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Tetrahydrobiopterin (BH4) levels linked to MTHFR gene and schizophrenia

BH4 is an enzyme that is used to make serotonin, dopamine, thyroid hormones, melanin and to detox ammonia. It is recharged by folate and/or niacin and/or vitamin CWith certain combinations of the MTHFR gene, some people have a limited supply of BH4. Those people can probably be identified as those who have tendencies towards depression, low energy, all-or-nothing focus, hypothyroid (even subclinical), are pale, and may have elevated blood ammonia. L-methylfolate regulates BH4 production. These people will do best on small amounts of very high quality protein, and lots of methyl folate

2013The role of tetrahydrobiopterin and catecholamines in the developmental regulation of tyrosine hydroxylase level in the brain. J Neurochem. Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan “We found that BH4 administration persistently elevated the BH4 and dopamine levels in the brain and fully restored the loss of TH protein caused by the BH4 deficiency in infants. On the other hand, dopa administration less persistently increased the dopamine content and only partially but significantly restored the TH protein level in infant BH4-deficient mice. We also found that the effects of BH4 or dopa administration on the TH protein content were attenuated in young adulthood. Our data demonstrate that BH4 and catecholamines are required for the post-natal augmentation of TH protein in the brain, and suggest that BH4 availability in early post-natal period is critical for the developmental regulation of TH protein level.”

2013Amelioration of Behavioral Abnormalities in BH4 (Tetrahydrobiopterin)-deficient Mice by Dietary Supplementation of Tyrosine. PLoS One. Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea. “In this study, we report that these aberrant motor deficits displayed by Spr (-/-) mice were ameliorated by the therapeutic tyrosine diet for 10 days. This study also suggests that dopamine deficiency in brains of Spr (-/-) mice may not be the biological feature of aberrant motor behaviors associated with BH4 (tetrahydrobiopterin) deficiency. Brain levels of dopamine (DA) and its metabolites in Spr (-/-) mice were not substantially increased by the dietary tyrosine therapy. However, we found that mTORC1 activity severely suppressed in brains of Spr (-/-) mice fed a normal diet was restored 10 days after feeding the mice the tyrosine diet. The present study proposes that brain mTORC1 signaling pathway is one of the potential targets in understanding abnormal motor behaviors associated with BH4-deficiency.”

201213C-Phenylalanine breath test detects altered phenylalanine kinetics in schizophrenia, Transl Psychiatry.  Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.  “serum phenylalanine levels were found to be significantly higher,3 and tyrosine levels lower4 in drug-free patients with schizophrenia than in healthy controls…The enzyme phenylalanine hydroxylase (PAH) converts phenylalanine to tyrosine using the cofactor tetrahydrobiopterin; this activity takes place in the liver and kidney…The enzyme tyrosine hydroxylase (TH) uses tetrahydrobiopterin to catalyze the conversion of tyrosine to l-3,4-dihydroxyphenylalanine (l-DOPA), which is the rate-limiting step in the syntheses of dopamine and noradrenaline.10 One of the mechanisms by which TH is regulated is feedback inhibition by its end products, that is, dopamine and noradrenaline”

2011Partial biopterin deficiency disturbs postnatal development of the dopaminergic system in the brain. J Biol Chem. Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan. “In contrast, the effects of BH4 (tetrahydrobiopterin) deficiency on dopamine and TH protein levels were more manifested during the postnatal development. Both of dopamine and TH protein levels were greatly increased from P0 to P21 in wild-type mice but not in those mutant miceSerotonin levels in those mutant mice were also severely suppressed after P7.”

2011, Activation of peroxisome proliferator-activated receptor-{delta} enhances regenerative capacity of human endothelial progenitor cells by stimulating biosynthesis of tetrahydrobiopterin. HypertensionHe TSmith LALu TJoyner MJKatusic ZS., Mayo Clinic  “…activation of PPARδ stimulates expression and activity of GTPCH I and biosynthesis of tetrahydrobiopterin via PTEN-AKT signaling pathway.

2005, Evidence for a tetrahydrobiopterin defecit in schizophreniaNeuropsychobiology.  “Tetrahydrobiopterin (BH(4)) is a vital cofactor maintaining availability of the amine neurotransmitters [dopamine (DA), noradrenaline (NA), and serotonin (5-HT)], regulating the synthesis of nitric oxide (NO) by nitric oxide synthase (NOS), and stimulating and modulating the glutamatergic system (directly and indirectly).  Study analysis showed a highly significant deficit of total biopterins for the schizophrenic sample after partialling out the effects of potential confounds…A mean decrement of 34% in plasma total biopterins for schizophrenics from control values. A deficiency of BH(4) could lead to hypofunction of the systems of DA, NA, 5-HT, NOS/NO, and glutamate, all of which have been independently implicated in schizophrenia psychopathology.”

2000, Tetrahydrobiopterin biosynthesis, regeneration and functions. Biochem J. Division of Clinical Chemistry, University Children’s Hospital, Zurich, Switzerland  “GTP cyclohydrolase I  (may be under the control of cytokine induction) regulates tetrahydrobiopterin cofactor biosynthesis…The pathway for the de novo biosynthesis of BH(4) from GTP involves GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase and sepiapterin reductase. Cofactor regeneration requires pterin-4a-carbinolamine dehydratase and dihydropteridine reductase…On a cellular level, BH(4) has been found to be a growth or proliferation factor for Crithidia fasciculata, haemopoietic cells and various mammalian cell lines. In the nervous system, BH(4) is a self-protecting factor for NO, or a general neuroprotecting factor via the NO synthase pathway, and has neurotransmitter-releasing function. With regard to human disease, BH(4) deficiency due to autosomal recessive mutations in all enzymes (except sepiapterin reductase) have been described as a cause of hyperphenylalaninaemia. Furthermore, several neurological diseases, including Dopa-responsive dystonia, but also Alzheimer’s disease, Parkinson’s disease, autism and depression, have been suggested to be a consequence of restricted cofactor availability.”  http://www.ncbi.nlm.nih.gov/pubmed/10727395 .

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