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On Mon, 25 Aug 1997 03:07:37 -0400 Baldwin Robertson <[log in to unmask]> pleaded: >Is there someone on the list who either is a biochemist or knows >one who might be interested in answering the following question about the >regulation of dopamine synthesis. It has been a while since my biochemistry days, but I shall endeavor to answer your question by explaining each step ot the process given below. I assume your question concerns only dopamine derived from Tyrosine and not from other sources. STEP A >The rate limiting step in the synthesis of the neurotransmitter, dopamine, >from the amino acid, tyrosine, in the brain is: > >tyrosine + O2 + tetrahydrobiopterin > >---> dopa + H2O + quinonoid dihydrobiopterin. > >This reaction is catalyzed by tyrosine hydroxylase, a monooxidase >like phenylalanine hydroxylase. Dopa (i.e., Levodopa) is an abbreviation for >3,4-dihydroxyphenylalanine. This reaction shows how tyrosine is converted into levodopa, the precursor of dopamine. The amount of levodopa produced is dependent on three factors: the amounts of tyrosine, tetrahydrobiopterin, and tyrosine hydroxylase. Tyrosine is what is being converted (the raw source). A cofactor is an element that is chemically altered during the process. In this case the tetrahydrobioterin contributes two hydrogen atoms to the H2O molecule thus becoming dihydrobioterin (tetra = 4, di = 2). A catalyst is an element that is necessary for the reation to take place but is not a part of the reation itself, therefor the tyrosine hydroxylase is unchanged. STEP B >Tetrahydrobiopterin, the cofactor that activates molecular oxygen >in this reaction, is regenerated by the reaction: > >quinonoid dihydrobiopterin + NADH + H+ > >---> tetrahydrobiopterin + NAD+ + H2O, >which is catalyzed by dihydropteridine reductase. In this process the dihydrobiopterin is converted (regenerated) back into tetrahydrobiopterin. This process does not have a direct effect on the main process (tyrosine --> dopamine) but the efficiency of the process may affect the total amount of tetrahydrobiopterin available. Again, the catalyst is not affected by the process but its amount can be a limiting factor in the process. SUB-SUMMARY >The overall net reaction catalyzed by tyrosine hydroxylase and >dihydropteridine reductase is > >tyrosine + O2 + NADH + H+ ---> dopa + NAD+ + H2O. This is a summary of what was discussed above as far as it pertains to the catalysts. STEP C >The next step is: dopa ---> dopamine, which is catalyzed by >dopa decarboxylase. This means levodopa is converted into dopamine by the presence of dopa decarboxylase but the dopa dycarboxylase is not part of the conversion. This step actually ends the process of converting tyrosine into dopamine. As you can see, dopamine does not have any effect on any other of the elements involved. Dopamine is an end product of, not an ingredient, in the process The following two processes affect the availabilty of dopamine regardless of its source and have nothing to do with the conversion of tyrosine into dopamine. STEP D >Dopamine is degraded in the reaction: > >dopamine ---> 3-o-methyldopamine, > >which is catalyzed by catechol-o-methyltransferase (COMT), This reaction is the lesser of the two as far as its effect on the amount of dopamine available. The drug Tolcapone is a COMT inhibitor. By inhibiting this reaction it makes more dopamine available to the brain. STEP E >and in the reaction: > >dopamine ---> 3,4-dihydroxyphenylethylaldehyde, > >which is catalyzed by monoamineoxidase-B (MAO-B). This reaction scavenges used dopamine from the system. Since the dopamine can be reused, inhibiting the process will make more dopamine available to the brain. Eldepryl (selegeline) is an MAO-B inhibitor. NOTE: Most doctors don't know that Eldepryl inhibits only MAO-B and not MAO-A. Since MAO-A is a factor in blood pressure they will not prescribe antihistamines if you are taking Eldepryl when in fact there is no interaction. STEP F There is another reaction which you (or your source) did not mention, and thart is the conversion of levodopa to dopamine in the blood, where it does nop good in alleviating PD symptoms. Carbidopa (the other active ingredient in Sinemet) inhibits that reaction. >My question is: How is the level of dopamine regulated? Assuming a totally natural process, the level of dopamine is regulated by several factors, the most important one being its release rate by the dopamine producing cells in the brain. Steps A through C can affect the level by adding more dopamine through the conversion of tyrosine, while steps steps D through F inhibit the conversion of dopa in the blood and the scavenging of dopamine, thereby making more available. What the top level regulator is (if any), is beyond my expertise. That question and those that follow are not really addressed in the cited reactions/processes. They deal simply with the conversion of tyrosine to dopamine and the degradation of dopa by COMT and MAO-B >Does dopamine inhibit tyrosine hydroxylase or does it inhibit the >expression of the enzyme? Not as far as the cited prosesses are concerned. > What is the specific mechanism for the inhibition reaction? That is, what are the specific > reactions that accomplish the regulation? My explanation of each step concerning the inhibitory processes give as much explanation as my understanding allows. As I said, it has been a long time since by biochemist days so someone else may have a more complete explanation. Bruce G, Warr, PhD (Cand) A Man For All Seasons AND Current Parkinson's Disease Patient 55/9 Sinemet CR and Mirapex