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
Hua Wang
Mikhail Linetsky
Junhong Guo
Jaewoo Choi
Li Hong
Amanda S. Chamberlain
Scott
J. Howell
Andrew M. Howes
Robert G. Salomon
10.1021/acs.chemrestox.5b00001.s001
https://acs.figshare.com/articles/journal_contribution/4_Hydroxy_7_oxo_5_heptenoic_Acid_HOHA_Lactone_is_a_Biologically_Active_Precursor_for_the_Generation_of_2_Carboxyethyl_pyrrole_CEP_Derivatives_of_Proteins_and_Ethanolamine_Phospholipids/2166202
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)-<i>sn</i>-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 (<i>t</i><sub>1/2</sub> = 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/H<sub>2</sub>O<sub>2</sub>/NO<sub>2</sub><sup>–</sup> promoted in vitro oxidation of either 1-palmityl-2-docosahexaneoyl-<i>sn</i>-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 H<sub>2</sub>O<sub>2</sub> 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.
2015-05-18 00:00:00
lipid oxidation product
oxidative truncation product
ARPE
protein lysyl residues
VEGF
CEP derivatives
blood cell ghosts
HOHA
2O
form CEP derivatives
DHA