Liquid molecular model explains discontinuity between site uniformity among three N-3 fatty acids and their 13C and 1H NMR spectra

Authors: SCHMIDT, WALTER; CHEN, FU - UNIVERSITY OF MARYLAND; BROADHURST, CATHERINE - UNIVERSITY OF MARYLAND; CRAWFORD, MICHAEL - IMPERIAL COLLEGE OF MEDICINE

Submitted to: Journal of Molecular Liquids
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/14/2020
Publication Date: 6/18/2020
Citation: Schmidt, W.F., Chen, F., Broadhurst, C.L., Crawford, M. 2020. Liquid molecular model explains discontinuity between site uniformity among three N-3 fatty acids and their 13C and 1H NMR spectra. Journal of Molecular Liquids. 314:113376. https://doi.org/10.1016/j.molliq.2020.113376.
DOI: https://doi.org/10.1016/j.molliq.2020.113376

Interpretive Summary: Numerous health benefits of seafoods are attributed to their n-3 long-chain polyunsaturated fatty acid content, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA, DHA and their precursor '-linolenic acid (ALA) differ vastly biochemically, but from a physical chemical standpoint are close analogs. There remains, for example, no satisfactory explanation why only DHA can be utilized in the brain, heart and retina. DHA, EPA and ALA are converted to numerous biochemicals that control inflammation, immunity, blood sugar, blood pressure and brain and nervous system growth, maintenance and protection. We have combined our previous Raman spectroscopy and calorimetry work on these n-3 fats with state-of-the art nuclear magnetic resonance analysis, resulting in structures that are accurate enough to explain their biochemical differences, and form the basis for new pharmaceuticals. Our work supports the concept that nearly all natural polyunsaturated fatty acids should be considered essential, not just two. This benefits ARS and the public because billions of dollars of medical, veterinary and scientific research funds are spent each year trying to understand and control chronic inflammation, systemic infections, diabetes and dementia. It also provides a theoretical argument supporting epidemiologically-based dietary recommendations for increasing all n-3 fats in the diet from a variety of foods.

Technical Abstract: Numerous health benefits of seafoods are attributed to their n-3 long-chain polyunsaturated fatty acid content, especially eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3). EPA, DHA and their precursor '-linolenic acid (ALA; 18:3n-3) differ vastly biochemically, but from a physical chemical standpoint are close structural analogs. There remains, for example, no satisfactory explanation why only DHA can be utilized in fast signal processing tissues such as neuronal, retinal and cardiac. Recently gradient temperature Raman spectroscopy has identified key lipid structural differences that require further NMR elucidation. 1H and 13C 1D experiments were performed on neat EPA, DHA, and ALA and 4 different 2D experiments on EPA. The methine 13C spectra show six chemical shifts for ALA; 10 for an EPA, and 12 for DHA. The chemical shift of the first -C= closest to the C1 carbonyl site is always the most upfield; that of the last =C- closest to the methyl end is always the most downfield. 1H chemical shift of almost none of the methine protons match. The 13C paired molecular sites identified as conformationally redundant are not identical to the 1H molecular sites identified as conformationally paired. For EPA long-range coupling is stronger and extends longer at the methyl-ended C18 to C10H2 section and is shorter at C5 to C7H2; also C18= and =C17 coupling differ. Repeating (H-C=C-H)-CH2 moieties are planar; unequal torsion alters both curvature and twist both ends of the lipids. The methyl end is the most elastic. Asymmetry in twist between the two ends results in torque at the methylene site near the geometric center, resulting in unusually strong electron 13C and 1H shielding.