[Company Logo Image]  Little Canaries

Home Search News Feedback

Methylation
 

 

Home
Up

 

 

 

What is methylation?

From the DNA Methylation Society webpage: (http://dnamethsoc.server101.com/WhatisDNAMethylation.htm)

The information to make the cells of all living organisms is contained in their DNA. DNA is made from 4 bases abbreviated as G, A, T, and C, and is built like a very long ladder with pairs of these letter making up each of the "rungs" of the ladder. The letter G pairs with C and A with T. Strings of these pairs store information like a coded message, with the information to make specific molecules grouped into regions called genes. Every cell in our bodies contains two copies of every one of our genes, with one copy of each gene coming from our mother and one copy from our father. (The only exceptions to this rule are genes on chromosomes that determine whether we develop as a male or a female.)

Not every gene should be expressed in every cell of our bodies. For example, we do not want our brain cells to make hemoglobin, the protein required to carry oxygen around in our blood. Only those cells that will ultimately make red blood cells should make hemoglobin. If brain cells contain an intact copy (in fact 2 copies) of the gene for the hemoglobin protein, why don't brain cells also make hemoglobin? In fact, the level of the intermediate in hemoglobin protein production (this intermediate is a short copy of the hemoglobin gene called RNA), is at least a million times lower in brain cells than in the cells that are in the process of turning into red blood cells. Hence, there must be processes that control what gene is turned on, or expressed, in each cell type and these processes can produce differences in activity of at least a million fold. These controlling processes actually determine what type of cell it is, for example whether it is a red blood cell, a brain cell, a muscle cell, or a skin cell!

To regulate the level at which any gene is expressed, there are complex sets of regulatory proteins that bind to parts of the DNA encoding each gene. In very complex organisms such as ourselves, many control factors have to be acting together to achieve the levels of power and refinement of gene regulation needed. One of these levels of control is provided by adding a small "tag" called a methyl group onto C, one of the bases that make up the DNA code. The methyl group tagged C's can be written as mC. Simpler organisms, such as many types of bacteria and the single-celled yeast, usually do not use methyl group tagged C's in regulating their genes. Some bacteria, but not all, use methyl group tagged A's (mA) for this purpose. However, most bacteria have specific patterns of mC and mA in their DNA as a signal that says "this is my DNA", and acts as part of an immunity mechanism that allows these cells to destroy the DNA from infecting viruses without destroying their own DNA.

Methyl group tags in the DNA of humans and other mammals play an important role in determining whether some genes are or are not expressed. Genes unnecessary for any given cell's function can be tagged with the methyl groups. The number and placement of the methyl tags provides a signal saying that the gene should not be expressed. There are proteins in the cell which specifically recognize and bind the tagged C's, preventing expression of the gene. In addition, some of these proteins provide an important signal determining just how tightly folded that section of the DNA becomes. Folding up the long thin DNA molecules in our cells is not a trivial problem. If all of the DNA present in each of our tiny cells was stretched out in a line, it would be almost 3 meters (10 feet) long! Hence, the DNA must be folded up and compacted. How the DNA is compacted plays an important role in determining which genes can be used. In general, genes in tightly compressed DNA are not well expressed, while genes in more loosely packed DNA are more available to the machinery involved in copying the gene into the intermediate for expression, RNA.

As would be expected from something important in determining which genes are used by our cells, DNA methylation is essential for the normal development and functioning of organisms. This has been shown by engineering mice that can't make the enzymes which put the methyl tags on DNA, called methyltransferases. These mice die before birth. Problems with the DNA methylation machinery also cause developmental diseases in people. People with mutations causing abnormal function of one of the DNA methyltransferase enzymes called Dnmt3b have a disease called ICF syndrome. These people have abnormal immune systems and other genetic problems. Similarly, abnormalities in one of the proteins recognizing and binding mC (called MeCP2) develop Rett syndrome, a form of mental retardation affecting young girls. Hence, we cannot develop and function normally without DNA methylation.

