One-Carbon metabolism in ME

ME patients have dysregulated one-carbon metabolism (1).

One-carbon metabolism has thoroughly been described in ref 2.

An easy to read description of one-carbon metabolism is found in ref 3.

Figure from ref 3:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518849/figure/fig1/

The plasma level of serine was increased in male ME patients, and purine synthesis was decreased in both male and female ME patients. (1). We may hypothesize that serine was not turned into methylene-THF, methyl-THF and formyl-THF in adequate amounts.

Bao et al have shown that mitochondrial dysfunction is able to remodel the one-carbon metabolism in human cell. The researchers induced mitochondrial dysfunction (mtDNA deletion) in a cellular model. They showed (4):

• an ATF4-mediated starvation-like transcription response
• expression of serine synthesis genes: PHGDH, PSAT1 and PSPH
• an increase in serine synthesis and a  decrease in serine consumption
• an impaired mitochondrial production of formate from serine
• detection of sulfane sulfur species
• increased H2S production
• the damage may be rescued with purine or formate supplementation

Formate is an essential metabolite and a potential toxic molecule (5).

May the dysregulated one-carbon metabolism in a ME be rescued with supplementation?

The genes PHGDH, PSAT1, MTHFD1 and MTHFD1L were differentially methylated in peripheral blood mononuclear cells (PBMC) from ME patients subtypes (6).

The gene ALDH1L2 encodes metochondrial 10-formyltetrahydrofolate dehydrogenase. ALDH1L2 was hypomethylated (genic region: 3'UTR) in PBMC from ME patients (7).

The gene AMT encodes one of four components of the glycine cleavage system, which is important to one-carbon metabolism. The AMT gene promotor was hypomethylated in PBMC from ME patients (7). AMT was differentially methylated in four different genic regions in PBMC from ME patient subtypes (6).

Oxidation of the sulfur of methionine results in methionine sulfoxide or methionine sulfone. The sulfur-containing amino acids methionine and cysteine are more easily oxidized than the other amino acids. Unlike oxidation of other amino acids, the oxidation of methionine can be reversed by enzymatic action, specifically by enzymes in the methionine sulfoxide reductase family of enzymes. The three known methionine sulfoxide reductases are MsrA, MsrB, and fRmsr. (8).

Methionine sulfoxide was increased in plasma from male ME patients (1). Methionine sulfone was increased in plasma from female ME patients (9).

The genes MSRA and MSRB3 were hypomethylated in PBMC from ME patients (7), and MSRA was differentially methylated in PBMC from ME patient subtypes (6).

Formate and serine in ME

Serum levels of formate (10):
Physiological level:   32,8  +/-13,3
Control:   36,9  +/-26,1
ME/CFS:   23,8   +/-5,1
p=0,08

Serum levels of serine (10):

Physiological level:   159,8  +/-26,6
Control:   155   +/-55,2
ME/CFS:   134   +/-34,5
p=0,34

Further reading: 

Mitochondrial translation requires folate-dependent tRNA methylation https://www.ncbi.nlm.nih.gov/pubmed/29364879

5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination https://www.ncbi.nlm.nih.gov/pubmed/30031689

Use of 13C315N1-Serine or 13C515N1-Methionine for Studying Methylation Dynamics in Cancer Cell Metabolism and Epigenetics.https://www.ncbi.nlm.nih.gov/pubmed/30725450

Serine Is an Essential Metabolite for Effector T Cell Expansion https://www.ncbi.nlm.nih.gov/pubmed/28111214

References:

1) 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

2) Cell Metab. 2017 Jan 10;25(1):27-42. doi: 10.1016/j.cmet.2016.08.009. Epub 2016 Sep 15.
One-Carbon Metabolism in Health and Disease.
Ducker GS1, Rabinowitz JD2. https://www.ncbi.nlm.nih.gov/pubmed/27641100

3) Br J Cancer. 2017 Jun 6;116(12):1499-1504. doi: 10.1038/bjc.2017.118. Epub 2017 May 4.
One-carbon metabolism in cancer. https://www.ncbi.nlm.nih.gov/pubmed/3072545

4) Elife. 2016 Jun 16;5. pii: e10575. doi: 10.7554/eLife.10575.
Mitochondrial dysfunction remodels one-carbon metabolism in human cells. https://www.ncbi.nlm.nih.gov/pubmed/27307216
Bao XR1,2,3, Ong SE3, Goldberger O1, Peng J1,3, Sharma R1, Thompson DA3, Vafai SB1,3, Cox AG4, Marutani E5, Ichinose F5, Goessling W3,4, Regev A3,6, Carr SA3, Clish CB3, Mootha VK1,2,3.

