Cytochrome c is an oxidative stress–activated plasmalogenase that cleaves plasmenylcholine and plasmenylethanolamine at the sn-1 vinyl ether linkage

作者：Christopher M. Jenkins, Kui Yang, Gaoyuan Liu, Sung Ho Moon, Beverly Gibson Dilthey, Richard W. Gross · 发表于：Journal of Biological Chemistry · 年份：2018 · DOI：10.1074/jbc.ra117.001629 · 被引用次数：74 · 研究领域：Nitric Oxide and Endothelin Effects、Enzyme Catalysis and Immobilization、Metal-Catalyzed Oxygenation Mechanisms

Plasmalogens are phospholipids critical for cell function and signaling that contain a vinyl ether linkage at the sn-1 position and are highly enriched in arachidonic acid (AA) at the sn-2 position. However, the enzyme(s) responsible for the cleavage of the vinyl ether linkage in plasmalogens has remained elusive. Herein, we report that cytochrome c, in the presence of either cardiolipin (CL), O 2 and H 2 O 2 , or oxidized CL and O 2 , catalyzes the oxidation of the plasmalogen vinyl ether linkage, promoting its hydrolytic cleavage and resultant production of 2-AA-lysolipids and highly reactive -hydroxy fatty aldehydes. Using stable isotope labeling in synergy with strategic chemical derivatizations and high-mass-accuracy MS, we deduced the chemical mechanism underlying this long sought-after reaction. Specifically, labeling with either 18 O 2 or H 2 18 O, but not with H 2 18 O 2 , resulted in M 2 isotopologues of the -hydroxyaldehyde, whereas reactions with both 18 O 2 and H 2 18 O identified the M 4 isotopologue. Furthermore, incorporation of 18 O from 18 O 2 was predominantly located at the -carbon. In contrast, reactions with H 2 18 O yielded 18 O linked to the aldehyde carbon. Importantly, no significant labeling of 2-AA-lysolipids with 18 O 2 , H 2 18 O, or H 2 18 O 2 was present. Intriguingly, phosphatidylinositol phosphates (PIP 2 and PIP 3 ) effectively substituted for cardiolipin. Moreover, cytochrome c released from myocardial mitochondria subjected to oxidative st...