Folie acid deficiency and methyl group metabolism in rat brain: Effects of l-dopa

Ordóñez, Luis A.; Wurtman, Richard J.

doi:10.1016/0003-9861(74)90410-x

Cited by 74 publications

(20 citation statements)

References 8 publications

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“…In fact, in a study of the use of AdoMet as an antidepressant for patients with chronic epilepsy, it was found that daily intravenous administration of AdoMet had no adverse effect on seizure frequency (49). On the other hand, the administration of folate, the levels of which are correlated with intracellular AdoMet levels in rat brain (53), can greatly aggravate seizure control in epilepsy patients (50) and in experimental animals (51,52). Thus, orally (or intravenously) administered AdoMet would probably not mimic the effect we observe in the Pcmt1Ϫ/Ϫ mice, which is most likely an intracellular alteration of AdoMet/AdoHcy levels.…”

Section: Discussionmentioning

confidence: 60%

Altered Levels of S-Adenosylmethionine and S-Adenosylhomocysteine in the Brains ofl-Isoaspartyl (d-Aspartyl)O-Methyltransferase-deficient Mice

Farrar¹,

Clarke²

2002

Journal of Biological Chemistry

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(D-aspartyl) O-methyltransferase (PCMT1) is a protein repair enzyme that initiates the conversion of abnormal D-aspartyl and L-isoaspartyl residues to the normal L-aspartyl form. In the course of this reaction, PCMT1 converts the methyl donor S-adenosylmethionine (AdoMet) to S-adenosylhomocysteine (AdoHcy). Due to the high level of activity of this enzyme, particularly in the brain, it seemed of interest to investigate whether the lack of PCMT1 activity might alter the concentrations of these small molecules. AdoMet and AdoHcy were measured in mice lacking PCMT1 (Pcmt1؊/؊), as well as in their heterozygous (Pcmt1؉/؊) and wild type (Pcmt1؉/؉) littermates. Higher levels of AdoMet and lower levels of AdoHcy were found in the brains of Pcmt1؊/؊ mice, and to a lesser extent in Pcmt1؉/؊ mice, when compared with Pcmt1؉/؉ mice. In addition, these levels appear to be most significantly altered in the hippocampus of the Pcmt1؊/؊ mice. The changes in the AdoMet/AdoHcy ratio could not be attributed to increases in the activities of methionine adenosyltransferase II or S-adenosylhomocysteine hydrolase in the brain tissue of these mice. Because changes in the AdoMet/AdoHcy ratio could potentially alter the overall excitatory state of the brain, this effect may play a role in the progressive epilepsy seen in the Pcmt1؊/؊ mice.One of the most common forms of protein damage in vitro and in vivo is deamidation and isoaspartyl formation caused by deprotonation of the peptide-bond nitrogen and its attack on the side chain carbonyl carbon of L-asparaginyl or L-aspartyl residues (1, 2). This spontaneous reaction results in the loss of ammonia (from asparaginyl residues) or water (from aspartyl residues) and the formation of the side chain into an intermediate succinimidyl ring. If this ring is hydrolyzed at the ␣-carbonyl group, the peptide bond is re-routed through the side chain carbonyl resulting in the formation of an L-isoaspartyl

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Section: Discussionmentioning

confidence: 60%

Altered Levels of S-Adenosylmethionine and S-Adenosylhomocysteine in the Brains ofl-Isoaspartyl (d-Aspartyl)O-Methyltransferase-deficient Mice

Farrar¹,

Clarke²

2002

Journal of Biological Chemistry

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“…States of folate deficiency have been shown to lower brain SAM levels and result in hypomethylation. 19 Depression is a common neuropsychiatric manifestation of severe folate deficiency, and surveys of the folate status of depressed patients have revealed that up to one-third of inpatients have folate deficiency. 20,21 Depressed patients in whom folate deficiency was corrected showed better symptomatic recovery and less time spent in hospital.…”

Section: Discussionmentioning

confidence: 99%

Proteomic-based genotyping in a mouse model of trait anxiety exposes disease-relevant pathways

et al. 2009

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In our biomarker identification efforts, we have reported earlier on a protein that differs in its electrophoretic mobility between mouse lines bred either for high or low trait anxiety. The altered electrophoretic behavior of enolase phosphatase (EP) is now identified to be caused by two single-nucleotide polymorphisms. In both cases, the genetic polymorphism introduces an amino acid change in the protein's sequence resulting in differential mobility on SDS gels. This was shown by recombinantly expressing the two EP isoforms. Functional studies indicate that the EP isoform from the high anxiety mouse line has a lower enzymatic activity than does its low anxiety mouse counterpart. EP is a member of the methionine salvage pathway that is responsible for the synthesis of S-adenosyl-L-methionine, a natural compound with potential antidepressant activities. In addition, it is linked to the polyamine pathway whose members have functions in anxiety/depression-related behaviors. In a freely-segregating F2 panel, both single-nucleotide polymorphisms were significantly associated with locomotion-independent trait anxiety, further supporting a functional role of EP for this phenotype. The study shows that proteomic analysis can reveal genotypic differences relevant for the phenotype. The identified protein alterations, in turn, can expose metabolic pathways pertinent to the behavioral phenotype.

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“…Other pathways involved in L-dopa-induced hyperHcy, are represented by: (1) decreased re-methylation of Hcy, which may result from exhaustion of the pool of methyl groups, also induced by deficiency of folate and vitamin B12 levels, or by genetically determined inefficiency of MS or MTHFR; and (2) dysfunction in transsulfuration pathway, induced by deficiency of vitamin B6, by lack of allosteric activation in CBS by SAM, or by genetic inefficiency of CBS. Experimental studies demonstrated a significant increase in Hcy concentration after L-dopa treatment (Daly et al 1997); this effect is related to a significant decrease in SAM and increase in SAH concentrations in brain and peripheral tissues (Ordez and Wurtman 1974, Taufek and Bone, 1980, Fuller et al 1984, Daly et al 1997. These effects could be prevented by COMT inhibitors treatment and accentuated during folate deficiency (Daly et al 1997).…”

Section: Effect Of Levodopa Treatment On Plasma Hcy Levelsmentioning

confidence: 94%

Role of lifestyle factors on plasma homocysteine levels in Parkison's disease patients treated with levodopa

Siniscalchi

Gallelli²,

Mercuri

et al. 2006

Nutritional Neuroscience

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Many papers documented that Parkinson's disease (PD) patients treated with levodopa (L-dopa) shows elevated plasma homocysteine (Hcy) levels. Several lifestyle factors are able to influence plasma Hcy levels. We review the evidence that L-dopa therapy is related with an increase in plasma Hcy levels and that several behaviours could be able to cause changes in plasma Hcy concentrations. Therefore, there are reasons to suggest that a healthy lifestyle lowering Hcy may prevent this potential iatrogenic complication during L-dopa therapy. Moreover, at present, no controlled prospective studies have evaluated this phenomenon.

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Folie acid deficiency and methyl group metabolism in rat brain: Effects of l-dopa

Cited by 74 publications

References 8 publications

Altered Levels of S-Adenosylmethionine and S-Adenosylhomocysteine in the Brains ofl-Isoaspartyl (d-Aspartyl)O-Methyltransferase-deficient Mice

Altered Levels of S-Adenosylmethionine and S-Adenosylhomocysteine in the Brains ofl-Isoaspartyl (d-Aspartyl)O-Methyltransferase-deficient Mice

Proteomic-based genotyping in a mouse model of trait anxiety exposes disease-relevant pathways

Role of lifestyle factors on plasma homocysteine levels in Parkison's disease patients treated with levodopa

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