Homocysteine-methionine cycle is a metabolic sensor system controlling methylation-regulated pathological signaling

Abstract

Homocysteine-Methionine (HM) cycle produces universal methyl group donor S-adenosylmethione (SAM), methyltransferase inhibitor S-adenosylhomocysteine (SAH) and homocysteine (Hcy). Hyperhomocysteinemia (HHcy) is established as an independent risk factor for cardiovascular disease (CVD) and other degenerative disease.We selected 115 genes in the extended HM cycle (31 metabolic enzymes and 84 methyltransferases), examined their protein subcellular location/partner protein, investigated their mRNA levels and mapped their corresponding histone methylation status in 35 disease conditions via mining a set of public databases and intensive literature research. We have 6 major findings. 1) All HM metabolic enzymes are located only in the cytosol except for cystathionine-β-synthase (CBS), which was identified in both cytosol and nucleus. 2) Eight disease conditions encountered only histone hypomethylation on 8 histone residues (H3R2/K4/R8/K9/K27/K36/K79 and H4R3). Nine disease conditions had only histone hypermethylation on 8 histone residues (H3R2/K4/K9/K27/K36/K79 and H4R3/K20). 3) We classified 9 disease types with differential HM cycle expression pattern. Eleven disease conditions presented most 4 HM cycle pathway suppression. 4) Three disease conditions had all 4 HM cycle pathway suppression and only histone hypomethylation on H3R2/K4/R8/K9/K36 and H4R3. 5) Eleven HM cycle metabolic enzymes interact with 955 proteins. 6) Five paired HM cycle proteins interact with each other.We conclude that HM cycle is a key metabolic sensor system which mediates receptor-independent metabolism-associated danger signal recognition and modulates SAM/SAH-dependent methylation in disease conditions and that hypomethylation on frequently modified histone residues is a key mechanism for metabolic disorders, autoimmune disease and CVD. We propose that HM metabolism takes place in the cytosol, that nuclear methylation equilibration requires a nuclear-cytosol transfer of SAM/SAH/Hcy, and that Hcy clearance is essential for genetic protection.

Exploring the Biochemical Origin of DNA Sequence Variation in Barley Plants Regenerated via in Vitro Anther Culture

“…Recently, a study showed that mitochondrial nicotinamide adenine dinucleotide (NAD) reduced oxidation links the TCA with methionine metabolism and nuclear DNA methylation [ 89 ]. The methionine cycle is a vital pathway in DNA methylation [ 90 ]. Studies show that 1-aminocyclopropane-1-carboxylic acid (ACC), the immediate precursor of ethylene, is involved in the regulation of the cell wall function and response to cell wall damage [ 91 ].…”

Effect of Methionine Diet on Metabolic and Histopathological Changes of Rat Hippocampus

“…This hHcy condition resulted in the disintegration of neuronal tissue in the cerebral cortex as well as the hippocampus. Moreover, Tóthová et al [12] have shown that hHcy on the same rat model also triggers remarkable epigenetic changes with the impairment in histone acetylation, likely within the context of hHcy-initiated DNA hypomethylation in vulnerable brain areas [9].…”

“…In addition, S-adenosyl homocysteine (SAH), an intermediate of metabolic conversion of Hcy, was shown to be a metabolic sensor controlling methylation-regulated signalling within the Met-Hcy cycle. As a consequence, it potentially initiates the DNA and protein hypomethylation with an impact on diverse tissue disturbances, including neuronal cells [9]. Likewise, the selective cytosolic and nuclear Hcy clearance is essential for cellular genetic protection.…”

Metabolomic Biomarkers for Detection, Prognosis and Identifying Recurrence in Endometrial Cancer

“…The finding of lower concentrations of progesterone in EC cases is in keeping with its anti-estrogenic effect [76]. Homocysteine, a homologue of the amino acid cysteine, is involved in maintaining the stability of the DNA and elevated levels have been linked to epithelial malignancies [97], while hydroxybutyrate, a product of acetyl-CoA and an important source of energy during the starvation phase when blood glucose levels are low, has also been linked to EC diagnosis and stage [76]. Further studies are needed to validate these markers before translation into clinical use.…”