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

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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 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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Most cited references 38

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NF-κB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis

Sha Yan, Zhenyao Xu, Fangzhou Lou … (2015)

NF-κB is constitutively activated in psoriatic epidermis. However, how activated NF-κB promotes keratinocyte hyperproliferation in psoriasis is largely unknown. Here we report that the NF-κB activation triggered by inflammatory cytokines induces the transcription of microRNA (miRNA) miR-31, one of the most dynamic miRNAs identified in the skin of psoriatic patients and mouse models. The genetic deficiency of miR-31 in keratinocytes inhibits their hyperproliferation, decreases acanthosis and reduces the disease severity in psoriasis mouse models. Furthermore, protein phosphatase 6 (ppp6c), a negative regulator that restricts the G1 to S phase progression, is diminished in human psoriatic epidermis and is directly targeted by miR-31. The inhibition of ppp6c is functionally important for miR-31-mediated biological effects. Moreover, NF-κB activation inhibits ppp6c expression directly through the induction of miR-31, and enhances keratinocyte proliferation. Thus, our data identify NF-κB-induced miR-31 and its target, ppp6c, as critical factors for the hyperproliferation of epidermis in psoriasis.

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Fluorouracil: biochemistry and pharmacology.

Marion Peters, H Pinedo (1988)

Fluorouracil (5FU) is still considered the most active antineoplastic agent in the treatment of advanced colorectal cancer. The drug needs to be converted to the nucleotide level in order to exert its effect. It can be incorporated into RNA leading to interference with the maturation of nuclear RNA. However, its conversion to 5-fluoro-2'deoxy-5' monophosphate (FdUMP) leading to inhibition of thymidylate synthase (TS) and subsequently of DNA synthesis, is considered to be its main mechanism of action. In the presence of a folate cofactor a covalent ternary complex is formed, the stability of which is the main determinant of the action of 5FU. Resistance against 5FU can be mainly attributed to aberrations in its metabolism or to alterations of TS, eg, gene amplification, altered kinetics in respect to nucleotides or folates. Biochemical modulation of 5FU metabolism can be applied to overcome resistance against 5FU. A variety of normal purines, pyrimidines, and other antimetabolites have been studied in this respect, but only some of them have been clinically successful. Delayed administration of uridine has recently been shown to "rescue" mice and patients from toxicity, while pretreatment with leucovorin is the most promising combination to enhance the therapeutic efficacy. 5FU is frequently administered in an intravenous (IV) injection, and shows a rapid distribution and a triphasic elimination. The nonlinearity of 5FU pharmacokinetics is related to saturation of its degradation. Continuous infusion of 5FU led to different kinetics. Regional administration, such as hepatic artery infusion, offers a way to achieve higher drug concentrations in liver metastases and is accompanied by lower systemic concentration. The current status of the biochemical and pharmacokinetic data is reviewed.

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Interaction of dihydrofolate reductase with methotrexate: ensemble and single-molecule kinetics.

Jackie L McCourt, P Rajagopalan, Stephen J. Benkovic … (2002)

The thermodynamics and kinetics of the interaction of dihydrofolate reductase (DHFR) with methotrexate have been studied by using fluorescence, stopped-flow, and single-molecule methods. DHFR was modified to permit the covalent addition of a fluorescent molecule, Alexa 488, and a biotin at the N terminus of the molecule. The fluorescent molecule was placed on a protein loop that closes over methotrexate when binding occurs, thus causing a quenching of the fluorescence. The biotin was used to attach the enzyme in an active form to a glass surface for single-molecule studies. The equilibrium dissociation constant for the binding of methotrexate to the enzyme is 9.5 nM. The stopped-flow studies revealed that methotrexate binds to two different conformations of the enzyme, and the association and dissociation rate constants were determined. The single-molecule investigation revealed a conformational change in the enzyme-methotrexate complex that was not observed in the stopped-flow studies. The ensemble averaged rate constants for this conformation change in both directions is about 2-4 s(-1) and is attributed to the opening and closing of the enzyme loop over the bound methotrexate. Thus the mechanism of methotrexate binding to DHFR involves multiple steps and protein conformational changes.

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Author and article information

Contributors

Honglin Wang

Journal

Journal ID (nlm-ta): EBioMedicine

Journal ID (iso-abbrev): EBioMedicine

Title: EBioMedicine

Publisher: Elsevier

ISSN (Electronic): 2352-3964

Publication date PMC-release: 25 December 2018

Publication date Collection: January 2019

Publication date (Electronic): 25 December 2018

Volume: 39

Pages: 575-590

Affiliations

[a ]Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai Institute of Immunology, Shanghai 200025, China

[b ]Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510006, China

[c ]Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

[d ]Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China

[e ]Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Author notes

[* ]Corresponding author at: Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 Chongqing South Road, Shanghai 200025, China. honglin.wang@ 123456sjtu.edu.cn

[1]

These authors contributed equally to this work.

Article

Publisher ID: S2352-3964(18)30613-3

DOI: 10.1016/j.ebiom.2018.12.036

PMC ID: 6355826

PubMed ID: 30591370

SO-VID: 0c755f76-62ca-4e7f-91c4-512646c72e38

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 1 November 2018

Date revision received : 12 December 2018

Date accepted : 18 December 2018

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

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Abstract

Background

Methods

Findings

Interpretation

Fund

Graphical abstract

Related collections

Cancer Metabolism

Most cited references 38

NF-κB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis

Fluorouracil: biochemistry and pharmacology.

Interaction of dihydrofolate reductase with methotrexate: ensemble and single-molecule kinetics.

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Cited by 11

Most referenced authors 846