Abnormal DNA methylation plays an important role in other developmental diseases as well. With most genes, it probably does not matter that both copies of the gene (the one from the mother plus the one from the father) are both active. However, with a few genes, only one copy is normally active. This could be the copy from the mother or the father, and the one which is active is specific for that particular gene. Imprinting is the term used when the expression of a gene depends on whether it is inherited from the mother or the father. Imprinting "breaks" one of Mendel's laws that genes act the same whether transmitted by either parent. Imprinting was first discovered in corn: kernels are dark purple if the Red gene is inherited from the egg but blotchy lavender if the same gene is transmitted through the pollen. This observation was made in 1910. Today we know that in the pollen (which contains the plant sperm cells) the Red gene is methylated and only slowly during kernel development are the methyl tags removed, permitting gene expression. In humans, some babies are born with abnormalities due to both copies of imprinted genes being active. This has been shown to be due to a failure in the establishment of the normal pattern of methyl group tags that blocks the activity of one of the copies of the gene. Diseases caused by this type of methylation problem include Prader-Willi syndrome, Angelman's syndrome and Beckwith-Wiedemann syndrome.

Abnormal placement of the DNA methylation tags also develops with aging. The tags can decrease in number in some genes, and increase in others, causing inappropriate decreases or increases in the activity of the genes affected. The changes in the placement of the methyl tags may be responsible for a variety of changes in cellular function that occur during aging. There is also evidence that abnormal placement of the methyl tags may contribute to the development of human lupus.

Very frequent abnormal increases or decreases in DNA methylation tags are found in most human cancers and contribute to their development. If the genes affected by abnormal methylation tagging happen to be involved in regulating cell proliferation, uncontrolled cell division can occur, and this uncontrolled cell growth is the problem underlying cancer. Scientists are trying to change the abnormal tags or the effects of these tags as one treatment for cancer and to use these tagging differences in early diagnosis of cancer and in monitoring various treatments of cancer. Additional practical aspects of studying DNA methylation are its importance in determining whether some types of bacteria are capable of causing disease; how plant crops develop, diversify, and can be improved; and the formation of birth defects associated with in vitro fertilization in people and cloning in animals. Of particular importance in flowering plants, methylation is part of the host plant defence against the movement of small invading DNA molecules that can jump from chromosome to chromosome, called transposons. A similar process happens in animals, where methylation is part of the defence against viruses that have incorporated their genes into the host's DNA.

Understanding the many complex roles of DNA methylation is a very active field of research involving laboratories throughout the world.

Methylation and Autism

According to Dr. Richard Deth at the Molecular Modeling Center of Northeastern University, here's what we know about methylation and autism right now:

bulletPlasma levels of methylation-related metabolites are abnormal in autistic children.
bulletPolymorphisms in methylation-related genes are increased in autistic children.
bulletNeurodevelopmental toxins (e.g. mercury and heavy metals) potently inhibit the methylation process.
bulletTreatments that promote the efficient functioning of the methylation process produce improvement in many autistic children.

According to Deth, persistant inflammation alters how genes are expressed.  This affects methylation because cells choose to address the inflammation in the body, rather than make energy required for natural detoxification via the methylation pathway.  Thus, when toxins are introduced by one route or another into the bodies of these children, not only do they provoke an immune response, but the body can't get rid of them because of it.

Dopamine receptors in the brain carry out methylation, but you can only fuel the process via the folate process.  The DRD4 receptor gene is central in this model.  Humans have repeats in this gene that are not present in nonprimates.  About 8% of us have 2 repeats, 65% of us have 4 repeats, and 20% carry the 7-repeat form of the D4 receptor.  This leads to an astounding array of possibilities for human personalities, attention capabilities, etc.  We know that the 7-repeat form of the gene, carried by 20% of us, is associated with a 3.5-fold higher increase in the risk of developing ADHD.  Additionally, these individuals are characterized as being novelty-seekers and risk-takers in their day-to-day life.  Apparently, the gene can work for you or against you, depending on the environmental factors that intervene.  It is also important to note that weaker methylation activity is also associated with this 7-repeat form, which is linked to autism.

In terms of dopa-stimulated phospholipid methylation in the brain, studies show that the potassium channel requires big movements to make the connection for methylation, and dopamine regulates the change in membrane fluidity.  Following the Hodgkin-Huxley model, this changing fluidity allows neurons to fire at a faster rate.  This formula is used to calculate the membrane potential assuming some initial state. The calculation is based on Sodium ion flow, Potassium ion flow and leakage ion flow (which is a nice way of saying all the insignificant ions which cross the membrane.) If there is a mother of computational neuroscience this is it. It resulted in an Nobel Prize for the authors. (Hodgkin, A. L. and Huxley, A. F. (1952) "A Quantitative Description of Membrane Current and its Application to Conduction and Excitation in Nerve" Journal of Physiology 117: 500-544).