5) Clin Chem Lab Med. 2013 Mar 1;51(3):571-8. doi: 10.1515/cclm-2012-0552.
Formate: an essential metabolite, a biomarker, or more?
Lamarre SG1, Morrow G, Macmillan L, Brosnan ME, Brosnan JT. https://www.ncbi.nlm.nih.gov/pubmed/23241677

6) de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-01

7) Trivedi et al: Identification of ME/CFS - associated DNA methylation patternsPlos One 2018, 13, 7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.02010

8) Wikipedia: Methionine sulfoxid

9) Germain et al: Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology. Metabolites. 2018 Dec 6;8(4). pii: E90. doi: 10.3390/metabo8040090.https://www.ncbi.nlm.nih.gov/pubmed/30563204

10) lin Chim Acta. 2012 Oct 9;413(19-20):1525-31. doi: 10.1016/j.cca.2012.06.022. Epub 2012 Jun 21. NMR metabolic profiling of serum identifies amino acid disturbances in chronic fatigue syndrome. Armstrong CW1, McGregor NR, Sheedy JR, Buttfield I, Butt HL, Gooley PR.

https://www.ncbi.nlm.nih.gov/pubmed/22728138

Chitotriosidase in ME

The enzyme chitotriosidase is involved in immune response to chitin-containing pathogens.

Chitin is a polymer of N-acetylglucosamine. Chitin is the main component of the cell wall of fungi.

Chitotriosidase is encoded by the gene CHIT1 (1).

The CHIT1 gene promotor was hypomethylated in peripheral blood mononuclear cells (PBMC) from ME patients (2).

The CHIT1 gene (genic region: body) was differentially methylated in PBMC from ME patient subtypes (3).

Chitotriosidase is mainly expressed by blood and tissue macrophages. It is an important nonspecific marker of macrophage activation. Elevated chitotriosidase is related to several diseases, fx lysomal storage diseases, neurological diseases and respiratory diseases (1).

Glucosylceramidase beta (GBA) cleaves the beta-glucosidic linkage of glycosylceramide. Mutations in the gene GBA cause the lysomal storage disease Gaucher. Chitotriosidase activity is several hundred-fold elevated in plasma from Gaucher patients in which macrophages play an essential role in the clerance of the disease sphingolipid storage material (1).

GM2 ganglioside activator (GM2A) is a glycolipid transport protein. Mutations in the gene GM2A are involved in lysomal storage diseases.

The GM2A gene promotor was hypomethylated in PBMC from ME patients (2).

Is the dysregulated sphingolipid metabolism in ME patients involved in the hypomethylated CHIT1 and GM2A gene promotors?

References:

1. Elmonem et al: Immunomodulatory effects of chitotriosidase enzyme. Hindawi 2016, ID2682680 https://www.ncbi.nlm.nih.gov/pubmed/26881065
2. Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns.
   Plos One 2018, 13, 7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201066
3. de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-015

What does 1-pyrroline-5-carboxylate do to ME?

ME patients had increased plasma levels of 1-pyrroline-5-carboxylic acid (P5C) and arginine. Females had increased OH-proline (1).

P5C is found at a crossroad, which exchanges metabolites from:

• proline degradation from collagen
• proline synthesis
• urea cycle
• TCA cycle

Research in tumor growth has shown(quote from ref 2):

"The metabolism of the nonessential amino acid proline contributes to tumor metabolic reprogramming. Previously we showed that MYC increases proline biosynthesis (PB) from glutamine. Here we show MYC increases the expression of the enzymes in PB at both protein and mRNA levels. Blockade of PB decreases tumor cell growth and energy production. Addition of Δ1- pyrroline-5-carboxylate (P5C) or proline reverses the effects of P5C synthase knockdown but not P5C reductases knockdown. Importantly, the reversal effect of proline was blocked by concomitant proline dehydrogenase/oxidase (PRODH/POX) knockdown. These findings suggest that the important regulatory contribution of PB to tumor growth derives from metabolic cycling between proline and P5C rather than product proline or intermediate P5C. We further document the critical role of PB in maintaining pyridine nucleotide levels by connecting the proline cycle to glycolysis and to the oxidative arm of the pentose phosphate pathway. These findings establish a novel function of PB in tumorigenesis, linking the reprogramming of glucose, glutamine and pyridine nucleotides, and may provide a novel target for antitumor therapy."

