or brought into the cells from the blood) into L-DOPA.

2. As described in the post by Laura, multiple slightly different forms of TH, some of which are produced by a subtle modification, the addition of one or more phosphate groups, may result in those forms being better (faster) catlysts.

3. Since the TH-reaction is the rate-limiting step in dopamine (DA) production, regulation of the above-mentioned phosphate group additions probably serve to regulate DA production.

4. A common way that cells keep enymes such as the phosphate-activated TH under control is to make them more subject to being broken down by the proteosome system, essentially a protein-disposal system inside cells which breaks them down to small protein fragments and amino acids.

5. Thus, a healthy DA neuron, capable of synthesizing more TH protein enzyme, remains in control of its DA production. This feedback system provides both an accelerator (phosphate addition to TH) and a brake (proteosomal TH degradation).

Laura, can you provide a source reference for that material in your post?

Robert

Sure thing. Funny, any other time I post the link but was too tired. Unfortunately, it is not free full text.


A possible pathophysiological role of tyrosine hydroxylase in Parkinson's disease suggested by postmortem brain biochemistry: a contribution for the special 70th birthday symposium in honor of Prof. Peter Riederer.
Nakashima A, Ota A, Kaneko YS, Mori K, Nagasaki H, Nagatsu T.
Source
Department of Physiology, Fujita Health University School of Medicine, Toyoake,

Quite a cozy little dust bunny under the bed here, isn't it? Dopamine is our bottom line. It is made from tyrosine which is made from phenylalanine with the help of tyrosine hydroxylase, all presumably powered by mitochondria. Further, if we need a shot of adrenaline or noradrenaline we cannabilize the material from the dopamine. A lot of things here all leading to a shortage, seems to me.

Yes, which leads back to why are our neuromelanin so vulnerable?

BTW, tried 500 mg of TH yesterday and felt great with no noticeable wear off. Today, it interfered with Sinemet absorption leaving me with two bad offs. Ths is a known, so how do we take it close enough to a Sinemet dose to benefit but far enough away so as not to interfere?

doesn't address tyrosine directly but interesting
http://www.pspinformation.com/nutrition/diet/diet.shtml
http://neuroscience.uth.tmc.edu/s4/chapter11.html

i've always assumed we get more than enough tryrosine and it's precursors thru a normal diet. how much Phenylalanine and tyrosine is in a glass of milk, 4oz of steak, an egg, etc? if the body didn't have a way iof controlling how these amino acids got into a brain and/or were converted in the brain to neurotransmitters, wouldn't eating a steak nearly kill us? just saying AA metabolism in the brain is very complicated, especially with active transport shuttling these aa''s across the brain barrier?

The essential amino acids cannot be synthesized by the brain and, therefore, must be supplied from protein breakdown and diet. Phenylalanine, leucine, tyrosine, isoleucine, valine, tryptophan, methionine and histidine, which are essential amino acids, and also the precursor of dopamine, L-DOPA, enter the brain as rapidly as glucose. These amino acids are transported into the brain by the leucine-preferring or the L-type transport proteins. These compounds compete with each other for entry into the brain. Therefore, an elevation of plasma level of one will inhibit uptake of the others. This competition may be important for certain metabolic diseases such as phenylketonuria (PKU), where high levels of phenylalanine in plasma reduce brain uptake of other essential amino acids.

Small neutral amino acids, such as alanine, glycine, proline and GABA (gamma-aminobutyric acid), are markedly restricted in their entry into the brain. These amino acids are non-essential amino acids and are transported by alanine-preferring or A-type transport protein. The A-type transport protein is not present on the luminal surface of the blood brain barrier. In contrast, these small neutral amino acids appear to be transported out of the brain across the blood-brain-barrier.

Thanks for this thread, and chemistry lessons

I couldn't help but notice the role of phenylanaline here, and it is in those 5-hour energy drinks which give us such a boost....I've posted about it before and we have speculated here what it is that helps....I had concluded, based on the collective wisdom here, that it probably was the B vitamins in it, yet B reduces (for some reason I still dont' understand) the efficacy of sinemet, so maybe that's not it....

