Chapter 9 - Ether-linked lipids and their bioactive species

Abstract

Ether lipids account for up to one-fifth of the human phospholipid pool, and inborn errors of metabolism that abolish ether lipid synthesis result in severe pathologies. Cellular and circulating phospholipids are primarily diacyl lipids consisting of long-chain fatty acyl residues esterified at the sn-1 and sn-2 positions of the glycero-3-phosphoryl backbone. However, select inflammatory cells, electrically excitable cells, and tumor cells contain significant amounts—up to 70% of the ethanolamine-linked phosphoglyceride or nearly half of the choline-linked phosphoglyceride pool—of phospholipids that contain an sn-1 ether bond. These occur with (plasmalogen) or without (plasmanyl) a unique 1'cis double bond. Whether such specialized phospholipids have a corresponding unique role had been unknown, but identification of mutations in enzymes catalyzing the first two steps of complex ether phospholipid synthesis as causal events in human genetic disorders has now shown that, indeed, these alkyl phospholipids have a unique and irreplaceable role in how cells and tissues organize themselves in complex organisms. The inability to synthesize alkyl phospholipids is not lethal to individual cells, but the defect in membrane trafficking in the absence of ether phospholipids instead manifests as defects in neurological and eye development in mice, and usually death in the human genetic disorders types 2 and 3 rhizomelic chondrodysplasia punctata. The unique role fulfilled by ether phospholipids is also evident in other genetic abnormalities, such as the paradigmatic Zellweger syndrome, that prevent peroxisome maturation and thereby abolish the first two steps in ether phospholipid bond formation. Ether phospholipids display distinct physical properties compared to their diacyl homologs—the vinyl ether of plasmalogens functions as a chain-breaking antioxidant, and ether phospholipids are precursors of highly potent signaling molecules.