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1.
Medicines associated with folate-homocysteine-methionine pathway disruption.
Vidmar, M, Grželj, J, Mlinarič-Raščan, I, Geršak, K, Dolenc, MS
Archives of toxicology. 2019;(2):227-251
Abstract
Folate is vital for cell development and growth. It is involved in one-carbon transfer reactions essential for the synthesis of purines and pyrimidines. It also acts in conjunction with cobalamin (vitamin B12) as a fundamental cofactor in the remethylation cycle that converts homocysteine to methionine. A deficiency in folate or vitamin B12 can lead to elevated homocysteine level, which has been identified as an independent risk factor in several health-related conditions. Adequate folate levels are essential in women of childbearing age and in pregnant women, and folate deficiency is associated with several congenital malformations. Low folate levels can be caused by dietary deficiencies, a genetic predisposition or treatment with medicines that affect folate concentration. Women who are pregnant or of child-bearing age commonly use medicines, so it is important to identify the basic biochemical mechanisms by which medicines interfere with the folate-homocysteine-methionine pathway. This review focuses on prescription medicines associated with folate disruption. It also summarizes their undesirable/toxic effects. Recommendations regarding folate supplementation during medical therapy are also reviewed.
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2.
Autism spectrum disorder (ASD) - biomarkers of oxidative stress and methylation and transsulfuration cycle.
Waligóra, A, Waligóra, S, Kozarska, M, Damasiewicz-Bodzek, A, Gorczyca, P, Tyrpień-Golder, K
Psychiatria polska. 2019;(4):771-788
Abstract
Autism spectrum disorder (ASD) affects people from all regions of the globe, regardless of nationality, living standards or social group. Currently, it is assumed that ASD pathogenesis is multifactorial because there is no one specific cause of the disorder. According to literature, ASD may result from genetic defects, metabolic disorders or exposure to environmental factors. There is a number of hypotheses that attempt to explain the intensity of emotional and behavioral symptoms or the increased sensory threshold that is characteristic of ASD. It is suggested that neurological changes may be due to oxidative stress occurring in early brain tissue development and reduced antioxidative barrier. Due to the abnormalities in the synthesis of neurotransmitters, often occurring in ASD, autism is investigated for disorders of vital biochemical processes of methylation and transsulfuration. Finding a biomarker for a disturbed oxidative-reduction equilibrium, methylation pathway pathology, or other reason could be an important diagnostic tool and the base for individual treatment for patients with varying degrees of severity. This work provides a review of the potential biological indicators for ASD taking into account the occurrence of oxidative stress and the methylation and transsulfuration cycles.
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3.
The use of amino acid PET and conventional MRI for monitoring of brain tumor therapy.
Galldiks, N, Law, I, Pope, WB, Arbizu, J, Langen, KJ
NeuroImage. Clinical. 2017;:386-394
Abstract
Routine diagnostics and treatment monitoring of brain tumors is usually based on contrast-enhanced MRI. However, the capacity of conventional MRI to differentiate tumor tissue from posttherapeutic effects following neurosurgical resection, chemoradiation, alkylating chemotherapy, radiosurgery, and/or immunotherapy may be limited. Metabolic imaging using PET can provide relevant additional information on tumor metabolism, which allows for more accurate diagnostics especially in clinically equivocal situations. This review article focuses predominantly on the amino acid PET tracers 11C-methyl-l-methionine (MET), O-(2-[18F]fluoroethyl)-l-tyrosine (FET) and 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine (FDOPA) and summarizes investigations regarding monitoring of brain tumor therapy.
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4.
The one-carbon metabolism pathway highlights therapeutic targets for gastrointestinal cancer (Review).
Konno, M, Asai, A, Kawamoto, K, Nishida, N, Satoh, T, Doki, Y, Mori, M, Ishii, H
International journal of oncology. 2017;(4):1057-1063
Abstract
After the initial use of anti-folates for treatment of malignancies, folate metabolism has emerged as a rational diagnostic and therapeutic target in gastrointestinal cancer. The one-carbon metabolic pathway, which comprises three critical reactions (i.e., folate and methionine cycles), underlies this effect in conjunction with the trans-sulfuration pathway. Understanding of the one-carbon metabolism pathway has served to unravel the link between the causes and effects of cancer phenotypes leading to several seminal discoveries such as that of diadenosine tri-phosphate hydrolase, microRNAs, 5-FU and, more recently, trifluridine. In the folate cycle, glycine and serine fuel the mitochondrial enzymes SHMT2, MTHFD2 and ALDH1L2, which play critical roles in the cancer survival and proliferation presumably through purine production. In the methionine cycle, S-adenocyl methionine serves hydrocarbons and polyamines that are critical for the epigenetic controls. The trans-sulfuration pathway is a critical component in the synthesis of glutathione, which is involved in the production of reactive oxygen species in cancer stem cells. Therefore, characterization of one-carbon metabolism is indispensable to the development of precision medicine in the context of cancer diagnostics and therapeutics. In the present study, we review the historical issues associated with one-carbon metabolism and highlight the recent advances in cancer research.
