title: 4-Hydroxy-7-oxo-5-heptenoic Acid (HOHA) Lactone is a Biologically Active Precursor for the Generation of 2-(ω-Carboxyethyl)pyrrole (CEP) Derivatives of Proteins and Ethanolamine Phospholipids.
abstract: 2-(ω-Carboxyethyl)pyrrole (CEP) derivatives of proteins were previously shown to have significant pathological and physiological relevance to age-related macular degeneration, cancer and wound healing. Previously, we showed that CEPs are generated in the reaction of ε-amino groups of protein lysyl residues with 1-palmityl-2-(4-hydroxy-7-oxo-5-heptenoyl)-sn-glycero-3-phosphatidylcholine (HOHA-PC), a lipid oxidation product uniquely generated by oxidative truncation of docosahexanenate-containing phosphatidylcholine. More recently, we found that HOHA-PC rapidly releases HOHA-lactone and 2-lyso-PC (t1/2 = 30 min at 37 °C) by nonenzymatic transesterification/deacylation. Now we report that HOHA-lactone reacts with Ac-Gly-Lys-OMe or human serum albumin to form CEP derivatives in vitro. Incubation of human red blood cell ghosts with HOHA-lactone generates CEP derivatives of membrane proteins and ethanolamine phospholipids. Quantitative analysis of the products generated in the reaction HOHA-PC with Ac-Gly-Lys-OMe showed that HOHA-PC mainly forms CEP-dipeptide that is not esterified to 2-lysophosphatidycholine. Thus, the HOHA-lactone pathway predominates over the direct reaction of HOHA-PC to produce the CEP-PC-dipeptide derivative. Myleoperoxidase/H2O2/NO2(-) promoted in vitro oxidation of either 1-palmityl-2-docosahexaneoyl-sn-glycero-3-phosphatidylcholine (DHA-PC) or docosahexaenoic acid (DHA) generates HOHA-lactone in yields of 0.45% and 0.78%, respectively. Lipid oxidation in human red blood cell ghosts also releases HOHA-lactone. Oxidative injury of ARPE-19 human retinal pigmented epithelial cells by exposure to H2O2 generated CEP derivatives. Treatment of ARPE-19 cells with HOHA-lactone generated CEP-modified proteins. Low (submicromolar), but not high, concentrations of HOHA-lactone promote increased vascular endothelial growth factor (VEGF) secretion by ARPE-19 cells. Therefore, HOHA-lactone not only serves as an intermediate for the generation of CEPs but also is a biologically active oxidative truncation product from docosahexaenoate lipids.
authors: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States.
authors: Hua
authors: H
authors: Wang
authors: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States.
authors: Mikhail
authors: M
authors: Linetsky
authors: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States.
authors: Junhong
authors: J
authors: Guo
authors: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States.
authors: Jaewoo
authors: J
authors: Choi
authors: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States.
authors: Li
authors: L
authors: Hong
authors: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States.
authors: Amanda S
authors: AS
authors: Chamberlain
authors: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States.
authors: Scott J
authors: SJ
authors: Howell
authors: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States.
authors: Andrew M
authors: AM
authors: Howes
authors: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States.
authors: Robert G
authors: RG
authors: Salomon
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000378:metabolism; D004912:Erythrocytes / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D010714:Phosphatidylethanolamines / Q000737:chemistry / Q000378:metabolism*; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C000602461:2-(omega-carboxyethyl)pyrrole; C000604795:4-hydroxy-7-oxo-5-heptenoic acid lactone; D007783:Lactones; D010714:Phosphatidylethanolamines; D011758:Pyrroles; D012709:Serum Albumin; D042461:Vascular Endothelial Growth Factor A; D004281:Docosahexaenoic Acids; C483858:phosphatidylethanolamine