From page 9: "The proline cycle transfers reducing and oxidizing potentials to maintain redox homeostasis between cytosol and mitochondria through interconversion of proline and P5C catalyzed by PRODH/POX and PYCRs, respectively. In mitochondria, PRODH/POX oxidizes proline to P5C and donates electrons through its flavine adenine dinucleotide into the electron transport chain (ETC) to generate ATP or reactive oxygen species (ROS) for apoptosis or cell growth depending on the metabolic context of tumor environment (10,19). P5C can be converted to proline intra-mitochondrially or in the cytosol by PYCRs using NADPH or NADH as cofactor. Therefore, the interconversion of P5C and proline results in the recycling of cellular NAD(P)H to NAD(P)+. During the 1970s and early 1980s, researchers in proline metabolism documented the metabolic interlock between proline cycle and the oxPPP through the cycling of NADPH and NADP+ in various cells and reconstituted cell systems (26–28). They showed that P5C is a potent stimulator of oxPPP in cultured fibroblasts (26). Together with these early studies, our current findings seen with PB knockdown, i.e. marked decrease in oxPPP activity and decreased levels of both total NAD and NADP, suggest the PYCR-catalyzed conversion of P5C to proline provides a metabolic linkage to oxidize NAD(P)H as well as to generate total NAD and NADP (Fig. 8)". (Ref 2 and references herein).




Figure 8. Proposed scheme of interactions of proline biosynthesis with glucose and glutamine metabolism. Proline biosynthesis from glutamine in cancer cells promotes cell growth through interacting with glycolysis and oxidative arm of pentose phosphate pathway. P5C, Δ1 -pyrroline-5-carboxylate; GSA, glutamic-gamma-semialdehyde; GLS, glutaminase; GS, glutaminesynthase; P5CS, pyrroline-5- carboxylatesynthase; P5CDH, pyrroline-5-carboxylatedehydrogenase; PRODH/POX, proline dehydrogenase/ oxidase; PYCR1/2, pyrroline-5-carboxylatereductase1, and 2; PYCRL, pyrroline-5-carboxylatereductase L. oxPPP, oxidative arm of pentose phosphate pathway. Ref: Liu, W. et al. Proline biosynthesis augments tumor cell growth and aerobic glycolysis: involvement of pyridine nucleotides. Sci. Rep. 5, 17206; doi: 10.1038/srep17206 (2015).

Is P5C used to control redox (NADP/NADPH) in ME?

Is P5C used to stimulate phosphoribosyl pyrophosphate and purine nucleotide production in ME (as shown in ref 3)?

Is P5C used as an intermediate to replenish the TCA cycle in ME?


References:

1) 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 

2) Liu, W. et al. Proline biosynthesis augments tumor cell growth and aerobic glycolysis: involvement of pyridine nucleotides. Sci. Rep. 5, 17206; doi: 10.1038/srep17206 (2015).
https://www.nature.com/articles/srep17206.pdf

3) J Biol Chem. 1988 Sep 15;263(26):13083-9. Stimulation of phosphoribosyl pyrophosphate and purine nucleotide production by pyrroline 5-carboxylate in human erythrocytes.
Yeh GC1, Phang JM. https://www.ncbi.nlm.nih.gov/pubmed/2458343

Fatty acid oxidation, CPS1 and urea cycle in ME

When beta-oxidation of fatty acids is blocked, there is an increase in omega-oxidation, which produces dicarboxylic acids (adipic, suberic and sebacic acid). Elevated levels in plasma or urine of dicarboxylic acids are indicative of dysregulated fatty acid oxidation. Inadequate level of carnitine can lead to elevated levels of dicarboxylic acids. This is fx. observed in enteric dysfunction (1),

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

• increased sebacic acid and pristanic acid (2)
• increased adipoylcarnitine (3, 4), and increased methyladipoylcarnitine (3)
• decreased carnitine (5)

3- methyladipic acid is formed upon omega-oxidation of phytanic acid. Pristanic acid is formed of phytanic acid (6).

In certain long-chain fatty acid oxidation defects, fatty acylation of an active site residue of carbamoylphosphate synthetase 1 (CPS1) directly affects the urea cycle detoxification capacity (7).

In valproic acid induced toxicity CPS1 may be inhibited of omega-oxidation metabolites (8).

Some ME patients have dysregulated urea cycle (9).

Use link below to se figure (10):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096969/figure/Fig3/

Yamano et al hypothesized that the increase in the ratio ornithine / citrulline in plasma from ME patients may reflect either CPS1 or ornithine transcarbamoylase (OCT) dysfunction (10).

In OTC deficiency carbamoyl phosphate cannot replenish the urea cycle. The carbamoyl phosphate instead goes into the uridine monophosphate (UMP)- synthetic pathway. This means that orotic acid levels in the blood will increase. I have not found increased levels of orotate in any of the ME metabolism studies.

N-acetylglutamic acid is an essential cofactor for activation of  CPS1. Some ME patients have increased N-acetylglutamic acid plasma level, thus the cofactor is present (3).

Is CPS1 activated or not in ME? Are omega-oxidation metabolites involved?

SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle

SIRT5 deacetylates CPS1 and upregulates its activity. During fasting, NAD in liver mitochondria increases, thereby triggering SIRT5 deacetylation of CPS1 and adaptation to the increase in amino acid catabolism (11). 

Figure from Takashi Nakagawa and Leonard Guarente, AGING, June 2009, Vol. 1 No. 6 ref 12. 

Is a dysregulated NAD/NADH ratio involved in CPS1 dysfunction in ME?

Glycine and CPS1

Glycine and CPS1 are connected through the one-carbon pool by the folate pathway and the urea cycle.

Higher CPS1 expression is associated with less glycine in the blood, and vice versa.

Glycine is a major biochemical mechanism to eliminate ammonia. Glycine conjugating with benzoic acid leads to hippuric acid, which is abundantly found in urine samples.

Variations in CPS1 quantity and thus the glycine pool may also influence one-carbon metabolism and the bioavailability of betaine (13).

Is glycine used to eliminate ammonia in ME patients?

Another route of excretion of excess nitrogen

Phenylacetylglutamine and 4-hydroxyphenyl acetylglutamine provide another route of excretion of excess nitrogen from the body. Phenylacetate in the blood (some from the host and some from gut fermentation) conjugates with glutamine to phenylacetylglutamine, which is excreted in the urine (1).

4-hydroxyphenylacetate is derived from fermentation af tyrosine by the gut microbiome (1).

Children with enteric dysfunction had elevated serum levels of phenylacetate, 4-hydroxyphenylacetate and phenylacetylglutamine (1).

4-hydroxyphenylacetate and derivates were increased in plasma from ME patients (2).

Alpha-N-phenylacetyl-L-glutamine was increased in plasma from ME patients (5).


Figure of urea cycle and ammonia excretion pathways (14):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3977640/figure/F1/

What is going on with nitrogen excretion and CPS1 in ME?


References

1) Semba et al. Environmental Enteric Dysfunction is Associated with Carnitine Deficiency and Altered Fatty Acid Oxidation. EBioMedicine. 2017 Mar;17:57-66. doi: 10.1016/j.ebiom.2017.01.026. Epub 2017 Jan 18.
https://www.ncbi.nlm.nih.gov/pubmed/28122695

2) 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

3) Germain et al: Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology. Metabolites. 2018 Dec 6;8(4). pii: E90. doi: 10.3390/metabo8040090.
https://www.ncbi.nlm.nih.gov/pubmed/30563204

4) 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 

5) 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

6) Wanders et al: Fatty acid omega-oxidation as a rescue pathway for fatty acid oxidation disorders in humans. FEBS J. 2011 Jan;278(2):182-94. doi: 10.1111/j.1742-4658.2010.07947.x. Epub 2010 Dec 13. https://www.ncbi.nlm.nih.gov/pubmed/21156023

7) Guuerrero et al: Laboratory diagnostic approaches in metabolic disorders. Ann Transl Med. 2018 Dec;6(24):470. doi: 10.21037/atm.2018.11.05. https://www.ncbi.nlm.nih.gov/pubmed/30740401

8) Lheureux et al: Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence? Crit Care. 2005 Oct 5;9(5):431-40. Epub 2005 Jun 10.
https://www.ncbi.nlm.nih.gov/pubmed/16277730

9) 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

10) Monro and Puri: A Molecular Neurobiological Approach to Understanding the Aetiology of Chronic Fatigue Syndrome (Myalgic Encephalomyelitis or Systemic Exertion Intolerance Disease) with Treatment Implications
Mol Neurobiol. 2018 Sep;55(9):7377-7388. doi: 10.1007/s12035-018-0928-9. Epub 2018 Feb 6.
https://www.ncbi.nlm.nih.gov/pubmed/29411266

11) Nakagawa et al: SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell. 2009 May 1;137(3):560-70. doi: 10.1016/j.cell.2009.02.026. https://www.ncbi.nlm.nih.gov/pubmed/19410549

12) Nakagawa T1, Guarente L. Urea cycle regulation by mitochondrial sirtuin, SIRT5. Aging (Albany NY). 2009 Jun 29;1(6):578-81. https://www.ncbi.nlm.nih.gov/pubmed/20157539

13) Matone et al. Network Analysis of Metabolite GWAS Hits: Implication of CPS1 and the Urea Cycle in Weight Maintenance. PLoS One. 2016 Mar 3;11(3):e0150495. doi: 10.1371/journal.pone.0150495. eCollection 2016. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150495

14) Miesel et al: Sodium benzoate for treatment of hepatic encephalopathy. Gastroenterol Hepatol (N Y). 2013 Apr;9(4):219-27. https://www.ncbi.nlm.nih.gov/pubmed/24711766

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