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Identification of a Natural Inhibitor of MAT2A Regulating One-Carbon Metabolism in Keratinocytes

60 Pages Posted: 7 Nov 2018

See all articles by Jing Bai

Jing Bai

Northeastern University - School of Materials Science and Engineering

Qianqian Yin

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

Fangzhou Lou

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

Zhikai Wang

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

Zhenyao Xu

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

Hong Zhou

Shanghai Jiao Tong University (SJTU)

Yuanyuan Gao

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

Qun Li

Shanghai Jiao Tong University (SJTU)

Wei Cai

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

Yang Sun

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

Liman Niu

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

Hong Wang

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

Zhenquan Wei

Shanghai Jiao Tong University (SJTU)

Shaoyong Lu

Shanghai Jiao Tong University (SJTU)

Aiwu Zhou

Shanghai Jiao Tong University (SJTU)

Jian Zhang

Shanghai Jiao Tong University (SJTU)

Honglin Wang

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

More...

Abstract

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 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 that 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.  

Funding: 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.

Declaration of Interest: The authors declare no competing financial interests.

Ethical Approval: Age- and sexmatched mice at 7-8 weeks of age were randomly used in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals with the approval (SYXK-2003-0026) of the Scientific Investigation Board of Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Keywords: Psoriasis; AKBA; metabolomics; MAT2A; methionine cycle; onecarbon metabolism

Suggested Citation

Bai, Jing and Yin, Qianqian and Lou, Fangzhou and Wang, Zhikai and Xu, Zhenyao and Zhou, Hong and Gao, Yuanyuan and Li, Qun and Cai, Wei and Sun, Yang and Niu, Liman and Wang, Hong and Wei, Zhenquan and Lu, Shaoyong and Zhou, Aiwu and Zhang, Jian and Wang, Honglin, Identification of a Natural Inhibitor of MAT2A Regulating One-Carbon Metabolism in Keratinocytes (January 11, 2018). Available at SSRN: https://ssrn.com/abstract=3279168

Jing Bai (Contact Author)

Northeastern University - School of Materials Science and Engineering

China

Qianqian Yin

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

KoGuan Law School
Shanghai 200030, Shanghai 200052
United States

Fangzhou Lou

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

KoGuan Law School
Shanghai 200030, Shanghai 200052
United States

Zhikai Wang

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

KoGuan Law School
Shanghai 200030, Shanghai 200052
United States

Zhenyao Xu

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

KoGuan Law School
Shanghai 200030, Shanghai 200052
United States

Hong Zhou

Shanghai Jiao Tong University (SJTU)

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Yuanyuan Gao

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

KoGuan Law School
Shanghai 200030, Shanghai 200052
United States

Qun Li

Shanghai Jiao Tong University (SJTU)

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Wei Cai

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

KoGuan Law School
Shanghai 200030, Shanghai 200052
United States

Yang Sun

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

KoGuan Law School
Shanghai 200030, Shanghai 200052
United States

Liman Niu

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

KoGuan Law School
Shanghai 200030, Shanghai 200052
United States

Hong Wang

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology

KoGuan Law School
Shanghai 200030, Shanghai 200052
United States

Zhenquan Wei

Shanghai Jiao Tong University (SJTU)

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Shaoyong Lu

Shanghai Jiao Tong University (SJTU)

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Aiwu Zhou

Shanghai Jiao Tong University (SJTU)

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Jian Zhang

Shanghai Jiao Tong University (SJTU)

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Honglin Wang

Shanghai Jiao Tong University (SJTU) - Shanghai Institute of Immunology ( email )

KoGuan Law School
Shanghai 200030, Shanghai 200052
United States

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