TECR (trans-2-enoyl-CoA reductase), VLCFAs and sphingolipids in ME

Very long-chain fatty acids (VLCFAs) are fatty acids (FAs) with a chain-length of ≥22 carbons. Mammals have a variety of VLCFAs differing in chain-length and the number of double bonds. Each VLCFA exhibits certain functions, for example in skin barrier formation, liver homeostasis, myelin maintenance, spermatogenesis, retinal function and anti-inflammation. These functions are elicited not by free VLCFAsthemselves, but through their influences as components of membrane lipids (sphingolipids and glycerophospholipids) or precursors of inflammation-resolving lipid mediators. VLCFAs are synthesized by endoplasmic reticulum membrane-embedded enzymes through a four-step cycle. The most important enzymes determining the tissue distribution of VLCFAs are FA elongases, which catalyze the first, rate-limiting step of the FA elongation cycle. Mammals have seven elongases (ELOVL1-7), each exhibiting a characteristic substrate specificity. Several inherited disorders are caused by mutations in genes involved in VLCFA synthesis or degradation (1).

FAs are elongated by endoplasmic reticulum (ER) membrane-embedded enzymes following their conversion to acyl-CoAs. FA elongation occurs by cycling through a four-step process: condensation, reduction, dehydration and reduction (1).

Fig. 2. from ref 2: Mammalian FA elongation cycle. The FA elongation cycle and enzymes involved in each step are illustrated. In each cycle, acyl-CoA incorporates two carbon units from malonyl-CoA.

In the last reduction step, trans-2-enoyl-CoA is converted to acyl-CoA, which is longer than the original acyl-CoA by two carbons. The trans-2-enoyl-CoA reductase responsible for this reaction is TER (also known as TECR), and the reaction requires NADPH as a cofactor (Moon and Horton, 2003 from ref 2).

TER is involved in both the production of VLCFAs used in the fatty acid moiety of sphingolipids as well as in the degradation of the sphingosine moiety of sphingolipids via S1P (3).

An impaired TER function affects VLCFA synthesis and thereby alters the cellular sphingolipid profile. Maintenance of a proper VLCFA level may be important for neural function (4).

The levels of sphingolipids and glycerolipids in plasma from ME patients are dysregulated (5).

The gene TECR (body) is hypermethylated in peripheral blood mononuclear cells (PBMC) from ME patients. This DNA methylation  is related to quality of life in the ME patients (table S7 in ref 6).

TECR is differentially methylated in PBMC from ME patients subtypes (table S3 in ref 7).

The gene TECR is hypomethylated in PBMC from ME patients (table S4 in ref 8).

TECR is located on chromosome 19 together with mir 639 (9):

Chromosome 19 - NC_000019.10

mir 639 is hypomethylated in CD4+ T cells from ME patients (10).

References

1) Akio Kihara: Very long-chain fatty acids: elongation, physiology and related disorders The Journal of Biochemistry, Volume 152, Issue 5, 1 November 2012, Pages 387–395,https://doi.org/10.1093/jb/mvs105
https://academic.oup.com/jb/article/152/5/387/2182729

2) Sassa and Kihara: Metabolism of Very Long-Chain Fatty Acids: Genes and Pathophysiology. Biomol Ther (Seoul). 2014 Mar; 22(2): 83–92.
doi: [10.4062/biomolther.2014.017]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975470/

3) Wakashima et al: Dual functions of the trans-2-enoyl-CoA reductase TER in the sphingosine 1-phosphate metabolic pathway and in fatty acid elongation. J Biol Chem. 2014 Sep 5;289(36):24736-48. doi: 10.1074/jbc.M114.571869. Epub 2014 Jul 21.
https://www.ncbi.nlm.nih.gov/pubmed/25049234

4) Abe et al: Mutation for nonsyndromic mental retardation in the trans-2-enoyl-CoA reductase TER gene involved in fatty acid elongation impairs the enzyme activity and stability, leading to change in sphingolipid profile. J Biol Chem. 2013 Dec 20;288(51):36741-9. doi: 10.1074/jbc.M113.493221. Epub 2013 Nov 12.

https://www.ncbi.nlm.nih.gov/pubmed/24220030

5) 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

6) de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324230/

7) 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

8) 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

9) Gene mir 639:https://www.ncbi.nlm.nih.gov/gene/693224

10) Brenu et al: Methylation profile of CD4+ T cells in CFS/ME. J. Clin Cell Immunol 5, 228 https://www.omicsonline.org/open-access/methylation-profile-of-cd-t-cells-in-chronic-fatigue-syndromemyalgic-encephalomyelitis-2155-9899.1000228.php?aid=27598