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Identification of a natural inhibitor of methionine adenosyltransferase 2A regulating one-carbon metabolism in keratinocytes

BACKGROUND: Psoriasis is a common chronic inflammatory skin disease which lacks effective strategies for the treatment. Natural compounds with biological activities are good tools to identify new targets with therapeutic potentials. Acetyl-11-keto-β-boswellic acid (AKBA) is the most bioactive ingred...

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Autores principales: Bai, Jing, Gao, Yuanyuan, Chen, Linjiao, Yin, Qianqian, Lou, Fangzhou, Wang, Zhikai, Xu, Zhenyao, Zhou, Hong, Li, Qun, Cai, Wei, Sun, Yang, Niu, Liman, Wang, Hong, Wei, Zhenquan, Lu, Shaoyong, Zhou, Aiwu, Zhang, Jian, Wang, Honglin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355826/
https://www.ncbi.nlm.nih.gov/pubmed/30591370
http://dx.doi.org/10.1016/j.ebiom.2018.12.036
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author Bai, Jing
Gao, Yuanyuan
Chen, Linjiao
Yin, Qianqian
Lou, Fangzhou
Wang, Zhikai
Xu, Zhenyao
Zhou, Hong
Li, Qun
Cai, Wei
Sun, Yang
Niu, Liman
Wang, Hong
Wei, Zhenquan
Lu, Shaoyong
Zhou, Aiwu
Zhang, Jian
Wang, Honglin
author_facet Bai, Jing
Gao, Yuanyuan
Chen, Linjiao
Yin, Qianqian
Lou, Fangzhou
Wang, Zhikai
Xu, Zhenyao
Zhou, Hong
Li, Qun
Cai, Wei
Sun, Yang
Niu, Liman
Wang, Hong
Wei, Zhenquan
Lu, Shaoyong
Zhou, Aiwu
Zhang, Jian
Wang, Honglin
author_sort Bai, Jing
collection PubMed
description BACKGROUND: Psoriasis is a common chronic inflammatory skin disease which lacks effective strategies for the treatment. Natural compounds with biological activities are good tools to identify new targets with therapeutic potentials. Acetyl-11-keto-β-boswellic acid (AKBA) is the most bioactive ingredient of boswellic acids, a group of compounds with anti-inflammatory and anti-cancer properties. Target identification of AKBA and metabolomics analysis of psoriasis helped to elucidate the molecular mechanism underlying its effect, and provide new target(s) to treat the disease. METHODS: To explore the targets and molecular mechanism of AKBA, we performed affinity purification, metabolomics analysis of HaCaT cells treated with AKBA, and epidermis of imiquimod (IMQ) induced mouse model of psoriasis and psoriasis patients. FINDINGS: AKBA directly interacts with methionine adenosyltransferase 2A (MAT2A), inhibited its enzyme activity, decreased level of S-adenosylmethionine (SAM) and SAM/SAH ratio, and reprogrammed one‑carbon metabolism in HaCaT cells. Untargeted metabolomics of epidermis showed one‑carbon metabolism was activated in psoriasis patients. Topical use of AKBA improved inflammatory phenotype of IMQ induced psoriasis-like mouse model. Molecular docking and site-directed mutagenesis revealed AKBA bound to an allosteric site at the interface of MAT2A dimer. INTERPRETATION: Our study extends the molecular mechanism of AKBA by revealing a new interacting protein MAT2A. And this leads us to find out the dysregulated one‑carbon metabolism in psoriasis, which indicates the therapeutic potential of AKBA in psoriasis. FUND: The National Natural Science Foundation, the National Program on Key Basic Research Project, the Shanghai Municipal Commission, the Leading Academic Discipline Project of the Shanghai Municipal Education Commission.
