The Mechanism of Lipoxygenases

Nelson, Mark J.; Seitz, Steven P.

doi:10.1007/978-1-4613-9783-0_6

Cited by 9 publications

(21 citation statements)

References 124 publications

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“…The observed reactivity resembles the generally accepted enzymatic mechanism of lipoxygenases in which a mononuclear nonheme Fe III −OH abstracts a hydrogen atom to form a Fe II −H 2 O species. 16 Hydrogen atom abstraction reactivity from ferric species has furthermore been demonstrated using ferric alkoxide and hydroxide model complexes. 17 Heating of 6 under identical conditions did not result in decay of the Fe III species, and a temperature of 85 °C was necessary to induce HAA from cyclohexadiene.…”

Section: Methodsmentioning

confidence: 99%

Ground State and Excited State Tuning in Ferric Dipyrrin Complexes Promoted by Ancillary Ligand Exchange

2017

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Three ferric dipyrromethene complexes featuring different ancillary ligands were synthesized by one electron oxidation of ferrous precursors. Four-coordinate iron complexes of the type (ArL)FeX2 [ArL = 1,9-(2,4,6-Ph3C6H2)2-5-mesityldipyrromethene] with X = Cl or tBuO were prepared and found to be high-spin (S = 5/2), as determined by superconducting quantum interference device magnetometry, electron paramagnetic resonance, and 57Fe Mössbauer spectroscopy. The ancillary ligand substitution was found to affect both ground state and excited properties of the ferric complexes examined. While each ferric complex displays reversible reduction and oxidation events, each alkoxide for chloride substitution results in a nearly 600 mV cathodic shift of the FeIII/II couple. The oxidation event remains largely unaffected by the ancillary ligand substitution and is likely dipyrrin-centered. While the alkoxide substituted ferric species largely retain the color of their ferrous precursors, characteristic of dipyrrin-based ligand-to-ligand charge transfer (LLCT), the dichloride ferric complex loses the prominent dipyrrin chromophore, taking on a deep green color. Time-dependent density functional theory analyses indicate the weaker-field chloride ligands allow substantial configuration mixing of ligand-to-metal charge transfer into the LLCT bands, giving rise to the color changes observed. Furthermore, the higher degree of covalency between the alkoxide ferric centers is manifest in the observed reactivity. Delocalization of spin density onto the tert-butoxide ligand in (ArL)FeCl(OtBu) is evidenced by hydrogen atom abstraction to yield (ArL)FeCl and HOtBu in the presence of substrates containing weak C–H bonds, whereas the chloride (ArL)FeCl2 analogue does not react under these conditions.

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Section: Methodsmentioning

confidence: 99%

Ground State and Excited State Tuning in Ferric Dipyrrin Complexes Promoted by Ancillary Ligand Exchange

2017

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“…Non-heme manganese and iron complexes with terminal hydroxo or oxo ligands are widely considered as the catalysts to mediate the transfer of hydrogen atoms in metalloproteins. 158 To investigate the transfer of hydrogen atoms in the synthetic model systems, Gupta and Borovik prepared non-heme manganese complexes [M I I I / I I H 3 1 (OH)] − / 2 − and [M III H 3 1(O)] 2− (M III/II = Mn and Fe, H 3 1 is a tripodal ligand, tris[(N′-tertbutylurealylato)-N-ethyl]aminato) (Figure 4). 159 Similar to the Cr(IV)−oxo complex used by Theopold (Figure 2), [Mn III H 3 1(O)] 2− 10 and [Fe III H 3 1(O)] 2− 11 reacted with organic substrates containing C−H bonds weaker than 80 kcal mol −1 , including 9,10-dihydroanthracene and 1,4-cyclohexadiene, to produce the corresponding dehydrogenated products.…”

Section: Understanding C−h Activation Based On Bond Energeticsmentioning

confidence: 99%

The Essential Role of Bond Energetics in C–H Activation/Functionalization

et al. 2017

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The most fundamental concepts in chemistry are structure, energetics, reactivity and their inter-relationships, which are indispensable for promoting chemistry into a rational science. In this regard, bond energy, the intrinsic determinant directly related to structure and reactivity, should be most essential in serving as a quantitative basis for the design and understanding of organic transformations. Although C-H activation/functionalization have drawn tremendous research attention and flourished during the past decades, understanding the governing rules of bond energetics in these processes is still fragmentary and seems applicable only to limited cases, such as metal-oxo-mediated hydrogen atom abstraction. Despite the complexity of C-H activation/functionalization and the difficulties in measuring bond energies both for the substrates and intermediates, this is definitely a very important issue that should be more generally contemplated. To this end, this review is rooted in the energetic aspects of C-H activation/functionalization, which were previously rarely discussed in detail. Starting with a concise but necessary introduction of various classical methods for measuring heterolytic and homolytic energies for C-H bonds, the present review provides examples that applied the concept and values of C-H bond energy in rationalizing the observations associated with reactivity and/or selectivity in C-H activation/functionalization.

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“…Lipoxygenases, which catalyze the oxidation of unsaturated fatty acids containing the cis,cis-1,4pentadiene moiety to the corresponding 1-hydroperoxy-trans,cis-2,4-diene, are widely found among plants and animals. 2 The mammalian enzymes typically act on arachidonic acid to produce hydroperoxides that are precursors to leukotrienes and lipoxins, compounds that have been implicated as potential mediators of inflammation. For this reason, many studies have focused on finding inhibitors of mammalian lipoxygenases as anti-inflammatory drugs.…”

Section: Lipoxygenasesmentioning

confidence: 99%

“…The details of how lipoxygenase oxidizes fatty acids have been a matter of debate. 2 Discussion centers around the role of the Fe(III) center in the catalytic mechanism. One mechanism (Figure 13a) proposes that the Fe(III) center reacts with linoleic acid to abstract the C-11 hydrogen, generating an Fe(II) center and the pentadienyl radical, which then reacts with O 2 .…”

Section: Lipoxygenasesmentioning

confidence: 99%

“…1 Lipoxygenases oxidize unsaturated fatty acids into precursors of leukotrienes and lipoxins and are potential targets for anti-inflammatory drugs. 2 Other enzymes like isopenicillin N synthase (IPNS) 3 and deacetoxycephalosporin C synthase, 4 an R-keto acid-dependent enzyme, are important in the biosynthesis of the β-lactam antibiotics such as penicillin and cephalosporin. Other R-keto acid-dependent enzymes participate in posttranslational modification of amino acids in collagen 5 and blood-clotting factors.…”

Section: Introductionmentioning

confidence: 99%

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