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5.
Lean Body Mass Harbors Sensing Mechanisms that Allow Safeguarding of Methionine Homeostasis.
Ingenbleek, Y
Nutrients. 2017;(9)
Abstract
Protein-depleted states generate allosteric inhibition of liver cystathionine β-synthase (CBS), which governs the first enzymatic step of the transsulfuration cascade, resulting in upstream accretion of homocysteine (Hcy) in body fluids. A similar Hcy increase may arise from normal hepatocytes undergoing experimentally-induced impairment of betaine-homocysteine methyltransferase (BHTM) activity or from components of lean body mass (LBM) submitted to any inflammatory disorder. LBM comprises a composite agglomeration of extrarenal tissues characterized by naturally occurring BHTM inactivity. As a result of cellular injury, LBM releases high concentrations of Hcy into the extracellular space, contrasting with the disruption of normal remethylation pathways. Hyperhomocysteinemia acts as a biomarker, reflecting the severity of insult and operating as an alarm signal. Elevated Hcy levels constitute a precursor pool recognized by a CBS coding region that reacts to meet increased methionine requirements in LBM tissues, using its enhanced production in hepatocytes. Preservation of methionine homeostasis benefits from its high metabolic priority and survival value.
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6.
L-Methionine Production.
Shim, J, Shin, Y, Lee, I, Kim, SY
Advances in biochemical engineering/biotechnology. 2017;:153-177
Abstract
L-Methionine has been used in various industrial applications such as the production of feed and food additives and has been used as a raw material for medical supplies and drugs. It functions not only as an essential amino acid but also as a physiological effector, for example, by inhibiting fat accumulation and enhancing immune response. Producing methionine from fermentation is beneficial in that microorganisms can produce L-methionine selectively using eco-sustainable processes. Nevertheless, the fermentative method has not been used on an industrial scale because it is not competitive economically compared with chemical synthesis methods. Presented are efforts to develop suitable strains, engineered enzymes, and alternative process of producing L-methionine that overcomes problems of conventional fermentation methods. One of the alternative processes is a two-step process in which the L-methionine precursor is produced by fermentation and then converted to L-methionine by enzymes. Directed efforts toward strain development and enhanced enzyme engineering will advance industrial production of L-methionine based on fermentation.
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7.
[Research advances in the association between maternal intake of methyl donor nutrients during pregnancy and DNA methylation in offspring].
Wu, MM, Yang, F
Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics. 2017;(5):601-606
Abstract
Maternal nutrition during pregnancy plays a vital role in the health of the offspring. Methyl donor nutrients, including folate, vitamin B12, choline, betaine, and methionine, directly affect DNA methylation and are closely associated with the health of the offspring. As an important part of epigenetics, DNA methylation plays an important role in the maintenance of normal cellular function, gene expression regulation, and embryonic development. Recent studies have shown that maternal nutrition may have a long-lasting effect on the health of the offspring via the changes in genomic DNA and/or methylation level in the promoter region in specific genes. Therefore, this review article focuses on the effect of maternal intake of methyl donor nutrients during pregnancy on DNA methylation, in order to explore the effect of the changed methylation status on the health of the offspring at the molecular level.
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8.
Meta-Analysis of the COMT Val158Met Polymorphism in Major Depressive Disorder: Effect of Ethnicity.
