fredag den 12. oktober 2018

CLYBL, itaconate and B12 - involved in ME?

The gene citrate lyase subunit beta-like (CLYBL) is a mitochondrial enzyme (1).

Figure 1. A Novel Pathway Linked to Vitamin B12 Metabolism. 

The metabolic role of CLYBL is linked to B12 metabolism and the immunomodulatory metabolite, itaconate (1).


The gene CLYBL (body) is hypermethylated in peripheral blood mononuclear cells (PBMC) from ME patients (table S1 in ref 2).

Some ME patients have single nucleotide polymorphism  (SNP) in the gene CLYBL (3). 

CLYBL, itaconate and B12

CLYBL participates in a relatively unexplored human C5 metabolic pathway.

CLYBL is required for maintaining mitochondrial B12 function.

Immunoresponsive gene 1 (IRG1) is expressed exclusively in activated macrophages. IRG1 produce itaconate through decarboxylation of cis-aconitate, a TCA-cycle intermediate.

In vitro test showed that itaconate added to human B-lymphocytes were converted to itaconyl-CoA inside the cells and dramatically lowered B12.

High concentrations of macrophage-derived itaconate might have autocrine and paracrine effects and poison B12 in nearby tissues, raising the possibility for a localized vitamin deficiency in the setting of inflammation (4). 

The B12 regulation may have important implications for other metabolic pathways and pathophysiological contexts. Serine, glycine and one-carbon (SGOC) metabolism, which requires B12 to couple the methionine and folate cycles, is important for nucleotide biosynthesis, redox homeostasis and methylation reactions (1, 4).

SGOC metabolism in ME

Naviaux et al have described  dysregulated SGOC metabolism in ME patients (ref 5 - do take a look at figure S6 in the article supplementary).

B12 in ME

Some ME patients respond to B12/folic acid support (6).

Further reading about STING and itaconate: 

Is STING involved in ME?


1) A Missing Link to Vitamin B12 Metabolism.

2) de Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11

3) Smith et al: Convergent genomic studies identify association of GRIK2 and NPAS2 with chronic fatigue syndrome.  2011;64(4):183-94. doi: 10.1159/000326692. Epub 2011 Sep 9. 

4) Shen et al: The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12. Cell, 171, 771-782, 2017

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. 

6) Response to Vitamin B12 and Folic Acid in Myalgic Encephalomyelitis and Fibromyalgia

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