PMID- 31605963 OWN - NLM STAT- MEDLINE DCOM- 20201023 LR - 20240214 IS - 2213-2317 (Electronic) IS - 2213-2317 (Linking) VI - 28 DP - 2020 Jan TI - Homocysteine-methionine cycle is a metabolic sensor system controlling methylation-regulated pathological signaling. PG - 101322 LID - S2213-2317(19)30958-9 [pii] LID - 10.1016/j.redox.2019.101322 [doi] LID - 101322 AB - 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-beta-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. CI - Copyright (c) 2019. Published by Elsevier B.V. FAU - Shen, Wen AU - Shen W AD - Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China; Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. FAU - Gao, Chao AU - Gao C AD - Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. FAU - Cueto, Ramon AU - Cueto R AD - Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. FAU - Liu, Lu AU - Liu L AD - Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. FAU - Fu, Hangfei AU - Fu H AD - Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. FAU - Shao, Ying AU - Shao Y AD - Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. FAU - Yang, William Y AU - Yang WY AD - Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. FAU - Fang, Pu AU - Fang P AD - Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. FAU - Choi, Eric T AU - Choi ET AD - Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA; Division of Vascular & Endovascular Surgery, Department of Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. FAU - Wu, Qinghua AU - Wu Q AD - Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China. Electronic address: ncwqh@163.com. FAU - Yang, Xiaofeng AU - Yang X AD - Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. FAU - Wang, Hong AU - Wang H AD - Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. Electronic address: hongw@temple.edu. LA - eng GR - R01 HL138749/HL/NHLBI NIH HHS/United States GR - R01 HL117654/HL/NHLBI NIH HHS/United States GR - R01 HL130233/HL/NHLBI NIH HHS/United States GR - R01 HL131460/HL/NHLBI NIH HHS/United States GR - R01 HL082774/HL/NHLBI NIH HHS/United States GR - R01 HL110764/HL/NHLBI NIH HHS/United States GR - R01 DK104116/DK/NIDDK NIH HHS/United States GR - R01 HL132399/HL/NHLBI NIH HHS/United States GR - R01 HL147565/HL/NHLBI NIH HHS/United States GR - R01 DK113775/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20190912 PL - Netherlands TA - Redox Biol JT - Redox biology JID - 101605639 RN - 0 (Histones) RN - 0LVT1QZ0BA (Homocysteine) RN - AE28F7PNPL (Methionine) SB - IM MH - Cytosol/metabolism MH - *Gene Regulatory Networks MH - Histones/metabolism MH - Homocysteine/*metabolism MH - Humans MH - Hyperhomocysteinemia/genetics/*metabolism MH - Methionine/*metabolism MH - Methylation MH - Protein Interaction Maps MH - Protein Transport PMC - PMC6812029 OTO - NOTNLM OT - Homocysteine-methionine cycle OT - Metabolic sensor OT - SAM/SAH-dependent methylation EDAT- 2019/10/13 06:00 MHDA- 2020/10/24 06:00 PMCR- 2019/09/12 CRDT- 2019/10/13 06:00 PHST- 2019/08/15 00:00 [received] PHST- 2019/09/03 00:00 [revised] PHST- 2019/09/06 00:00 [accepted] PHST- 2019/10/13 06:00 [pubmed] PHST- 2020/10/24 06:00 [medline] PHST- 2019/10/13 06:00 [entrez] PHST- 2019/09/12 00:00 [pmc-release] AID - S2213-2317(19)30958-9 [pii] AID - 101322 [pii] AID - 10.1016/j.redox.2019.101322 [doi] PST - ppublish SO - Redox Biol. 2020 Jan;28:101322. doi: 10.1016/j.redox.2019.101322. Epub 2019 Sep 12.