Wang, M, Ma, Y, Yuan, W, Su, K, Li, MD
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology. 2016;(3):434-45
Abstract
The COMT (catechol-O-methyltransferase) Val158Met polymorphism (rs4680) is a potential susceptibility variant for major depressive disorder (MDD). Although many genetic studies have examined the association between MDD and this polymorphism, the results were inconclusive. In the present study, we conducted a series of meta-analyses of samples consisting of 2905 MDD cases and 2403 controls with the goal of determining whether this variant indeed has any effect on MDD. We revealed a significant association in the comparison of Val/Val + Val/Met vs. Met/Met (OR =1.180; 95 % CI = 1.019, 1.367; P = 0.027), Val/Met vs. Val/Val (OR =1.18; 95 % CI = 1.038, 1.361; P = 0.013), and Val/Met vs. Met/Met (OR =1.229; 95 % CI = 1.053, 1.435; P = 0.009). Further meta-analyses of samples with European ancestry demonstrated a significant association of this SNP with MDD susceptibility in Val/Val + Val/Met vs. Met/Met (OR =1.231, 95 % CI = 1.046, 1.449; P = 0.013) and Val/Met vs. Met/Met (OR =1.284, 95 % CI = 1.050, 1.484; P = 0.012). For the samples with East Asian ancestry, we found a significant association in both allelic (Val vs. Met: OR =0.835; 95 % CI = 0.714, 0.975; P = 0.023) and genotypic (Met/Met + Val/Met vs. Val/Val: OR =1.431, 95 % CI = 1.143, 1.791; P = 0.002; Val/Met vs. Val/Val: OR =1.482, 95 % CI = 1.171, 1.871; P = 0.001) analyses. No evidence of heterogeneity among studies or publication bias was observed. Together, our results indicate that the COMT Val158Met polymorphism is a vulnerability factor for MDD with distinct effects in different ethnic populations.
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9.
The dynamics of methionine supply and demand during early development.
McBreairty, LE, Bertolo, RF
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. 2016;(6):581-7
Abstract
Methionine is an indispensable amino acid that, when not incorporated into protein, is converted into the methyl donor S-adenosylmethionine as entry into the methionine cycle. Following transmethylation, homocysteine is either remethylated to reform methionine or irreversibly trans-sulfurated to form cysteine. Methionine flux to transmethylation and to protein synthesis are both high in the neonate and this review focuses on the dynamics of methionine supply and demand during early development, when growth requires expansion of pools of protein and transmethylation products such as creatine and phosphatidylcholine (PC). The nutrients folate and betaine (derived from choline) donate a methyl group during remethylation, providing an endogenous supply of methionine to meet the methionine demand. During early development, variability in the dietary supply of these methionine cycle-related nutrients can affect both the supply and the demand of methionine. For example, a greater need for creatine synthesis can limit methionine availability for protein and PC synthesis, whereas increased availability of remethylation nutrients can increase protein synthesis if dietary methionine is limiting. Moreover, changes to methyl group availability early in life can lead to permanent changes in epigenetic patterns of DNA methylation, which have been implicated in the early origins of adult disease phenomena. This review aims to summarize how changes in methyl supply and demand can affect the availability of methionine for various functions and highlights the importance of variability in methionine-related nutrients in the infant diet.
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10.
Role of methionine containing antioxidant combination in the management of pain in chronic pancreatitis: a systematic review and meta-analysis.
Talukdar, R, Murthy, HV, Reddy, DN
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]. 2015;(2):136-44
Abstract
BACKGROUND Pain in CP results from inflammation and neuroimmune alterations that are associated with oxidative stress, among other mechanisms. This is marked by depletion of antioxidant defenses including methionine, which is a donor of methyl moieties that maintains the acinar transsulfuration pathway. We performed a systematic review and meta-analysis of trials evaluating methionine-containing antioxidants in CP. PATIENT AND METHODS Literature search was conducted in Medline/Pubmed, EMBASE, and Cochrane databases. Systematic review and meta-analysis was performed per PRISMA guidelines. Main study outcome was pain relief. GRADE system was used for quality assessment. Heterogeneity was assessed by the Q and I(2) measures; publication bias by Egger's test. Random-effect model (DerSimonian and Laird) was used if there was heterogeneity. RESULTS Eight studies (n = 411) were identified that used methionine-containing antioxidants. The study duration ranged from 10 wks to 12 months. All studies used methionine, organic selenium, ascorbate, beta-carotene and alpha-tocoferol. Four studies (including two RCTs) that reported change in pain scores were metaanalyzed. Though overall effect [standardized difference in means (95% CI)] on pain score reduction was -0.95 (-1.738 to -0.160) (z = -2.36; p = 0.018), the significance was lost when the two RCTs were meta-analyzed. RCTs that reported the number of pain free patients had a statistically significant overall effect of -3.204 (p = 0.001). Though more patients on methionine containing antioxidants had adverse events, majority of them were mild. CONCLUSION Methionine containing antioxidants appear to result in pain reduction in a significant proportion of CP patients. Further randomized controlled trials with homogeneous outcome measures are needed.