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

Overview

Journal Chem Res Toxicol

Publisher American Chemical Society

Specialty Toxicology

Date 2015 Mar 21

PMID 25793308

Citations 14

Authors

Hua Wang

Mikhail Linetsky

Junhong Guo

Jaewoo Choi

Li Hong

Amanda S Chamberlain

Scott J Howell

Andrew M Howes

Robert G Salomon

Affiliations

Soon will be listed here.

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.

Citing Articles

(Photo)toxicity of Partially Oxidized Docosahexaenoate and Its Effect on the Formation of Lipofuscin in Cultured Human Retinal Pigment Epithelial Cells.

Bakker L, Boulton M, Rozanowska M Antioxidants (Basel). 2024; 13(11).

PMID: 39594569 PMC: 11591205. DOI: 10.3390/antiox13111428.

Cysteinyl leukotriene-like metabolites are generated in retinal pigment epithelial cells through glutathionylation/reduction of an oxidatively truncated fragment of arachidonate.

Linetsky M, Mondal A, Liu S, Hite A, Enduri S, Cheng Y Results Chem. 2024; 6.

PMID: 38855016 PMC: 11160973. DOI: 10.1016/j.rechem.2023.100995.

4-Hydroxy-7-oxo-5-heptenoic acid (HOHA) lactone induces apoptosis in retinal pigment epithelial cells.

Linetsky M, Guo J, Udeigwe E, Ma D, Chamberlain A, Yu A Free Radic Biol Med. 2020; 152:280-294.

PMID: 32222470 PMC: 7276294. DOI: 10.1016/j.freeradbiomed.2020.03.017.

Inhibition of integrin αβ-mediated macrophage adhesion to end product of docosahexaenoic acid (DHA) oxidation prevents macrophage accumulation during inflammation.

Cui K, Podolnikova N, Bailey W, Szmuc E, Podrez E, Byzova T J Biol Chem. 2019; 294(39):14370-14382.

PMID: 31395659 PMC: 6768641. DOI: 10.1074/jbc.RA119.009590.

Light-induced generation and toxicity of docosahexaenoate-derived oxidation products in retinal pigmented epithelial cells.

Cheng Y, Linetsky M, Gu X, Ayyash N, Gardella A, Salomon R Exp Eye Res. 2018; 181:325-345.

PMID: 30296412 PMC: 6443467. DOI: 10.1016/j.exer.2018.09.012.

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