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Methionine metabolism in health and cancer: a nexus of diet and precision medicine

Abstract

Methionine uptake and metabolism is involved in a host of cellular functions including methylation reactions, redox maintenance, polyamine synthesis and coupling to folate metabolism, thus coordinating nucleotide and redox status. Each of these functions has been shown in many contexts to be relevant for cancer pathogenesis. Intriguingly, the levels of methionine obtained from the diet can have a large effect on cellular methionine metabolism. This establishes a link between nutrition and tumour cell metabolism that may allow for tumour-specific metabolic vulnerabilities that can be influenced by diet. Recently, a number of studies have begun to investigate the molecular and cellular mechanisms that underlie the interaction between nutrition, methionine metabolism and effects on health and cancer.

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Fig. 1: Methionine metabolism and related metabolic processes.
Fig. 2: Epigenetic modifications that are methionine-dependent.
Fig. 3: Dietary methionine intake has age-dependent effects on health.

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Acknowledgements

We thank numerous colleagues over the years who have helped shape our thoughts on methionine metabolism, particularly those at the Orentreich Foundation for the Advancement of Science.

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S.M.S. and J.W.L. outlined, wrote, revised and edited the content of the manuscript. Z.D. contributed the content related to Box 2. X.G. drafted the sections on dietary methionine.

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Correspondence to Jason W. Locasale.

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Glossary

Dietary methionine restriction

(MR). A diet characterized by reduced methionine levels compared to a standard reference diet; the degree of restriction can vary between studies.

Progeroid

Genetic predisposition that causes subjects to exhibit advanced physiological ageing.

S-adenosyl-methionine

(SAM). Methionine-derived universal methyl donor required for all cellular methylation reactions.

One-carbon metabolism

Set of biochemical reactions that allow for the transfer of single carbon units from dietary nutrients, particularly amino acids, in order to fuel critical cellular processes.

Polyamine

Methionine-derived polycations that interact with negatively charged moieties of DNA and other proteins and lipids.

Methylthioadenosine phosphorylase

(MTAP). Enzyme involved in the salvage of methionine and adenine from by-products of polyamine biosynthesis.

Methylation

Biochemical addition of a methyl group (composed of one carbon and three hydrogen atoms, or CH3) to another substrate.

Methionine adenosyltransferase 2A

(MAT2A). Enzyme that catalyses the ATP-dependent conversion of methionine to SAM.

Protein arginine N-methyltransferase 5

(PRMT5). Methyltransferase that catalyses the monomethylation and symmetrical dimethylation of arginine residues of proteins.

Collateral vulnerabilities

Co-deletion of a gene proximal to a tumour suppressor gene, resulting in a targetable vulnerability independent of the tumour suppressor deletion.

Ornithine decarboxylase

(ODC). Enzyme that catalyses the conversion of ornithine to putrescine, the initial and committing step of polyamine biosynthesis.

Adenosylmethionine decarboxylase 1

(AMD1). Enzyme responsible for the decarboxylation of SAM for polyamine biosynthesis.

Histones

DNA-interacting proteins responsible for organizing DNA into structural units called nucleosomes.

N-homocysteinylation

Addition of a thiol-containing homocysteine molecule to proteins via acylation of a lysine residue.

Age-related disorders

Physiological states or diseases (including metabolic, neurological or other types) whose incidence is more prevalent in ageing populations.

Dietary methionine depletion

A diet characterized by total removal of methionine.

Walker-256 carcinosarcoma

A rat-derived transplantable carcinosarcoma cell line; tends to exhibit carcinoma characteristics when transplanted in younger rats, and sarcoma characteristics in older rats.

Yoshida sarcoma

A transplantable allograft sarcoma tumour model derived from ascites; one of the first cancer cell lines successfully generated.

Metabolomics

Systematic identification and quantification of metabolic products (metabolites).

Sulfur metabolism

Biological processes involving methionine and cysteine.

Patient-derived xenograft

(PDX). Preclinical cancer model whereby patient-excised tumour cells are directly implanted into immunodeficient mice.

5-fluorouracil

(5-FU). A pyrimidine analogue that inhibits nucleotide synthesis, functioning as an antimetabolite chemotherapy.

Gene–environment interactions

Relationships through which genetic status influences how a given cell/organism responds to environmental variation.

Methionine aminopeptidase 2

(MetAP2). Metallopeptidase responsible for removing N-terminal methionine residues from newly translated proteins.

Cystemustine

A chloroethylnitrosourea chemotherapy agent approved for the treatment of high-grade melanomas and gliomas.

Precision diets

Systematic development of personalized diets; can be individual-specific or more broadly orientated towards a particular nutrient or disease.

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Sanderson, S.M., Gao, X., Dai, Z. et al. Methionine metabolism in health and cancer: a nexus of diet and precision medicine. Nat Rev Cancer 19, 625–637 (2019). https://doi.org/10.1038/s41568-019-0187-8

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