The toxic side of one-carbon metabolism and epigenetics

Morellato, Agustín E.; Umansky, Carla; Pontel, Lucas B.

doi:10.1016/j.redox.2020.101850

Cited by 43 publications

(24 citation statements)

References 75 publications

(57 reference statements)

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“…In addition, serine metabolism fuels the methionine salvage pathway, which is the main mechanism of synthesizing of the methyl donor S-adenosyl methionine (SAM). Subsequently, SAM provides methyl groups for epigenetic methylation and is metabolized to homocysteine (Hcy), which can enter the trans-sulfuration pathway to produce cysteine and finally GSH [ 41 ]. According to our results, the DNA methyltransferases DNMT1 and DNMT3b were also downregulated in the livers of IUGR piglets.…”

Section: Discussionmentioning

confidence: 99%

Integrative Analysis of Liver Metabolomics and Transcriptomics Reveals Oxidative Stress in Piglets with Intrauterine Growth Restriction

Gao

Chen

Zhao

et al. 2022

Biology

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The correlation between oxidative stress and liver metabolic dysfunction in piglets with intrauterine growth restriction (IUGR) remains limited. Therefore, the objective of the present study was to investigate potential mechanisms of metabolic characteristics induced by oxidative stress in the livers of IUGR piglets using metabolomic and transcriptomic analysis. Analysis of the phenotypic characteristics showed that the liver weight of the intrauterine growth restriction piglets was significantly lower than that of normal birth weight piglets. Intrauterine growth restriction piglets exhibited disordered hepatic cord arrangement and vacuolization as well as excessive lipid accumulation in hepatocytes. In addition, the activities of antioxidant enzymes were significantly decreased in the liver of the intrauterine growth restriction piglets, whereas the level of the lipid peroxidation marker MDA was significantly increased. Finally, our findings revealed that intrauterine growth restriction piglets were involved in a variety of metabolic abnormalities, including mitochondrial dysfunction, imbalance of fatty acid composition, disruption to sources of one-carbon unit supply, and abnormal galactose conversion, which may be responsible for oxidative stress in the liver. In summary, these data provided a detailed theoretical reference for revealing the hepatic metabolic characteristics of intrauterine growth restriction piglets.

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Section: Discussionmentioning

confidence: 99%

Integrative Analysis of Liver Metabolomics and Transcriptomics Reveals Oxidative Stress in Piglets with Intrauterine Growth Restriction

Gao

Chen

Zhao

et al. 2022

Biology

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“…The simplest aldehyde formaldehyde is quite toxic, because it is reactive with many cellular components including DNA and protein under normal physiological conditions. [1] Formaldehyde can be generated endogenously or acquired from external sources. [2] While formaldehyde can be assimilated via serine pathway or ribulose monophosphate pathway, [3] it is more often metabolized by formaldehyde dehydrogenase (FalDH) mediated oxidation process to formate, a less reactive compound which can be further oxidized to CO 2 or incorporated into other metabolic pathways.…”

Section: Introductionmentioning

confidence: 99%

“…The simplest aldehyde formaldehyde is quite toxic, because it is reactive with many cellular components including DNA and protein under normal physiological conditions [1] . Formaldehyde can be generated endogenously or acquired from external sources [2] .…”

Section: Introductionmentioning

confidence: 99%

Engineering Formaldehyde Dehydrogenase from Pseudomonas putida to Favor Nicotinamide Cytosine Dinucleotide

et al. 2022

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The enzyme formaldehyde dehydrogenase (FalDH) from Pseudomonas putida is of particular interest for biotechnological applications as it catalyzes the oxidation of formaldehyde independent of glutathione. However, the consumption of a stoichiometric amount of nicotinamide adenine dinucleotide (NAD) can be challenging at the metabolic level as this may affect many other NAD-linked processes. A potential solution is to engineer FalDH to utilize non-natural cofactors. Here we devised FalDH variants to favor nicotinamide cytosine dinucleo-tide (NCD) by structure-guided modification of the binding pocket for the adenine moiety of NAD. Several mutants were obtained and the best one FalDH 9B2 had over 150-fold higher preference for NCD than NAD. Molecular docking analysis indicated that the cofactor binding pocket shrunk to better fit NCD, a smaller-sized cofactor. FalDH 9B2 together with other NCD-linked enzymes offer opportunities to assemble orthogonal pathways for biological conversion of C1 molecules.

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“…[1][2][3] Methylation is essential for epigenetic regulation via nucleobase and histone methylation and consequently closely connected to human health and disease. [4,5] Especially in drug synthesis, methylation is a highly effective modification that can increase the potency of a substance up to three orders of magnitude, leading to the term "magic methyl effect". [6,7] SAM-dependent enzymes have the potential to provide an environmentally friendly alternative to commonly used toxic, and potentially unselective alkylating agents.…”

Section: Introductionmentioning

confidence: 99%

Biomimetic S-Adenosylmethionine Regeneration Starting from Different Byproducts Enables Biocatalytic Alkylation with Radical SAM Enzymes

Gericke

Karst

Mhaindarkar

et al. 2022

Preprint

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S-Adenosylmethionine (SAM) is an essential and versatile cofactor in nature. SAM-dependent enzymes, such as conventional methyltransferases (MTs), amino(carboxy)propyl transferases, and radical SAM enzymes, are of great interest as biocatalytic tools for chemical synthesis and the pharmaceutical industry. The use of SAM analogues adds to the diversity of reaction types and products. While SAM regeneration protocols for conventional MTs are available, in vitro SAM regeneration for polyamine-forming enzymes and radical SAM enzymes has not been solved yet. Here, we report a biomimetic cofactor regeneration cycle for three important types of SAM dependent enzymes featuring adenine as a central intermediate. SAM is regenerated from its main degradation products, S-adenosylhomocysteine, 5′ methylthioadenosine, and 5′-deoxyadenosine. We further show the chemical diversification of the system using SAM analogues such as S-adenosylethionine for MT reactions. Interestingly, the enzyme cascades also enable the transfer of an ethyl group with a cobalamin-dependent radical SAM MT. The possibility to regenerate SAM (analogues) for biocatalytic use with a broad range of enzymes will be a starting point for further application of the diverse chemistry accessible by SAM-based catalysis, as well as provide new options for mechanistic studies.

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The toxic side of one-carbon metabolism and epigenetics

Cited by 43 publications

References 75 publications

Integrative Analysis of Liver Metabolomics and Transcriptomics Reveals Oxidative Stress in Piglets with Intrauterine Growth Restriction

Integrative Analysis of Liver Metabolomics and Transcriptomics Reveals Oxidative Stress in Piglets with Intrauterine Growth Restriction

Engineering Formaldehyde Dehydrogenase from Pseudomonas putida to Favor Nicotinamide Cytosine Dinucleotide

Biomimetic S-Adenosylmethionine Regeneration Starting from Different Byproducts Enables Biocatalytic Alkylation with Radical SAM Enzymes

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