Targeting methionine cycle as a potential therapeutic strategy for immune disorders

ABSTRACT

Introduction: Methionine cycle plays an essential role in regulating many cellular events, especially transmethylation reactions, incorporating the methyl donor S-adenosylmethionine (SAM). The transmethylations and substances involved in the cycle have shown complicated effects and mechanisms on immunocytes developments and activations, and exert crucial impacts on the pathological processes in immune disorders.

Areas covered: Methionine cycle has been considered as an effective means of drug developments. This review discussed the role of methionine cycle in immune responses and summarized the potential therapeutic strategies based on the cycle, including SAM analogs, methyltransferase inhibitors, S-adenosylhomocysteine hydrolase (SAHH) inhibitors, adenosine receptors specific agonists or antagonists and homocysteine (Hcy)-lowering reagents, in treating human immunodeficiency virus (HIV) infections, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), systemic sclerosis (SSc) and other immune disorders.

Expert opinion: New targets and biomarkers grown out of methionine cycle have developed rapidly in the past decades. However, impacts of epigenetic regulations on immune disorders are unclear and whether the substances in methionine cycle can be clarified as biomarkers remains controversial. Therefore, further elucidation on the role of epigenetic regulations and substances in methionine cycle may contribute to exploring the cycle-derived biomarkers and drugs in immune disorders.

KEYWORDS:

• Methionine cycle
• S-adenosylhomocysteine hydrolase inhibitors
• rheumatoid arthritis
• systemic lupus erythematosus
• immunosuppression
• epigenetic regulation
• plasma homocysteine

Article highlights

• SAM in the methionine cycle is associated with a wide spectrum of methylation of DNA and protein, which can modify the developments, differentiations and activations of immune cells.

• SAHH is the critical enzyme which catalyzes the hydrolysis of S-adenosylhomocysteine (SAH) to adenosine and Hcy. Subsequently, SAH can inhibit transmethylation reactions in a feedback way. Disturbed Hcy metabolism contributes to immunodeficiency or immune dysfunction. However, whether Hcy can be clarified as a biomarker for immune disorders remains controversial.

• Adenosine, an important metabolite in methionine cycle, plays diverse roles on immune cells functions via corresponding receptors and is closely related to immune disorders, including SLE, RA and inflammatory diseases.

• Potential therapeutic strategies targeting for methionine cycle, including SAM analogs, methyltransferase inhibitors, SAHH inhibitors, adenosine receptors specific agonists or antagonists and Hcy-lowering reagents, have emerged in treating HIV infections, SLE, RA, MS, SSc and other immune disorders.

• Epigenetic regulations mediated by methionine cycle are closely related to immune cells functions and signaling pathways. DNA and histone modifications could regulate immune-related genes expression and role of methylation alterations has been investigated abundantly in immune disorders.

• Profound researches should be performed to discover new patent drugs and identify potential biomarkers built on methionine cycle.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by the ‘Personalized Medicines—Molecular Signature-based Drug Discovery and Development’, Strategic Priority Research Program of the Chinese Academy of Sciences, Grant No. XDA12020215 and National Key Basic Research Programme, Grant No. 2014CB541906.