             3                   4
          I = m  h G  (E - E  ) + n  G (E - E ) + G (E - E )
                    Na      Na        K      K     L      L
 

The upshot for autistic kids is that, when the neurons fire more quickly, the firing rate can move smoothly from gamma frequency to beta frequency via increased levels of dopamine.  Two parts of the brain can fire neuron signals at the same rate or at different rates.  Let's say you want to say the word "bicycle."  If the part of the brain that recognizes the bicycle and the part of the brain that sends the directions to the mouth to say bicycle are in synchronization (same frequency), you will look at the bicycle and say "bicycle."  If, however, one part of the brain is operating at one frequency and the other part of the brain is not as efficient because reduced methylation activity can't fuel the uptake in firing frequency, you might look at the bicycle and know that it is indeed a bicycle, but when you go to say the word bicycle, what ends up coming out of your mouth sounds more like "ish-ish-ull" instead. 

Synchronization is the key to this model.  Information spreads more readily from one region of the brain to the next if the firing frequencies of the two areas are synchronized.  Think of it as though you're tuning a radio; when you've almost got the right frequency, you can hear bits and pieces of the station coming through, but it's fuzzy and not quite right.  When you finally hit the right frequency, you can hear it loud and clear.  If you don't reach the right frequency, you're not going to hear your station at all -- you might, in fact, hear a very different station instead, which might even help to explain some of the "unusual" things our kids do.  Nerve firing equals information; more synchronization allows for more complex thinking.

Here's the kicker: this ability to interact among brain regions develops during infancy.  Awareness precedes attention, and attention facilitates novelty detection and learning.  If your brain has a methylation disruption in infancy, the norepinephrine-based synchronization will not occur properly, and awareness of the world around you will decrease.  Furthermore, dopamine changes the frequency of neural networks, so if the level of gamma frequency synchronization is reduced, children won't develop complex thinking during the natural course of brain development. 

Go to the source and read a copy of Deth's research article about dopamine and methylation by clicking here.  To read Dr. Jill James's related research paper, click here.

Methyl-B12

The theory behind this treatment rests in the process of methylation itself.  Take a look at this diagram:

See Vitamin B12 up there?  We need that vitamin to be able to complete the methylation process and get rid of nasty toxins in our bodies.  In autistic kids, this process gets jammed up because of the exposure to heavy metals and environmental insults.  By injecting kids with additional methyl-B12, we're giving them the chance to jump-start this process and relieve the oxidative stress of inflammation to detoxify.  The leading proponent of this method is James Neubrander, and you can find out more about the shot protocols by clicking here. 

In his testimony to the Congressional Committee on Government Reform, Richard Deth had the following to say about methyl-B12 supplementation:

"If impaired methylation is important in causing autism, metabolic interventions that augment methylation should be effective treatments. More specifically, if thimerosal’s inhibition of methylcobalamin synthesis is important in causing autism, then the administration of methylcobalamin should significantly improve autism. Indeed, this has proved to be the case. As first reported by Dr. James Neubrander, injections of methylcobalamin, given once every three days, has brought about significant improvement in approximately 80% of children with autism. While the degree of improvement varies, a significant number of children have improved to the point that they are no longer considered to be "on the autism spectrum". Areas of particular improvement include language, attention and social skills, which are hallmark symptoms of autism. Within the next few months, the M.I.N.D. Institute at the University of California at Davis School of Medicine is slated to carry out a controlled study of methylcobalamin effectiveness in autism.

Other methylation-promoting treatments are also proving helpful in autism. In the metabolic study carried out by Dr. Jill James and colleagues, autistic subjects were treated with folinic acid (leucovorin), a folic acid derivative that augments levels of 5-methylTHF, along with betaine (trimethylglycine), which feeds methyl groups to the folate pathway. These two agents normalized most of the abnormal metabolites listed in Table 2, and this was accompanied by clinical improvement in autism symptoms. Subsequent addition of methylcobalamin to this regimen brought about further improvement.

