Identification of a Natural Inhibitor of MAT2A Regulating One-Carbon Metabolism in Keratinocytes
60 Pages Posted: 7 Nov 2018More...
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
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