Polyamines, 5'-methylthioadenosine and symmetrical dimethylarginine in ME

The polyamines (putrescine, spermidine and spermine) are involved in replication, transcription, translation, and stabilization of macro-molecular complexes. They may also play a role in autoimmunity (1).

Decarboxylated S-adenosylmethionine (dcSAM) and ornithine generates putrescine and subsequently spermine and spermidine. In these reactions, dcSAM is converted to 5′-methylthioadenosine (MTA). Accumulation of MTA inhibits the enzyme protein arginine N-methyltrasferase 5 (PRMT5), which uses SAM as a methyl donor to synthesize symmetrical dimethylarginine (sDMA) from arginine. In the methionine cycle, MTA is cleaved to 5-methylthioribose-1-phosphate (MTR) and adenine by the enzyme methylthioadenosine phosphorylase (MTAP). MTAP deficient cells are more reliant on de novo purine synthesis to generate AMP, since they are unable to cleave MTA to salvage adenine (2).

Figure 8 . The Methione Cycle from reference 2, Luengo et al: Targeting Metabolism for Cancer Theraphy. Methionine is an essential amino acid that can be used for methylation reactions, cysteine synthesis, and polyamine generation. Methionine is converted to S-adenosylmethionine (SAM) by methionine adenosyltransferase (MAT) (2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744685/figure/F8/?report=objectonly

Some ME patients have changed plasma/serum levels in different studies compared to normal controls of the following metabolites:

• increased arginine (only males) and decreased adenosine (= adenine + ribose) (only females) (3)
• increased ornithine (4)
• increased spermidine and N-acetylputrescinium (5)
• increased MTA (6)
• decreased SDMA (only females) (7)

Some ME patients have single nucleotide polymorphism (SNP) in the gene MTAP (8).

MTA was identified as part of a biomarker panel in critically ill patients with malnutrition (9).

PRMT5 is involved in B-cell differentiation (10).

PRMT5 has a role in the regulation of Circadian Per1 gene (11).

Some ME patients have upregulated expression of PER1 in the immune cells (12).

References:

1) Brooks: Increased Polyamines Alter Chromatin and Stabilize Autoantigens in Autoimmune Diseases. Front Immunol. 2013; 4: 91. https://www.ncbi.nlm.nih.gov/pubmed/23616785

2) Luengo et al. Targeting Metabolism for Cancer Therapy.Cell Chem Biol. 2017 Sep 21;24(9):1161-1180. doi: 10.1016/j.chembiol.2017.08.028. https://www.ncbi.nlm.nih.gov/pubmed/?term=28938091

3) Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N et al (2016) Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A 113:E5472–E5480. https://doi.org/10.1073/pnas.1607571113

4) Yamano et al: Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles. Sci Rep. 2016 Oct 11;6:34990. doi: 10.1038/srep34990. https://www.ncbi.nlm.nih.gov/pubmed/27725700

5) Germain et al: Metabolic profiling of a ME/CFS discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol. BioSyst. 2017, 13, 371 https://pubs.rsc.org/en/Content/ArticleLanding/2017/MB/C6MB00600K#!divAbstract

6) Nagy-Szakal et al: Insights into ME/CFS phenotypes through comprehensive metabolomics. Nat. Sci. Rep, 2018, 8. https://www.nature.com/articles/s41598-018-28477-9

7) Fluge et al: Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy / chronic fatigue syndrome. JCI Insight. 2016; 1(21):e89376. Doi 10.1172/jci.insight.89276

8) Smith et al: Convergent genomic studies identify association of GRIK2 and NPAS2 with chronic fatigue syndrome. Neuropsychobiology. 2011;64(4):183-94. doi: 10.1159/000326692. Epub 2011 Sep 9.  https://www.ncbi.nlm.nih.gov/pubmed/21912186

9) Mogensen et al: Metabolites Associated With Malnutrition in the Intensive Care Unit Are Also Associated With 28-Day Mortality. JPEN J Parenter Enteral Nutr. 2017 Feb;41(2):188-197. doi: 10.1177/0148607116656164. Epub 2016 Jul 19.
https://www.ncbi.nlm.nih.gov/pubmed/?term=27406941

10) Mei et al: PRMT5-mediated H4R3sme2 Confers Cell Differentiation in Pediatric B-cell Precursor Acute Lymphoblastic Leukemia. Clin Cancer Res. 2019 Jan 11. doi: 10.1158/1078-0432.CCR-18-2342. https://www.ncbi.nlm.nih.gov/pubmed/?term=30635341

11) Na et al: Role of type II protein arginine methyltransferase 5 in the regulation of Circadian Per1 gene. PLoS One. 2012;7(10):e48152. doi: 10.1371/journal.pone.0048152. Epub 2012 Oct 25. https://www.ncbi.nlm.nih.gov/pubmed/23133559

12) Sweetman et al: Changes in the transcriptome of circulating immune cells of a New Zealand cohort with myalgic encephalomyelitis/chronic fatigue syndrome. Sweetman et al: Int J Immunopathol Pharmacol. 2019 Jan-Dec;33:2058738418820402. doi: 10.1177/2058738418820402.
https://www.ncbi.nlm.nih.gov/pubmed/30791746