While encouraging, these metabolic interventions do not help many autistic children, and there is a need for additional treatment approaches. Moreover, improving methylation capacity is only one component of the multi-dimensional approach to treating autism. Other elements such as a gluten-free/casein-free diet, chelation of heavy metals and intensive behavioral therapy are also important. Additional metabolic interventions, particularly interventions directed at normalizing adenosine metabolism may prove fruitful. Clearly further research is needed, building upon the framework of knowledge about how genetic and environmental factors can synergize to cause autism.

Autism is a neurological disorder caused by dysfunctional metabolic control over methylation reactions, and thimerosal appears to be a precipitating causative factor in many cases. The methionione cycle and the trans-sulfuration pathway leading to cysteine and glutathione synthesis are abnormal in autism. Genetic polymorphisms, present in only a small subpopulation, represent risk factors for autism. As illustrated in Fig. 11, some of these genetic factors impair detoxification and clearance of heavy metals, including thimerosal, and also impair the capacity for methylation. Delayed clearance of thimerosal further impairs methylation, including both DNA methylation and dopamine-stimulated phospholipid methylation, adversely affecting growth factor-directed development and the capacity for attention, respectively. Autism can be treated, and some of the most effective treatments, such as methylcobalamin, act by improving methylation. This encouraging therapeutic development reinforces the conclusion that thimerosal does indeed cause autism, and it does this by interfering with methylcobalamin synthesis. This molecular understanding should lead to new and improved treatments for autism and should provide a scientifically sound basis for the removal of thimerosal from all vaccines."

 

 

Bibliography

Sweetman L, Nyhan WL. Excretion of hypoxanthine and xanthine in a genetic disease of purine metabolism. Nature 1967; 215: 859-860.

Stone RL, Aimi J, Barshop BA, Jaeken J, Van den Berghe G, Zalkin H et al. A mutation in adenylosuccinate lyase associated with mental retardation and autistic features. Nat. Genet 1992; I: 59-63.

Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi, HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet 1999; 23: 185-188.

Rousseau F, Heitz D, Mandel JL. The unstable and methylatable mutations causing the fragile X syndrome. Hum Mutat 1992; 1:91-96.

Olney JW, Wozniak DF, Farber NB, Jevtovic-Todorovic V, Bittigau P, Ikonomidou C. The enigma of fetal alcohol neurotoxicity .Ann Med 2002; 34: 109-119.

Lidsky TI and Schneider JS. Lead neurotoxicity in children: basic mechanisms and clinical correlates. Brain 2003; 126: 5-19.

Bernard S, Enayati A, Redwood L, Roger H, Binstock T. Autism: a novel form of mercury poisoning. Med Hypotheses 2001; 56: 462-471.

LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, Kennedy JL. Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Mol Psychiatry 1996; I: 121-124.

Deth, R.C. (2003) in Molecular Origins of Human Attention, (Kluwer Academic Publishers, Boston).

Waly M, 01teanu H, Banerjee R, Choi SW, Mason JB, Parker BS, Sukumar S, Shim S, Sharma A, Benzecry JM, Power-Charnitsky V A, Deth RC. Activation of methionine synthase by insulin-like growth factor-l and dopamine: a target for neurodevelopmental toxins and thimerosal. Mol Psychiatry .2004; 9:358- 70.

Pichichero ME, Cernichiari E, Lopreiato J, Treanor J. Mercury concentrations and metabolism in infants receiving vaccines containing thiomersal: a descriptive study. Lancet. 2002; 360: 1737-1741.

James, Jet al. Abnormal levels of transsulfuration and methionine cycle metabolic intermediates in autism indicate impaired redox status. J Clin Invest (Manuscript under review)

Page T, Yu A, Fontanesi J, Nyhan WL. Developmental disorder associated with increased cellular nucleotidase activity .Proc Natl Acad Sci U SA 1997; 94: 11601- 11606

Stubbs G, Litt M, Lis E, Jackson R, Voth W, Lindberg A, Litt R. Adenosine deaminase activity decreased in autism. JAm Acad Child Psychiatry 1982; 21: 71- 74.

Persico AM, Militerni R, Bravaccio C, Schneider C, Melmed R, Trillo S et al. Adenosine deaminase alleles and autistic disorder: case-control and family-based association studies. Am J Med Genet 2000; 96: 784- 790.

