α-Parinaric acid is a
conjugated polyunsaturated
fatty acid. Discovered by Tsujimoto and Koyanagi in 1933,[1] it contains 18 carbon atoms and 4
conjugated double bonds. The repeating
single bond-
double bond structure of α-parinaric acid distinguishes it structurally and chemically from the usual "methylene-interrupted" arrangement of
polyunsaturated fatty acids that have double-bonds and single bonds separated by a
methylene unit (−CH2−). Because of the
fluorescent properties conferred by the alternating double bonds, α-parinaric acid is commonly used as a molecular probe in the study of
biomembranes.
The biochemical mechanism by which α-parinaric acid is formed in the plant Impatiens balsamina was elaborated using techniques of
molecular biology. The enzyme responsible for the creation of the conjugated double bonds was identified using
expressed sequence tags, and called a "conjugase". This enzyme is related to the family of fatty acid
desaturase enzymes responsible for putting double bonds into fatty acids.[6]
Chemical synthesis
α-Parinaric acid may be
synthesized chemically using
α-linolenic acid as a starting compound. This synthesis enables the transformation of 1,4,7-octatriene methylene-interrupted cis double bonds of naturally occurring polyunsaturated fatty acids to 1,3,5,7-octatetraenes in high yield.[7] More recently (2008), Lee et al. reported a simple and efficient chemical synthesis using a modular design method called iterative cross-coupling.[8]
Uses
Membrane probes
Both the alpha and beta (all trans) isomers of parinaric acid are used as molecular probes of lipid-lipid interactions, by monitoring
phase transitions in bilayer lipid membranes.[9] α-Parinaric acid was shown to integrate normally into the
phospholipid bilayer of mammalian cells,[10] nervous tissue,[11] with minimal effects on the
biophysical properties of the membrane. Molecular interactions with neighboring membrane lipids will affect the fluorescence of α-parinaric acid in predictable ways, and the subsequent subtle changes in energy intensities may be measured
spectroscopically.
Researchers have put α-parinaric to good use in the study of membrane biophysics. For example, it was used to help establish the existence of a "fluidity gradient" across the membrane bilayer of some
tumor cells ― the inner monolayer of the membrane is less fluid than the outer monolayer.[12]
Lipid-protein interactions
α-Parinaric acid is also used as a
chromophore to study interactions between membrane proteins and lipids. Because of the similarity of α-parinaric acid to normal membrane lipids, it has minimal perturbing influence.[13] By measuring shifts in the
absorption spectrum, enhancement of α-parinaric acid
fluorescence, induced
circular dichroism, and energy transfer between
tryptophan amino acids in the protein and the bound chromophore, information may be gleaned about the molecular interactions between protein and lipid.[13] For example, this technique is used to investigate how fatty acids bind to
serum albumin (a highly abundant blood protein),[14][15] lipid transport processes including structural characterization of
lipoproteins,[16] and
phospholipid-transfer proteins.[17]
Clinical uses
The concentrations of fatty acids in blood serum or
plasma can be measured using α-parinaric acid, which will compete for binding sites on serum albumin.[18]
Food chemistry
α-Parinaric acid has been used to study the
hydrophobicity and
foaming characteristics of food proteins,[19][20] as well as the foam stability of beer.[21] In this latter research, α-parinaric acid was used in a fluorescent
assay to assess the lipid–binding potential of the proteins in the beer, as these proteins help protect beer from foam–reducing medium– and long–chain fatty acids.
Cytotoxic effects on tumor cells
α-Parinaric acid is
cytotoxic to human
leukemia cells in
cell culture at concentrations of 5
μM or less, by sensitizing the tumor cells to
lipid peroxidation, the process where
free radicals react with electrons from cell membrane lipids, resulting in cell damage.[22] It is similarly cytotoxic to malignant
gliomas grown in cell culture.[23] Normal (non-tumorous)
astrocytes grown in culture are far less sensitive to the cytotoxic effects of α-parinaric acid.[23] This preferential toxicity towards tumor cells is due to a differential regulation of
c-Jun N-terminal kinase, and
forkhead transcription factors between malignant and normal cells.[24]
References
^Tsujimoto M, Koyanagi H. (1933). New unsaturated acid in the kernel oil of "akarittom", "Parinarium laurinum". I. Kogyo Kagaku Zasshi36 (Suppl): 110–113.
^Hilditch TP et al. (1964). The Chemical Constitution of Natural Fats, Fourth Edition. pg. 253.
^Gunstone F.D. (1996). Fatty Acid and Lipid Chemistry. Berlin: Springer Verlag. p. 10.
ISBN0-8342-1342-7.
^Endo S, Zhiping G, Takagi T. (1991). Lipid components of seven species of Basidiomycotina and three species of Ascomycotina. Journal of the Japan Oil Chemists' Society40(7): 574–577.
^Spitzer V, Tomberg W, Zucolotto M. (1996). Identification of alpha-parinaric acid in the seed oil of Sebastiana brasiliensis Sprengel (Euphorbiaceae). Journal of the American Oil Chemists' Society73(5): 569–573.
^Keuper HJK, Klein RA, Spener F. (1985). Spectroscopic investigations on the binding site of bovine hepatic fatty-acid binding protein: evidence for the existence of a single binding site for two fatty-acid molecules. Chemistry and Physics of Lipids38(1–2): 159–174.
^Ben-Yashar V, Barenholz Y (November 1991). "Characterization of the core and surface of human plasma lipoproteins. A study based on the use of five fluorophores". Chem. Phys. Lipids. 60 (1): 1–14.
doi:
10.1016/0009-3084(91)90009-Z.
PMID1813177.
^Kasurinen J, van Paridon PA, Wirtz KW, Somerharju P (September 1990). "Affinity of phosphatidylcholine molecular species for the bovine phosphatidylcholine and phosphatidylinositol transfer proteins. Properties of the sn-1 and sn-2 acyl binding sites". Biochemistry. 29 (37): 8548–54.
doi:
10.1021/bi00489a007.
PMID2271538.
^Berde CB, Kerner JA, Johnson JD. (1980). Use of the conjugated polyene fatty-acid parinaric-acid in assaying fatty-acids in serum or plasma. Clinical Chemistry26(8): 1173–1177.
^Townsend A-A, Nakai S. (1983). Relationships between hydrophobicity and foaming characteristics of food proteins. Journal of Food Science48(2): 588–594.
^Zhu H, Damodaran S. (1994). Heat-induced conformational changes in whey protein isolate and its relation to foaming properties. Journal of Agricultural and Food Chemistry42(4): 846–855.
^Cooper DJ, Husband FA, Mills EN, Wilde PJ (December 2002). "Role of beer lipid-binding proteins in preventing lipid destabilization of foam". J. Agric. Food Chem. 50 (26): 7645–50.
doi:
10.1021/jf0203996.
PMID12475284.