KDM2B, PHYH, P3H2, PLOD3 and ME

Alpha-ketoglutarate dependent dioxygenases are also called 2-oxoglutarate oxygenases. They are a large family of enzymes with most diverse functions (1).

The following examples are relevant for ME research.

KDM2B
KDM2B (lysine demethylase 2B) is one of the 2OG-oxygenases described in ref 1. The gene KDM2B is hypermethylated in ME patients (2). And KDM2B is hypomethylated in CD4⁺  T cells from ME patients (3). KDM2B is able to regulate histone 3 methylation. KDM2B expression is also known to regulate ribosome biogenesis, and is a positive regulator of glycolysis. KDM2B is an important mediator of hematopoietic cell development.

PHYH
PHYH (phytanoyl-CoA 2-hydroxylase) is a peroxisomal protein that is involved in the alpha-oxidation of 3-methyl branched fatty acids. The gene is hypermethylated in ME patients (2).

P3H2
P3H2 (prolyl 3-hydroxylase 2, also known as LEPREL1) play a critical role in collagen chain assembly, stability and cross-linking by catalyzing post-translational 3-hydroxylation of proline residues. This is important to basement membranes. Interestingly, P3H2 has a FIS1 mitochondrial fission protein1) domain. P3H2 is hypomethylated in ME patients (2).

PLOD3
PLOD3 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3) catalyzes the hydroxylation of lysyl residues in collagen-like peptides. PLOD3 is found in the basement membrane. Reduced levels are associated to disease. Spinal fluid PLOD3 levels in ME patients:9 and normal value:14 (4). Interestingly, PLOD3 is located on chromosome 7 besides FIS1 and CLDN15. CLDN15 is hypermethylated in ME patients and this is associated to quality of life (2).CLDN15 (claudin 15) is an integral membrane pretein and component of tight junction strands. CLDN15 has been associated with irritabel bowel syndrome.

References:

1. Loenarz and Schofield: Expanding chemical biology of 2-oxoglutarate oxygenases. Nat Chem Biol, 2008, 4, 3.
2. Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11
3. Brenu et al: Methylation profile of CD4+ T cells in CFS/ME. J. Clin Cell Immunol 5, 228
4. Schutzer et al: Distinct Cerebrospinal Fluid Proteomes Differentiate Post- Treatment Lyme Disease from Chronic Fatigue Syndrome. PLOS One February 2011, volume 6, Issue

         Knowledge about the genes: www.ncbi.nlm.nih.gov/gene