Sharma, A., Kramer, M., Wick, P.F., Liu, D., Chari, S., Tan, W.B., Ouellette, D., Nagata, M., DuRand, C., Kotb, M. and Deth, R.C.: "Dopamine D4 receptor-mediated methylation of membrane phospholipids and its implications for mental illnesses such as schizophrenia." Molecular Psychiatry 4: 235-246 (1999).

Zhao, R., Chen, Y., Tan, W., Waly, M., Malewicz, B., Stover, P., Rosowsky, A. and Deth, R.C.: "Influence of single-carbon folate and de novo purine synthesis pathways on D4 dopamine receptor-mediated phospholipid methylation." J. Neurochem. 78: 788-796 (2001).

Waly, M., Sharma, A. and Deth, R.C.: "Protein kinase C regulates basal and D4 dopamine receptor-mediated phospholipid methylation in neuroblastoma cells." Eur. J. Pharmacol. 427: 83-90 (2001).

Eigsti IM, Shapiro T. A systems neuroscience approach to autism: bio- logical, cognitive, and clinical perspectives. Ment Retard Dev Disabil Res Rev 2003;9:205-15.

White JF. Intestinal pathology in autism. Exp Biol Med (Maywood) 2003;228:639-49.

Sweeten n, Bowyer SL, Posey DJ, Halberstadt OM, McDougle CJ. In- creased prevalence of familial autoimmunity in probands with pervasive developmental disorders. Pediatrics 2003;112:E420-4.

Bolte S, Poustl{a F. The relation betWeen geneml cognitive level and adap- tive behavior domains in individuals with autism with and witlKJut co- morbid mental retardation. O1ild PsychialIy Hum Dev 2002;33: 165- 72.

McKusick V A, ed. Mendelian inheritance in man. A catalog of human genes and genetic disorders. 12th ed. Baltimore: Johns Hopkins Univer- sity Press, 1998. [Daily updated online version, OMIM, available from the National Center for Biotechnology Information. Internet: http:11 www Incbilnlm/nih/ gov lomim. ]

Mount RH, Charman T, Hastings RP, Reilly S, Cass H. Features of autism in Rett syndrome and severe mental retardation. I Autism Dev Disord 2003;33:435-42.

Arrieta I, Nunez T, Gil A, Flores P, Usobiaga E, Martinez B. Autosomal folate sensitive fragile sites in an autistic Basque sample. Ann Genet 1996;39:69-74.

Baieli S, Pavone L, Meli C, Fiumara A, Coleman M. Autism and phe- nylketonuria. I Autism Dev Disord 2003;33:201-4.

Iaeken I, Van den BG. An infantile autistic syndrome characterised by the presence of succinylpurines in body fluids. Lancet 1984;2: 1058 -61.

Page T. Metabolic approaches to the treatment of autism spectrum dis- orders. I Autism Dev Disord 2000;30:463-9.

Pesi R. Micheli V, Iacomelli G, et aI. Cytosolic 5' -nucleotidase hyper- activity in erythrocytes ofLesch-Nyhan syndrome patients. Neuroreport 2000;11:1827-31.

Rimland B. High dose vitamin B6 and magnesium in treating autism: response to study by Findling et aI. I Autism Dev Disord 1998 ;28 :581- 2.

Alberti A, Pirrone P, Elia M, Wacing RH, Romano C. Sulphation deficit in "Iow-functioning" autistic children: a pilot study. BioI Psychiatry 1999;46:420-4.

Megson MN .Is autism a G-alpha protein defect reversible with natural vitamin A? Med Hypotheses 2000;54:979-83.

Stubbs G, Litt M, Lis Eo et aI. Adenosine deaminase activity decreased in autism. I Am Acad Child Psychiatry 1982;21:71-4.

Pogribna M, Melnyk S, Pogribny I, Chango A, Yi P, lames SI. Homo- cysteine metabolism in children with Down syndrome: in vitro modu- lation. Am I Hum Genet 2001 ;69:88-95.

Kent L, Evans I, Paul M, Sharp M. Comorbidity of autistic spectrum disorders in children with Down syndrome. Dev Med Child Neurol 1999;41:15J-8.

Finkelstein ID. Pathways and regulation ofhomocysteine metabolism in mammals. Semin Thromb Haemost 2000;26:219-25.