And if it were the B vitamins, why would the manufacturer put the phenylanaline in? What role does that ingredient play? If it has no role, it wouldn't be in there....same with tyrosine, it's in there as well...

I noticed just this past week a news article stating that the FDA wants to regulate energy drinks.

Just revisited Rick's post. The dietary form is not as efficacious as powder form, so our l-Tyrosine rich foods are just a booster -no worry about overdosing on a steak. This is last paragraph from his post; not sure if it Rick's explanation or direct quote of researcher?


Some of the papers have titles that include the words “dietary tyrosine,” even though L-tyrosine is given without the amino acids that accompany it when it is ingested as part of protein. The use of L-tyrosine in purified form ensures that it is metabolized less via protein synthesis and more by catecholamine synthesis. Given that purified L-tyrosine is handled metabolically in a somewhat different way from ingesting it as part of the diet, calling it a dietary or natural remedy is misleading. Effectively, it is being used as a drug. Safety data on long-term L-tyrosine use in healthy people is lacking. In one of the longest studies, 2.5 g L-tyrosine 3 times daily had no beneficial or adverse effects when given to people with mild essential hypertension for 2 weeks. The measures in this study were limited to heart rate and blood pressure.

The key then is we want something not isolated by protein synthesis but metabolized more by catecholamine system which is not just dopamine but norepinephrine. Hence my thread on the "wrong transmitter". Far too much attention is focused on dopamine, IMHO. Especially, in light of the fact that PWP lose 10% more norepinephrine than dopamine. Our treatment with dopaminergics alone is far from optimal. Robert has progressed very slowly and he has been on an SNRI for the 12 years since he has been diagnosed. I wonder if adding L-Tyrosine to the mix would have been even better. At any rate, as an alternative to wires in my brain, I am willing to give it a trial run.

Just noticed in above trial...they took 2.5 grams three times a day with no ill effect? Yikes. Note: this is people who have have no L-Tyrosine deficiency like we do but begs my original question, do we have a dosage threshold where L-Tyrosine accelerates cell loss of dopamine?

From a recent study cited by Olsen in the past few days. This study compared TH levels between Incidental Lewy Body Disease and PD.

Neuron density was higher in the ILBD patients than in 13 patients with clinical PD, but the percentage of neurons that were negative for tyrosine hydroxylase (TH), indicating dopaminergic cell dysfunction, was also higher.

[I]The researchers - John Duda (Philadelphia Veterans Affairs Medical Center, Pennsylvania, USA) and colleagues - suggest that these TH-negative cells may be "struggling to survive" in patients with ILBD, but have died in patients with PD, accounting for the low overall neuron density in PD patients (66.7% lower than in patients without Lewy bodies).

Neuronal density in ILBD patients declined in line with increasing burden of α-synuclein, but the proportion of TH-negative cells was not associated with α-synuclein burden, which "further suggests that [Lewy pathology] is not the only cause of nigral neuron loss," comments the team.

Schulz-Schaeffer says: "We should disengage from the notion of Lewy body-associated cell death as the main phenomenon in PD and concentrate on synaptic pathology and axonal degeneration of still-existing cells in our search for therapy and for understanding the pathophysiology of PD."[/I]

Things are going awry in our ability to synthesize amino acids but what is causing that?

I have taken a single 350 mg capsule of N-Acetyl-Tyrosine. The first day I ran into the "absorption road block" and have taken the other three at bedtime instead. I have slept like the proverbial log with one exception, a hyperactive bladder from midnight to about 4:00 AM. A real hassle struggling awake in time but zero problem getting back to sleep.

Slower to gather what passes for my wits in the morning (90 to 120 minutes vs 60 min) but once I have cleared that hurdle, the other three days have been quite good.

Bedtime has been coming abruptly with a max warning of ten minutes. This largely my own fault as I have been skipping my usual last dose in order to observe what is happening.

Given the relatively low dose that I have been using, I am going to keep at this one although slowly due to a half-dozen others that I am at various stages with.

Now, a question. Since we draw on dopamine when we need material to make adrenaline, does the fight or flight response burn up dopamine?

Bump bump bump...