| Autor: |
Röth D; Department of Molecular Imaging and Therapy, Beckman Research Institute of the City of Hope, Duarte, California, USA., Chiang AJ; Department of Molecular Imaging and Therapy, Beckman Research Institute of the City of Hope, Duarte, California, USA.; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, California, USA., Hu W; Department of Molecular Imaging and Therapy, Beckman Research Institute of the City of Hope, Duarte, California, USA.; Nuclear Magnetic Resonance Core, Beckman Research Institute of the City of Hope, Duarte, California, USA., Gugiu GB; Department of Molecular Imaging and Therapy, Beckman Research Institute of the City of Hope, Duarte, California, USA.; Mass Spectrometry and Proteomics Core, Beckman Research Institute of the City of Hope, Duarte, California, USA., Morra CN; Integrative Molecular and Biomedical Sciences (IMBS), Baylor College of Medicine, Houston, Texas, USA.; Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA; and., Versalovic J; Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA; and.; Department of Pathology, Texas Children's Hospital, Houston, Texas, USA., Kalkum M; Department of Molecular Imaging and Therapy, Beckman Research Institute of the City of Hope, Duarte, California, USA.; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, California, USA.; Mass Spectrometry and Proteomics Core, Beckman Research Institute of the City of Hope, Duarte, California, USA. |
| Abstrakt: |
Colonization of the gut by certain probiotic Lactobacillus reuteri strains has been associated with reduced risk of inflammatory diseases and colorectal cancer. Previous studies pointed to a functional link between immunomodulation, histamine production, and folate metabolism, the central 1-carbon pathway for the transfer of methyl groups. Using mass spectrometry and NMR spectroscopy, we analyzed folate metabolites of L. reuteri strain 6475 and discovered that the bacterium produces a 2-carbon-transporting folate in the form of 5,10-ethenyl-tetrahydrofolyl polyglutamate. Isotopic labeling permitted us to trace the source of the 2-carbon unit back to acetate of the culture medium. We show that the 2C folate cycle of L. reuteri is capable of transferring 2 carbon atoms to homocysteine to generate the unconventional amino acid ethionine, a known immunomodulator. When we treated monocytic THP-1 cells with ethionine, their transcription of TNF-α was inhibited and cell proliferation reduced. Mass spectrometry of THP-1 histones revealed incorporation of ethionine instead of methionine into proteins, a reduction of histone-methylation, and ethylation of histone lysine residues. Our findings suggest that the microbiome can expose the host to ethionine through a novel 2-carbon transporting variant of the folate cycle and modify human chromatin via ethylation.-Röth, D., Chiang, A. J., Hu, W., Gugiu, G. B., Morra, C. N., Versalovic, J., Kalkum, M. The two-carbon folate cycle of commensal Lactobacillus reuteri 6475 gives rise to immunomodulatory ethionine, a source for histone ethylation. |
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