A series of stereospecifically labeled polyunsaturated fatty acids were prepared by biosynthesis from [S-DR- 3H]and [S-~S-~Hlstearic acids.The labeled stearic acids were synthesized by a novel scheme employing readily available alkyne and aldehyde starting materials.The stereochemical purity of the prochiral tritium labels was judged to be >99%, as determined by analysis of the octadec-l-yn-S(R)-and S(S)-ol intermediates in the synthesis.Previously, the labeled arachidonic acids were used to investigate the stereoselectivity of hydrogen abstraction in the biosynthesis of leukotriene epoxides.We have now investigated the selectivity of hydrogen abstraction in a chemical synthesis of 14,15-leukotriene (LT) A4 from mixtures of [3-I4C]-and either [lo-or [~O-L~-"H]~B(S)-HPETE methyl esters.Reaction with either chirally labeled precursor led to 70- 95% retention of 'H relative to 14C in the 14,lB-LTA4 and 10-2-14,lB-LTA4 products after purification by high performance liquid chromatography.The 15dienone obtained from this reaction was consistently enriched in 3H relative to 14C after isolation and purification.Evidence was obtained to indicate that the majority of the 'H in the products was retained in its original location and configuration.These results indicate that the biomimetic chemical reaction is stereorandom with respect to hydrogen loss from carbon 10 and that, in contrast to the reaction as it occurs in leukocytes and platelets, in the chemical model the reaction begins by decomposition of the hydroperoxide group, with hydrogen loss from carbon 10 occurring as a late or final step.Studies on leukotriene biosynthesis in leukocytes and platelets have revealed that, during the course of leukotriene A, and 14,15-leukotriene A4 formation from their respective hy-
Both jasmonic acid (JA) and its methyl ester, methyl jasmonate (MeJA), are thought to be significant components of the signaling pathway regulating the expression of plant defense genes in response to various stresses. JA and MeJA are plant lipid derivatives synthesized from [alpha]-linolenic acid by a lipoxygenase-mediated oxygenation leading to 13-hydroperoxylinolenic acid, which is subsequently transformed by the action of allene oxide synthase (AOS) and additional modification steps. AOS converts lipoxygenase-derived fatty acid hydroperoxide to allene epoxide, which is the precursor for JA formation. Overexpression of flax AOS cDNA under the regulation of the cauliflower mosaic virus 35S promoter in transgenic potato plants led to an increase in the endogenous level of JA. Transgenic plants had six- to 12-fold higher levels of JA than the nontransformed plants. Increased levels of JA have been observed when potato and tomato plants are mechanically wounded. Under these conditions, the proteinase inhibitor II (pin2) genes are expressed in the leaves. Despite the fact that the transgenic plants had levels of JA similar to those found in nontransgenic wounded plants, pin2 genes were not constitutively expressed in the leaves of these plants. Transgenic plants with increased levels of JA did not show changes in water state or in the expression of water stress-responsive genes. Furthermore, the transgenic plants overexpressing the flax AOS gene, and containing elevated levels of JA, responded to wounding or water stress by a further increase in JA and by activating the expression of either wound- or water stress-inducible genes. Protein gel blot analysis demonstrated that the flax-derived AOS protein accumulated in the chloroplasts of the transgenic plants.
To identify factors affecting the efficacy of indomethacin in closing symptomatic patent ductus arteriosus (PDA), we studied the pharmacokinetics of intravenous indomethacin, 0.2 mg per kilogram of body weight, in 35 premature infants with symptomatic PDA. Most infants responded to indomethacin with ductus constriction. Indomethacin infusions that were ineffective (seven doses in six patients) were associated with significantly faster clearance, a shorter half-life, and lower plasma levels (p less than 0.05). Six infants had later reopening of the ductus. All six received indomethacin in the first postnatal week; they could not be distinguished from infants with permanent closure on the basis of indomethacin kinetics, but they were of low gestational age. There was a 20-fold variation in plasma indomethacin levels 24 hours after a dose. In view of this variation and the relation between plasma levels and ductus constriction, we suggest that measurement of the plasma indomethacin level could be of value in infants with no response to a first dose.
Abstract Three distinct pairs of HETEs can be distinguished on the basis of their UV spectra. We used hydroxy‐linoleates (hydroxy‐octadeca‐ cis‐trans ‐dienoates) as a base for comparisons; both the 9‐ and 13‐hydroxy isomers have identical chromophores with λ max near 234 nm. The presence of a double bond three carbons removed from the conjugated diene (the chromophore of 9‐ and 11‐HETE) causes a shift in the observed λ max to near 235 nm. A double bond β to the chromophore (5‐ and 15‐HETE) gives a further shift of 1.5 nm, giving a λ max between 236–236.5 nm. With double bonds in both these positions (8‐ and 12‐HETE), the λ max is observed near 237 nm. It is apparent that the exact λ max of the cis‐trans diene chromophore is influenced in a consistent way by the adjacent methylene interrupted cis double bonds.
The cyclopentane core is ubiquitous among a large number of biologically relevant natural products. Cyclopentenones have been shown to be versatile intermediates for the stereoselective preparation of highly substituted cyclopentane derivatives. Allene oxides are oxygenated fatty acids which are involved in the pathways of cyclopentenone biosynthesis in plants and marine invertebrates; however, their cyclization behavior is not well understood. Recent work by Brash and co-workers (J. Biol. Chem., 2013, 288, 20797) revealed an unusual cyclization property of the 9(S)-HPODE-derived allene oxides: the previously unreported 10Z-isomer cyclizes to a cis-dialkylcyclopentenone in hexane/isopropyl alcohol (100 : 3, v/v), but the known 10E-isomer does not yield cis-cyclopentenone under the same conditions. The mechanism for cyclization has been investigated for unsubstituted and methyl substituted vinyl allene oxide using a variety of methods including CASSCF, ωB97xD, and CCSD(T) and basis sets up to cc-pVTZ. The lowest energy pathway proceeds via homolytic cleavage of the epoxide ring, formation of an oxyallyl diradical, which closes readily to a cyclopropanone intermediate. The cyclopropanone opens to the requisite oxyallyl which closes to the experimentally observed product, cis-cyclopentenone. The calculations show that the open shell, diradical pathway is lower in energy than the closed shell reactions of allene oxide to cyclopropanone, and cyclopropanone to cyclopentenone.
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