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TETRAHYDROBIOPTERIN CYCLE — (BH4 CYCLE):
"To assist the impaired methylation cycle from A1298C, a FDA restricted dosage of Levomefolic acid (L-methylfolate) is required to offset the methylation pathway enzyme deficiencies adequately for the vitamin B12 dependent methylation cycle to function. Levomefolic acid is the active form of folic acid used at the cellular level for DNA reproduction, the cysteine cycle and the regulation of homocysteine among other functions. [Deplin (or a real equivalent) dosage of 10-15mg daily is often necessary.] MTHFR enzyme's end product, methylfolate, supports two major pathways: BH4 and Methylation.
If your BH4 cycle is not working effectively, you may experience mental or emotional and/or physical symptoms. [See: BH4 section just below] ***[See: FOLATE]
The MTHFR A1298C mutation appears to disrupt the function of the BH4 Cycle. That is the Recycling of BH2 into BH4 [Tetrahydrobiopterin]. Tetrahydrobiopterin [BH4] is absolutely critical for many functions within the body including but not limited to:
- BH4 assists with the breakdown of PHENYLALANINE
- Helps as a cofactor for the formation NEUROTRANSMITTERS:
- a. Serotonin
- b. Melatonin
- c. Dopamine
- d. Norepinephrine (noradrenaline)
- e. Epinephrine (adrenaline)
BH4 regeneration is supported by methylfolate and SAMe.
[One place to purchase BH4 — www.spectrum-supplements.com/tetrahydrobiopterin-60-capsules.html and
One place to purchase Deplin — www.deplin.com/savings-options/ [See: FOLATE]
MTHFR A1298C and the TETRAHYDROBIOPTERIN [BH4] CYCLE
See: The Methylation Community & Your Body Chemistry — Yasko_Education_diagrams_explanations.pdf
Picture the connection between the Folate Cycle [— An additional explanation of folate] and the MTHFR enzyme running in the reverse direction and the regeneration of BH2 into BH4. There isn't much research to be found about the MTHFR A1298C x 2 [+/+] homozygote set of mutations.
1. Some sources brush it off as though the MTHFR A1298C [+/+] had no impact upon health at all. In my opinion that is false.
2. The MTHFR A1298C [+/+] combination doesn't appear to have too much of an effect on what would be the "forward" direction of the MTHFR enzyme reaction so those with MTHFR A1298C may have what appears to be a pretty normal Homocysteine level.
3. What is really difficult to find is some really good research on the supposed "BACKWARD" direction [reaction] of the MTHFR enzyme. Many enzymes can push a reaction forward from left to right or backward from right to left. Other enzymes can only push a reaction in one direction...forward from left to right. An example of an enzyme that can only go in one direction is the Cystathionine Beta Synthase [CBS] enzyme which irreversibly converts Homocysteine into Cystathionine.
The problem implied by the presence of the double copy of the MTHFR A1298C [+/+] mutations is that the MTHFR enzyme reaction may not be able to go effectively in the backward direction from right to left. BUT...I cannot find any PROOF of this claim anywhere. I have found NO reliable scientific research project that addresses the MTHFR A1298C mutation and the reverse reaction of the MTHFR enzyme. So far I can only find "Claims" that the double copy of MTHFR A1298C [+/+] interferes with the reverse direction of the enzyme MTHFR. Dr. Amy Yasko
BH4 - USES AND REGENERATION [View Diagram and more — www.nature.com/npp/journal/v37/n1/fig_tab/npp2011205f3.html#figure-title]
"Tetrahydrobiopterin: Target for inflammatory effects on neurotransmitter metabolism. Tetrahydrobiopterin (BH4) is a critical cofactor for the rate-limiting enzymes involved in the synthesis of the monoamine neurotransmitters, including:
(1) the synthesis of tyrosine (tyr) from phenylalanine (phe) by PAH;
(2) the synthesis of L-3,4-dihydroxyphenylalanine (L-DOPA) from tyrosine (tyr) by tyrosine hydroxylase (TH) leading to the production of dopamine and norepinephrine; and
(3) the synthesis of 5-hydoxy-L-tryptophan (5-HTP) from tryptophan (tryp), leading to the production of serotonin.
(4) BH4 is also a cofactor for the enzyme NOS, which converts arginine (arg) to NO."
"During these enzymatic reactions, BH4 is degraded to BH2, which can be regenerated to BH4 through pathways supported by L-methylfolate, and SAMe. BH4 is relatively unstable and in the presence of inflammation and oxidative stress BH4 can undergo non-enzymatic oxidation leading to its irreversible degradation of BH4 to XPH2." Figure 3. — www.nature.com/npp/journal/v37/n1/fig_tab/npp2011205ft.html with links to details for more info.
*** Explains MTHFR malfunctions, Lab tests, Therapy process, Nutritional supplements and Dietary changes, etc. — www.heartfixer.com/AMRI-Nutrigenomics.htm#CBS:%C2%A0%20Cystathionine%20Beta%20Synthase
LAB TESTS INCLUDE: Vitamin D, homocysteine, blood ammonia, Urine: for sulfate and/or sulfite & ammonia and amino acids testing, mineral status (deficiencies in Molybdenum, Boron, and Copper - The best approach is a 24 hour urine study for nutritional minerals (with a concomitant measurement of toxic metals, which should start coming out on their own as your detox pathways open up)), homocysteine levels (an elevated homocysteine as a marker of a Methyl Cycle abnormality.) These levels will likely change in response to treatments and your MD must follow these diagnostic results closely.
*** Multiple Chemical Sensitivity: Toxicological and Sensitivity Mechanisms, Martin L. Pall, Professor Emeritus of Biochemistry and Basic Medical Sciences, Washington State University — www.thetenthparadigm.org/mcs09.htm
"Of these tests, the capsaicin cough response test, the blood histamine, nerve growth factor and other inflammatory marker test of Kimata1 and the nasal lavage tests may be the easiest to apply in a clinical setting and therefore may be the best as practical specific biomarker tests." (Empahsis mine) [1. Kimata H. (2004) Effect of exposure to volatile organic compounds on plasma levels of neuropeptides, nerve growth factor and histamine in patients with self-reported multiple chemical sensitivity. Int J Hyg Environ Health 207,159-163.]
Dr. Pall debunks "psychological symptoms" or "somatoform disorders" as the underlying cause. "We have a detailed and generally well supported model for the entire group of multisystem illnesses. ... These other diseases were formerly considered psychogenic: Multiple sclerosis (MS), Parkinson's disease, Lupus, Interstitial cystitis, Migraine, Rheumatoid arthritis, Asthma, Gastric and duodenal ulcers, and Ulcerative colitis. ... Each of these has been been shown, of course, to be a real physiological disease, caused by genuine demonstrable pathophysiologic mechanisms."
NITRIC OXIDE CYCLE (NO):
Nitric Oxcide Cycle (click on left or right images) — NitricOxide.org
Shows link of the MTHFR A1298C to breakdown in the BH4 cycle. — www.intechopen.com/books/pulmonary-hypertension/nitric-oxide-in-pathophysiology-and-treatment-of-pulmonary-hypertension
BH4 and Nitric Oxide — cardiovascres.oxfordjournals.org/content/65/4/823.full
How can we cure NO cycle diseases? — www.townsendletter.com/FebMarch2010/cureNO0210.html