A Vitamin B2‐Photocatalysed Approach to Methionine Analogues
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ABSTRACT:
SUBMITTER: Knowles O
PROVIDER: S-EPMC10946832 | biostudies-literature | 2022 Nov
REPOSITORIES: biostudies-literature
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Project description:Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no effective treatment. Diet, as a modifiable risk factor for AD, could potentially be targeted to slow disease onset and progression. However, complexity of the human diet and indirect effects of the microbiome make it challenging to identify protective nutrients. Multiple factors contribute to AD pathogenesis, including amyloid beta (Aβ) deposition, energy crisis, and oxidative stress. Here, we use Caenorhabditis elegans to define the impact of diet on Aβ proteotoxicity. We discover that dietary vitamin B12 alleviates mitochondrial fragmentation, bioenergetic defects, and oxidative stress, delaying Aβ-induced paralysis without affecting Aβ accumulation. Vitamin B12 has this protective effect by acting as a cofactor for methionine synthase, impacting the methionine/S-adenosylmethionine (SAMe) cycle. Vitamin B12 supplementation of B12-deficient adult Aβ animals is beneficial, demonstrating potential for vitamin B12 as a therapy to target pathogenic features of AD triggered by proteotoxic stress.
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Project description:Methionine adenosyltransferases (MATs) catalyze the formation of S-adenosyl-l-methionine (SAM) inside living cells. Recently, S-alkyl analogues of SAM have been documented as cofactor surrogates to label novel targets of methyltransferases. However, these chemically synthesized SAM analogues are not suitable for cell-based studies because of their poor membrane permeability. This issue was recently addressed under a cellular setting through a chemoenzymatic strategy to process membrane-permeable S-alkyl analogues of methionine (SAAMs) into the SAM analogues with engineered MATs. Here we describe a general sensitive activity assay for engineered MATs by converting the reaction products into S-alkylthioadenosines, followed by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) quantification. With this assay, 40 human MAT mutants were evaluated against 7 SAAMs as potential substrates. The structure-activity relationship revealed that, besides better engaged SAAM binding by the MAT mutants (lower Km value in contrast to native MATs), the gained activity toward the bulky SAAMs stems from their ability to maintain the desired linear SN2 transition state (reflected by higher kcat value). Here the I117A mutant of human MATI was identified as the most active variant for biochemical production of SAM analogues from diverse SAAMs.
| S-EPMC3947680 | biostudies-literature
Project description:Memory-epigenetics which is the loss of memory due to epigenetic modifications can be due to the silencing of genes involved in cognitive functions and this is the basis of the current study. We hypothesize that a diet containing high methionine and low vitamins can lead to memory impairment by increasing global DNA methylation and therefore, silencing the netrin-1 gene, which encodes the glycoprotein involved in neurogenesis, axonal guidance and maintenance of the synaptic plasticity. Wild type (C57BL/6J) mice were fed with a diet containing excess methionine (1.2%), low-folate (0.08 mg/kg), vitamin B6 (0.01 mg/kg), and B12 (10.4 mg/kg) for 6 weeks. Mice were examined weekly for the long-term memory function, using a passive avoidance test, which determined loss of fear-motivated long-term memory starting from the fourth week of diet. Similarly, an increase in brain %5-methyl cytosine was observed starting from the 4th week of diet in mice. Mice fed with a high methionine, low folate and vitamins containing diet showed a decrease in netrin-1 protein expression and an increase in netrin-1 gene promotor methylation, as determined by methylation-sensitive restriction enzyme-polymerase chain reaction analysis. The increase in methylation of netrin-1 gene was validated by high-resolution melting and sequencing analysis. Furthermore, the association of netrin-1 with memory was established by administering netrin that considerably restored long-term fear motivated memory. Taken together, these results suggest that a diet rich in methionine and lacking in folate and vitamin B6/B12 can induce defects in learning and memory. Furthermore, the data indicates that decrease in netrin-1 expression due to hyper-methylation of its gene can be associated with memory loss. The animal procedures were approved by the Institutional Animal Care and Use Committee, University of Louisville, USA (No. A3586-01) on February 2, 2018.
| S-EPMC6425846 | biostudies-literature
Project description: Not available
| S-EPMC6494183 | biostudies-literature
Project description:BackgroundNutrients involved in one-carbon metabolism may play a key role in pancreatic carcinogenesis. The aim of this study was to examine the association between pancreatic cancer risk and intake or blood levels of vitamins B6, B12 and methionine via meta-analysis.MethodsA systematic search was performed in PubMed, Web of Knowledge and Chinese National Knowledge Infrastructure (CNKI) up to April 2020 to identify relevant studies. Risk estimates and their 95% confidence intervals (CIs) were retrieved from the studies and combined by a random-effect model.ResultsA total of 18 studies were included in this meta-analysis on the association of vitamin B6, B12 and methionine with pancreatic cancer risk. The combined risk estimate (95% CI) of pancreatic cancer for the highest vs lowest category of vitamin B6 intake and blood pyridoxal 5'-phosphate (PLP, active form of vitamin B6) levels was 0.63 (0.48-0.79) and 0.65 (0.52-0.79), respectively. The results indicated a non-linear dose-response relationship between vitamin B6 intake and pancreatic risk. Linear dose-response relationship was found, and the risk of pancreatic cancer decreased by 9% for every 10 nmol/L increment in blood PLP levels. No significant association were found between pancreatic cancer risk and vitamin B12 intake, blood vitamin B12 levels, methionine intake and blood methionine levels.ConclusionOur study suggests that high intake of vitamin B6 and high concentration of blood PLP levels may be protective against the development of pancreatic cancer. Further research are warranted to confirm the results.
| S-EPMC7534168 | biostudies-literature