Abstract
The (O-acyl)-ω-hydroxy FAs (OAHFAs) comprise an unusual lipid subclass present in the skin, vernix caseosa, and meibomian gland secretions. Although they are structurally related to the general class of FA esters of hydroxy FAs (FAHFAs), the ultra-long chain (30-34 carbons) and the putative ω-substitution of the backbone hydroxy FA suggest that OAHFAs have unique biochemistry. Complete structural elucidation of OAHFAs has been challenging because of their low abundance within complex lipid matrices. Furthermore, because these compounds occur as a mixture of closely related isomers, insufficient spectroscopic data have been obtained to guide structure confirmation by total synthesis. Here, we describe the full molecular structure of ultra-long chain OAHFAs extracted from human meibum by exploiting the gas-phase purification of lipids through multi-stage MS and novel multidimensional ion activation methods. The analysis elucidated sites of unsaturation, the stereochemical configuration of carbon-carbon double bonds, and ester linkage regiochemistry. Such isomer-resolved MS guided the first total synthesis of an ultra-long chain OAHFA, which, in turn, confirmed the structure of the most abundant OAHFA found in human meibum, OAHFA 50:2. The availability of a synthetic OAHFA opens new territory for future investigations into the unique biophysical and biochemical properties of these lipids.
Highlights
The (O-acyl)- -hydroxy FAs (OAHFAs) comprise an unusual lipid subclass present in the skin, vernix caseosa, and meibomian gland secretions
OAHFAs have been detected in the skin [5], in equine sperm [6] and amniotic fluid [7], and in waxy secretions from meibomian glands located within the eyelids that supply the tear film lipid layer [8,9,10]
We have developed a customized suite of MS-based strategies that provide unambiguous structure determination of OAHFAs extracted from human meibum [24]
Summary
The (O-acyl)- -hydroxy FAs (OAHFAs) comprise an unusual lipid subclass present in the skin, vernix caseosa, and meibomian gland secretions. They are structurally related to the general class of FA esters of hydroxy FAs (FAHFAs), the ultra-long chain (30–34 carbons) and the putative -substitution of the backbone hydroxy FA suggest that OAHFAs have unique biochemistry. The analysis elucidated sites of unsaturation, the stereochemical configuration of carbon-carbon double bonds, and ester linkage regiochemistry Such isomer-resolved MS guided the first total synthesis of an ultra-long chain OAHFA, which, in turn, confirmed the structure of the most abundant OAHFA found in human meibum, OAHFA 50:2. The lipid components of these tissues are renowned for containing FAs with noncanonical acyl chain lengths and sites of unsaturation [e.g., sapienic acid, 16:1(n-10), is present in vernix caseosa, skin, and sebaceous secretions] and methyl-branched acyl chains (e.g., iso-16:0 and anteiso-17:0 within WEs of skin, vernix caseosa, and meibum) [21,22,23]
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