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Cited by 48

The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index.

Mass spectrometry-directed structure elucidation and total synthesis of ultra-long chain (O-acyl)-ω-hydroxy fatty acids

Hancock, Sarah E., Ailuri, Ramesh, Marshall, David L., Brown, SimonH.J., Saville, Jennifer T., Narreddula, Venkateswara R., Boase, Nathan R., Poad, BerwyckL.J., Trevitt, Adam J., Willcox, MarkD.P., Kelso, Michael J., Mitchell, Todd W., Blanksby, Stephen J.·2018·Journal of Lipid Research
DOI 10.1194/jlr.m086702
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Abstract

-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.

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Figures

Figure 1 (A) Putative molecular structure of OAHFA 18:1/32:1 1 derived from meibum. (B) Collisioninduced dissociation (CID) mass spectrum of m/z 757.7 precursor ion. (C) The ozone-induced dissociation (OzID) mass spectrum of the m/z 757.7 precursor ion provided evidence for double bond positions at n-9 and n-7 locations in both HFA and FA. Sequential CID/OzID spectra identifying carbon-carbon double bond location in (D) HFA 32:1 chain and (E) FA 18:1 chain. * indicates an artefact signal in the spectrum
Figure 1 (A) Putative molecular structure of OAHFA 18:1/32:1 1 derived from meibum. (B) Collisioninduced dissociation (CID) mass spectrum of m/z 757.7 precursor ion. (C) The ozone-induced dissociation (OzID) mass spectrum of the m/z 757.7 precursor ion provided evidence for double bond positions at n-9 and n-7 locations in both HFA and FA. Sequential CID/OzID spectra identifying carbon-carbon double bond location in (D) HFA 32:1 chain and (E) FA 18:1 chain. * indicates an artefact signal in the spectrumCC-BY · From the PDF
Figure 2 (A) MS3 spectrum of AMPP-derivatized meibum derived OAHFA 18:1/32:1 shows a diagnostic neutral loss of 42 Da (m/z 601) indicative of the presence of a terminal alkene that can be directly ascribed to  -substitution of the ester on the HFA backbone. (B) Radical-directed dissociation (RDD) mass spectrum of 4-I-AMPP-derivatized meibum OAHFA 50:2 showed product ions resulting from carbon-carbon bond dissociation along the entire acyl chain length. The uninterrupted nature of this pattern is consistent with the absence of methyl branching. A straight-chain hydrocarbon structure was thus assigned to both FA and HFA portions of the molecule.
Figure 2 (A) MS3 spectrum of AMPP-derivatized meibum derived OAHFA 18:1/32:1 shows a diagnostic neutral loss of 42 Da (m/z 601) indicative of the presence of a terminal alkene that can be directly ascribed to  -substitution of the ester on the HFA backbone. (B) Radical-directed dissociation (RDD) mass spectrum of 4-I-AMPP-derivatized meibum OAHFA 50:2 showed product ions resulting from carbon-carbon bond dissociation along the entire acyl chain length. The uninterrupted nature of this pattern is consistent with the absence of methyl branching. A straight-chain hydrocarbon structure was thus assigned to both FA and HFA portions of the molecule.CC-BY · From the PDF
Scheme 1: Synthesis of OAHFA 18:1( n9, cis )/ ω -O-32:1( n9, cis ) 1 . Reagents and conditions: (a) (i) Mg, THF, 4 h, reflux then 4 in THF, Li2CuCl4, -10 °C to RT, 12 h, (ii) TsOH, methanol, reflux, 16 h, 62% (over two steps); (b) HBr, cyclohexane, reflux, 6 h, 69%; (c) DHP, TsOH, THF, 0 °C to RT, 16 h, 92%; (d) (i) tert -butyl(dec-9-yn-1-yloxy)dimethylsilane 8 , nBuLi, THF-HMPA, -78 °C to -40 °C, 1 h; 7 in THF, TBAI, -78 °C to 60 °C, 24 h (ii) TBAF, THF, 0 °C to RT, 12 h, 64% (for two steps); (e) Lindlar catalyst, quinoline, benzene, RT, 12 h, 98%; (f) oleic acid, DCC, DMAP, CH2Cl2, 0 °C to RT, 24 h, 78%; (g) CSA, methanol-THF, 0 °C to RT, 12 h, 95%; (h) Jones´ reagent, acetone, RT, 1 h, 87% yielding the target 1 .
Scheme 1: Synthesis of OAHFA 18:1( n9, cis )/ ω -O-32:1( n9, cis ) 1 . Reagents and conditions: (a) (i) Mg, THF, 4 h, reflux then 4 in THF, Li2CuCl4, -10 °C to RT, 12 h, (ii) TsOH, methanol, reflux, 16 h, 62% (over two steps); (b) HBr, cyclohexane, reflux, 6 h, 69%; (c) DHP, TsOH, THF, 0 °C to RT, 16 h, 92%; (d) (i) tert -butyl(dec-9-yn-1-yloxy)dimethylsilane 8 , nBuLi, THF-HMPA, -78 °C to -40 °C, 1 h; 7 in THF, TBAI, -78 °C to 60 °C, 24 h (ii) TBAF, THF, 0 °C to RT, 12 h, 64% (for two steps); (e) Lindlar catalyst, quinoline, benzene, RT, 12 h, 98%; (f) oleic acid, DCC, DMAP, CH2Cl2, 0 °C to RT, 24 h, 78%; (g) CSA, methanol-THF, 0 °C to RT, 12 h, 95%; (h) Jones´ reagent, acetone, RT, 1 h, 87% yielding the target 1 .CC-BY · From the PDF

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Metadata

Authors
Hancock, S. E., Ailuri, R., Marshall, D. L., Brown, S. J., Saville, J. T., Narreddula, V. R., Boase, N. R., Poad, B. J., Trevitt, A. J., Willcox, M. P., Kelso, M. J., Mitchell, T. W., & Blanksby, S. J.
ORCID
Hancock, Sarah E.
Venue
Journal of Lipid Research
Publisher
Elsevier BV
Published
2018-08
Volume
59
Issue
8
Pages
1510-1518
ISSN
0022-2275
DOI
10.1194/jlr.m086702
Cited by
48
References
52
Language
en
Licence
Funders
  • Australian Research Council (LP140100711, FT110100249)
  • Queensland University of Technology

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