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spelling pubmed-63558262019-02-08 Identification of a natural inhibitor of methionine adenosyltransferase 2A regulating one-carbon metabolism in keratinocytes Bai, Jing Gao, Yuanyuan Chen, Linjiao Yin, Qianqian Lou, Fangzhou Wang, Zhikai Xu, Zhenyao Zhou, Hong Li, Qun Cai, Wei Sun, Yang Niu, Liman Wang, Hong Wei, Zhenquan Lu, Shaoyong Zhou, Aiwu Zhang, Jian Wang, Honglin EBioMedicine Research paper BACKGROUND: Psoriasis is a common chronic inflammatory skin disease which lacks effective strategies for the treatment. Natural compounds with biological activities are good tools to identify new targets with therapeutic potentials. Acetyl-11-keto-β-boswellic acid (AKBA) is the most bioactive ingredient of boswellic acids, a group of compounds with anti-inflammatory and anti-cancer properties. Target identification of AKBA and metabolomics analysis of psoriasis helped to elucidate the molecular mechanism underlying its effect, and provide new target(s) to treat the disease. METHODS: To explore the targets and molecular mechanism of AKBA, we performed affinity purification, metabolomics analysis of HaCaT cells treated with AKBA, and epidermis of imiquimod (IMQ) induced mouse model of psoriasis and psoriasis patients. FINDINGS: AKBA directly interacts with methionine adenosyltransferase 2A (MAT2A), inhibited its enzyme activity, decreased level of S-adenosylmethionine (SAM) and SAM/SAH ratio, and reprogrammed one‑carbon metabolism in HaCaT cells. Untargeted metabolomics of epidermis showed one‑carbon metabolism was activated in psoriasis patients. Topical use of AKBA improved inflammatory phenotype of IMQ induced psoriasis-like mouse model. Molecular docking and site-directed mutagenesis revealed AKBA bound to an allosteric site at the interface of MAT2A dimer. INTERPRETATION: Our study extends the molecular mechanism of AKBA by revealing a new interacting protein MAT2A. And this leads us to find out the dysregulated one‑carbon metabolism in psoriasis, which indicates the therapeutic potential of AKBA in psoriasis. FUND: The National Natural Science Foundation, the National Program on Key Basic Research Project, the Shanghai Municipal Commission, the Leading Academic Discipline Project of the Shanghai Municipal Education Commission. Elsevier 2018-12-25 /pmc/articles/PMC6355826/ /pubmed/30591370 http://dx.doi.org/10.1016/j.ebiom.2018.12.036 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research paper
Bai, Jing
Gao, Yuanyuan
Chen, Linjiao
Yin, Qianqian
Lou, Fangzhou
Wang, Zhikai
Xu, Zhenyao
Zhou, Hong
Li, Qun
Cai, Wei
Sun, Yang
Niu, Liman
Wang, Hong
Wei, Zhenquan
Lu, Shaoyong
Zhou, Aiwu
Zhang, Jian
Wang, Honglin
Identification of a natural inhibitor of methionine adenosyltransferase 2A regulating one-carbon metabolism in keratinocytes
title Identification of a natural inhibitor of methionine adenosyltransferase 2A regulating one-carbon metabolism in keratinocytes
title_full Identification of a natural inhibitor of methionine adenosyltransferase 2A regulating one-carbon metabolism in keratinocytes
title_fullStr Identification of a natural inhibitor of methionine adenosyltransferase 2A regulating one-carbon metabolism in keratinocytes
title_full_unstemmed Identification of a natural inhibitor of methionine adenosyltransferase 2A regulating one-carbon metabolism in keratinocytes
title_short Identification of a natural inhibitor of methionine adenosyltransferase 2A regulating one-carbon metabolism in keratinocytes
title_sort identification of a natural inhibitor of methionine adenosyltransferase 2a regulating one-carbon metabolism in keratinocytes
topic Research paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355826/
https://www.ncbi.nlm.nih.gov/pubmed/30591370
http://dx.doi.org/10.1016/j.ebiom.2018.12.036
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