The discovery and early structural studies of arachidonic acid

Abstract

Arachidonic acid and esterified arachidonate are ubiquitous components of every mammalian cell. This polyunsaturated fatty acid serves very important biochemical roles, including being the direct precursor of bioactive lipid mediators such as prostaglandin and leukotrienes. This 20 carbon fatty acid with four double bonds was first isolated and identified from mammalian tissues in 1909 by Percival Hartley. This was accomplished prior to the advent of chromatography or any spectroscopic methodology (MS, infrared, UV, or NMR). The name, arachidonic, was suggested in 1913 based on its relationship to the well-known arachidic acid (C20:0). It took until 1940 before the positions of the four double bonds were defined at 5,8,11,14 of the 20-carbon chain. Total synthesis was reported in 1961 and, finally, the configuration of the double bonds was confirmed as all-cis-5,8,11,14. By the 1930s, the relationship of arachidonic acid within the family of essential fatty acids helped cue an understanding of its structure and the biosynthetic pathway. Herein, we review the findings leading up to the discovery of arachidonic acid and the progress toward its complete structural elucidation.

Keywords: Hazura’s rule; chemical analysis; essential fatty acid; fractional crystallization; linoleic acid; octobromoarachidic acid; ozonolysis; potassium permanganate; total synthesis.

Fig. 1.

Photograph of Percival Hartley, the first individual to isolate and purify arachidonic acid and determine that it was an eicosatetraenoic acid (9). With permission of the Royal Society.

Fig. 2.

Chemical analysis of the octobromoarachidic acid by Hartley (9).

Fig. 3.

Chemical analysis of the octahydroxyarachidic acid by Hartley (9).

Fig. 4.

Arachidonic acid is named. The lower paragraph on page 215 of the Lewkowitsch compendium marks the origin of “arachidonic” acid (11).

Fig. 5.

Photograph of Ida Smedley-Maclean. With permission from the British Federation of University Women.

Fig. 6.

Outline of the chemical reactions of arachidonic acid with ozone and alkaline permanganate to yield degradation products indicative of positions of double bonds in arachidonic acid. The reaction at the first double bond of arachidonic acid at carbon-5 is indicated.

Fig. 7.

IR spectroscopy of arachidonic acid and other unsaturated fatty acids. The trans bending vibration at 965–975 cm⁻¹ is indicated by the letter “D” in the figure. Reprinted with permission from (24). Copyright 1952 American Chemical Society.

Fig. 8.

Final chemical steps employed in the synthesis of arachidonic acid that define the cis configurations of all double bonds (26, 27).