Part I: Total Syntheses of Novel Oxidatively-truncated Phosphatidylserines Part II: A Nonenzymatic Route to Lysophosphatidylcholine: Spontaneous Deacylation of Oxidatively Damaged Phospholipids
Year: 2010
Type: article
Abstract: Identification of an interaction between the scavenger receptor CD36 and oxidized phosphatidylserines (oxPSs) can offer insight into the mechanism of the externalization of PSs which is essential for triggering anti-inflammatory responses in macrophages.To determine relative affinities for CD36, a diverse family of oxidatively-truncated PSs possessing various oxidatively truncated sn-2 acyl groups, i.e., ω-carboxylalkanoyl, ωoxoalkanoyl, and γ-keto-α,β-unsaturated carbonyl, were efficiently synthesized (Chapter 2).Elevated levels of sn-2-lysophosphatidylcholine (lysoPC) have been linked to cardiovascular complications, and some oxidized phosphatidylcholines undergo facile spontaneous non-enzymatic deacylation.This leads to the expectation that lipaseinhibiting drugs cannot completely prevent the release of lysoPC from oxidatively damaged phospholipids (Chapter 4).The decomposition of 4-hydroxy-7-oxohept-5-enoic acid ester of 2-lyso-phosphatidylcholine (HOHA-PC, t 1/2 = 30 min) was more rapid than that of 5-hydroxy-8-oxo-6-octenoic acid ester of 2-lyso-phosphatidylcholine (HOOA-PC, t 1/2 = 2 h) under neutral conditions (pH 7.4).In contrast, after 24 h, the decomposition of 9-hydroxy-12-oxododec-10-enoic acid ester of 2-lyso-phosphatidylcholine (HODA-PC), xxx for which intramolecular transesterification is disfavorable since it requires formation of a 10-membered lactone, was only 50% complete.The decomposition of HOHA-PC to generate, inter alia, lysoPC occurs more readily (t 1/2 = 30 min) under near-neutral conditions (pH 7.4) as compared to weakly acidic (t 1/2 = 3 h at pH 6) or moderately acidic conditions (t 1/2 = 6 h at pH 4).To investigate non-enzymatic spontaneous deacylation of oxidized PCs, efficient new syntheses of HOHA, HOOA and HODA-PCs were devised (Chapter 3).We postulated that 4-hydroxydocosahexaenoyl-phosphatidylcholine (4-HDHE-PC) was not detected previously in the singlet oxygen reaction product mixture (after reduction) because it is unstable owing to the proximity of the hydroxyl group to the ester carbonyl (Chapter 5).To support hypothesis, we demonstrated that 4-HDHE-PC undergoes spontaneous deacylation to form 4-hydroxydocosahexaenoic acid lactone and lysoPC.The formation of lysoPC and lactonized by-product was confirmed by LC/MS/MS.The rate of 4-HDHE-PC decomposition is affected by the reaction environment: deacylation was faster in homogeneous solution (t 1/2 = 8 h at pH 7.4), a relatively more aqueous environment, than in heterogeneous solution (liposome, t 1/2 = 15 h), where the oxidized acyl chain is buried in a relatively more hydrophobic environment.
Author: Jaewoo Choi
Institution: Case Western Reserve University
Language: English
Subfield: Biochemistry (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2283846292