Melnyk S, Pogribna M, Pogribny I, Hine RJ, James SI. Anew HPLC method for the simultaneous determination of oxidized and reduced plasma aminothiols using coulometric electrochemical detection. I Nutr Biochem 1999;10:490-7.

Melnyk S, Pogribna M, Pogribny IP, lames SI. Measurement of plasma and intracellular S-adenosylmethionine and S-adenosylhomocysteine utilizing coulemetric electrochemical detection: alteration with plasma homocysteine and pyridoxal 5'-phosphate concentrations. Clin Chem 2000;46:265-72.

KellerF, Persico AM. The neurobiological context of autism. Mol Neu- robioI2003;28:1-22.

Beaudet AL. Is medical genetics neglecting epigenetics? Genet Med 2002;4:399-402.

London EA. The environment as an etiologic factor in autism: aneW direction for research. Environ Health Perspect 2000;108(suppl 3):401-4.

Yeargin-Allsopp M, Rice C, Karapurkar T, Doernberg N, Boyle C, Murphy C. Prevalence of autism in a US metropolitan area. IAMA 2003;289:49-55.

Bertrand I, Mars A, Boyle C, Bove F, Yeargin-Allsopp M, Decoufle P. Prevalence of autism in a United States population: the Brick Township, New Jersey, investigation. Pediatrics 2001;108:1155-61.

DestefanoF,BhasinTK, ThompsonWW, Yeargin-AllsoppM,BoyleC. Age at first measles-mumps-rubella vaccination in children with autism and school-matched control subjects: a population-based study in met- ropolitan Atlanta. Pediatrics 2004; 113:259- 66.

Steinhausen HC, Gobel D, Breinlinger M, Wohlleben B. A community survey of infantile autism. I Am Acad Child Psychiatry 1986;25:186-9.

Miller AL. The methionine-homocysteine cycle and its effects on cog- nitive diseases. Altem Med Rev 2003;8:7-19.

Serra IA, Dominguez RO, de Lustig ES, et aI. Parkinson's disease is associated with oxidative stress: comparison of peripheral antioxidant profiles in living Parkinson's, Alzheimer's and vascular dementia pa- tients. ] Neural Transm 2001;108:1135-48.

Schulz ]B, Lindenau ], Seyfried ], Dichgans ]. Glutathione, oxidative stress and neurodegeneration. Eur I Biochem 2000;267:4904-11.

Muntjewerff ]W, Van der Put N, Eskes T, et aI. Homocysteine metab- olism and B-vitamins in schizophrenic patients: low plasma folate as a possible independent risk factor for schiwphrenia. Psychiatry Res 2003; 121:1-9.

Ono H, Sakamoto A, Sakura N. Plasma total glutathione concentrations in healthy ~diatric and adult subjects. Clin Chim Acta 2001 ;312:227-9.

Armstrons MD, Stave U. A study of plamsa free amino acids levels: Normal values for children and adults. Metabolism 1973;22:561-9.

Delvin EE, Rozen R, Merouani A, Genest J Jr, Lambert M. Influence of methylenetetrabydrofolate reductase genotype, age, vitamin B-12, and folate status on plasma homocysteine in children. Am J Clin Nutr 21XX>; 72:1469-73.

Ueland PM. Helland S. Binding of adenosine to intracellular S-adenosylhomocysteine hydrolase in isolated rat hepatocytes. J Biol Chem 1983;258:747-52.

Kloor D, Osswald H S-adenosylhomocysteine hydrolase as a target for intracellular adenosine action. Trends Phannacol Sci 2004;25:294-7.

Kloor D, Ltidtke A, Stoeva S, Osswald H. Adenosine binding sites at S-adenosylhomocysteine hydrolase are controlled by the NAD+ /NADH ratio of the enzyme. Biochem PharmacoI2003;66:2117-23.

Clarke S, Banfield K. S-adenosy1methionine-de~ndent methyltrans- ferases. In: Carmel R, Iacobsen DW, eds. HonK>Cysteine in health and disease. Boston: Cambridge University Press, 2001:63-78.

Yi P, Melnyk S, PogribnaM, Pogribny IP, HiRes RJ, James SI. Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNAhypomethylation. I Bioi Chem 2000;275:29318-23.

Gulati S, Chen z, Brody LC, Rosenblatt DS, Banerjee R. Defects in auxiliary redox proteins lead to functional methionine synthase defi- ciency. I Biol Chem 1997;272:19171-5.

Castro C, Gratson AA, Evans lC, et al. Dissecting the catalytic mecha- nism of betaine-homocysteine S-methyltransferase by use of intrinsic tryptophan fluorescence and site-directed mutagenesis. Biochemistry 2004;43:5341-51.

Avila MA, Carretero MY, Rodriguez EN, Mato lM. Regulation by hypoxia of methionine adenosyltransferase activity and gene expression in rat hepatocytes. Gastroenterolngy 1998;114:364-71.

Wu a. Fang YZ, Yang S, Lupton lR, Turner NO. Glutathione metabo- lism and its implications for health. l Nutr 2004;134:489-92.

Lu SC. Regulationofhepatic glutathione synthesis: currentconcepl'! and controversies. FASEB 11999;13:1169-83.

Bottini N, De Luca D, Saccucci P. et al. Autism: evidence of association with adenosine deaminase genetic polymorphism. Neurogenetics 2001 ; 3:111-3.

Decking UK, Schlieper a, Kroll K, Schrader I. Hypoxia-induced inhi- bition of adenosine kinase potentiates cardiac adenosine release. Circ Res 1997;81:154-64.

Chen YF, Li PL, Zou AP. Oxidative stress enhances the production and actions of adenosine in the kidney. Am I Physiol Regullntegr Comp Physio12001;281:R1808-16.

Atmaca M, Fry lR. Adenosine-mediated inhibition of glutathione syn- thesis in rat isolated hepatocytes. Biochem PharmacolI996;52:1423- 8.

Brodie AB, Reed Dl. Glutathione changes occurring after S-adenosylhomocysteine hydrolase inhibition. Arch Biochem Biophys 1985;240:621-6.

Park El, Renducbintala MS, Garrow TA. Diet-induced changes in he- patic betaine-homocysteine methyltransferase activity are mediated by changes in the steady-state level of its mRNA. lNutrBiochem 1997;8: 541-5.

Priest DO, Schmitz JC, Bunni MA, Stuart RK. Pharmacokinetics of leucovorin metabolites in human plasma as a function of dose adminis- tered orally and intravenously. l Natl Cancer Inst 1991;83:1806-12.

Scott JM, Weir DO. The methyl folate trap. A physiological response in man to prevent methyl group deficiency in kwashiorkor (methionine deficiency) and an explanation for folic-acid induced exacerbation of subacute combined degeneration in pernicious anaemia. Lancet 1981; 2:337-40.

Wu Y ,Zheng J,LindenJ, HoloshitzJ. Genoprotective pathways. Part I. Extracellular signaling through G(s) protein-coupled adenosine recep- tors prevents oxidative DNA damage. Mutat Res 2004;546:93-102.

Almeida CG, De Mendonca A, Cunha RA, Ribeiro JA. Adenosine pro- motes neuronal recovery from reactive oxygen s~cies induced lesion in rat hippocampal slices. Neurosci Lett 2003;339:127-30.

Gulati S, Brody LC, Banerjee R. Posttranscriptional regulation of mam- malian methionine synthase by BJ 2. Biochem BiophysRes Comm 1999; 259:436-42.

01teanu H, Banerjee R. Redundancy in the pathway for redox regulation 5 of mammalian methionine synthase: reductive activation by the dual flavoprotein, novel reductase 1. J BioI Chem 2003;278:38310-4.

Sogut S, Zoroglu SS, Ozynrt H, et al. Changes in nitric oxide levels and 5' antioxidant enzyme activities may have a role in the pathophysiological mechanisms involved in autism. Clin ChimActa 2003;331:111-7.

Yorbik 0, Sayal A, Akay C, Akbiyik DI, Sohmen T. Investigation of antioxidant enzymes in children with autistic disorder. Prostaglandins Leukot Bssent Fatty Acids 2002;67:341-3.

Zoroglu SS, Armutcu F, Ozen S, et al. Increased oxidative stress and altered activities of erythrocyte free radical scavenging enzymes in au- tism. Bur Arch Psychiatry Clin Neurosci 2004;254: 143-7.

You are visitor number Hit Counter to this site.

[ Home ] [ Up ]

Send mail to littlecanaries@aol.com with questions or comments about this web site.
Copyright © 2005 Little Canaries
Last modified: 04/24/05