Role of the nonheme Fe(II) center in the biosynthesis of the plant hormone ethylene

Rocklin, Amy M.; Tierney, David L.; Kofman, Victoria; Brunhuber, Norbert M. W.; Hoffman, Brian M.; Christoffersen, Rolf E.; Reich, Norbert O.; Lipscomb, John D.; Que, Lawrence

doi:10.1073/pnas.96.14.7905

Cited by 111 publications

(128 citation statements)

References 43 publications

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“…The remaining two reducing equivalents required for the fourelectron reduction of oxygen are often provided by a co-substrate. The reducing cosubstrates used by various family members include α-ketoglutarate (in the αKG-dependent enzymes 3 ), tetrahydrobiopterin (in the pterin-dependent aromatic amino acid hydroxylases 5 ), reduced nicotinamides (in the Rieske dioxygenases and (S)-2-hydroxypropylphosphonic acid epoxidase 1 ), and ascorbic acid (in 1-aminocyclopropane 1-carboxylic acid oxidase 6 ). A few of the enzymes oxidize their substrates by four electrons and thus do not require a reducing co-substrate.…”

Section: Introductionmentioning

confidence: 99%

Non-Heme Fe(IV)–Oxo Intermediates

et al. 2007

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High-valent non-heme iron-oxo intermediates have been proposed for decades as the key intermediates in numerous biological oxidation reactions. In the last three years, the first direct characterization of such intermediates has been provided by studies of several αKG-dependent oxygenases that catalyze either hydroxylation or halogenation of their substrates. In each case, the Fe(IV)-oxo intermediate is implicated in cleavage of the aliphatic C-H bond to initiate hydroxylation or halogenation. The observation of non-heme Fe(IV)-oxo intermediates and Fe(II)-containing product(s) complexes with almost identical spectroscopic parameters in the reactions of two distantly related αKG-dependent hydroxylases suggests that members of this sub-family follow a conserved mechanism for substrate hydroxylation. In contrast, for the αKG-dependent non-heme-iron halogenase, CytC3, two distinct Fe(IV) complexes form and decay together, suggesting that they are in rapid equilibrium. The existence of two distinct conformers of the Fe site may be the key factor accounting for the divergence of the halogenase reaction from the more usual hydroxylation pathway after C-H cleavage. Distinct transformations catalyzed by other mononuclear non-heme enzymes are likely also to involve initial C-H-cleavage by Fe(IV)-oxo complexes, followed by diverging reactivities of the resulting Fe(III)-hydroxo/substrate radical intermediates.

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Section: Introductionmentioning

confidence: 99%

Non-Heme Fe(IV)–Oxo Intermediates

et al. 2007

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“…Both IPNS and ACCO are oxidases that utilize O 2 for substrate oxidation, which is proposed to occur through an initial H-atom abstraction. [5][6][7][8][9][10] Isopenicillin N-synthase is an enzyme found in fungi and bacteria that catalyzes the formation of isopenicillin N, a bicyclic precursor to the β lactam antibiotics including the penicillins and cephalosporins. 5-6 IPNS binds a tripeptide substrate δ-(L-α-aminoadipoyl)-L-cysteinyl-Dvaline (ACV) and performs a four electron oxidative ring closure, fully reducing one equivalent of O 2 to H 2 O and closing the β lactam and thiazolidine rings of isopenicillin N (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

VTVH-MCD and DFT Studies of Thiolate Bonding to {FeNO}⁷/{FeO₂}⁸ Complexes of Isopenicillin N Synthase: Substrate Determination of Oxidase versus Oxygenase Activity in Nonheme Fe Enzymes

et al. 2007

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Isopenicillin N synthase (IPNS) is a unique mononuclear non-heme Fe enzyme that catalyzes the four electron oxidative double ring closure of its substrate ACV. A combination of spectroscopic techniques including EPR, absorbance, circular dichroism (CD), magnetic CD, and variabletemperature, variable-field MCD (VTVH-MCD) were used to evaluate the geometric and electronic structure of the {FeNO} 7 complex of IPNS coordinated with the ACV thiolate ligand. Density Function Theory (DFT) calculations correlated to the spectroscopic data were used to generate an experimentally calibrated bonding description of the Fe-IPNS-ACV-NO complex. New spectroscopic features introduced by the binding of the ACV thiolate at 13,100 and 19,800 cm −1 are assigned as the NO π*(ip) → Fe d x2−y2 and S π → Fe d x2−y2 charge transfer (CT) transitions, respectively. Configuration interaction mixes S CT character into the NO π*(ip) → Fe d x2−y2 CT transition, which is observed experimentally from the VTVH-MCD data from this transition. Calculations on the hypothetical {FeO 2 } 8 complex of Fe-IPNS-ACV reveal that the configuration interaction present in the {FeNO} 7 complex results in an unoccupied frontier molecular orbital (FMO) with correct orientation and distal O character for H-atom abstraction from the ACV substrate. The energetics of NO/O 2 binding to Fe-IPNS-ACV were evaluated and demonstrate that charge donation from the ACV thiolate ligand renders the formation of the Fe III -superoxide complex energetically favorable, driving the reaction at the Fe center. This single center reaction allows IPNS to avoid the O 2 bridged binding generally invoked in other non-heme Fe enzymes that leads to oxygen insertion (i.e. oxygenase function) and determines the oxidase activity of IPNS.

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“…The reduced oxygen then undergoes O-O bond cleavage to yield a molecule of water and leave an Fe(IV)=O species as in the 2-oxoacid dioxygenases or tetrahydropterin-linked hydroxylases. Finally, the high valent iron species is used as a reagent to complete a second part of the reaction, and in doing so, accepts two more electrons to form the second molecule of water.Some well-studied examples of 2-His+Asp/Glu oxidases are isopenicillin N-synthase (IPNS) [79][80][81] , fosfomycin synthase (FOS) 82,83 , and 1-aminocyclopropane-1-carboxylate oxidase (ACCO), which catalyzes the formation of ethylene, a hormone in plants [84][85][86] . These enzymes activate O 2 and ultimately form water using either 4 electrons from substrate (IPNS), two from substrate and two from NADH (FOS), or two from substrate and 2 from ascorbate (ACCO).…”

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confidence: 99%

Versatility of biological non-heme Fe(II) centers in oxygen activation reactions

2008

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Oxidase and oxygenase enzymes allow the use of relatively unreactive O 2 in biochemical reactions. Many of the mechanistic strategies employed in nature for this key reaction are represented within the 2-His-1-carboxylate facial triad family of non-heme Fe(II) containing enzymes. The open face of the metal coordination sphere opposite the three endogenous ligands participates directly in the reaction chemistry. Here, data from several studies are presented showing that reductive O 2 activation within this family is initiated by substrate (and in some cases co-substrate or cofactor) binding, which then allows coordination of O 2 to the metal. From this starting point, both the O 2 activation process and the reactions with substrates diverge broadly. The reactive species formed in these reactions have been proposed to encompass four oxidation states of iron and all forms of reduced O 2 as well as several of the reactive oxygen species that derive from O-O bond cleavage.Dioxygen serves at least three quite different roles that profoundly impact aerobic life. The most commonly appreciated role is to serve as the terminal electron acceptor in processes such as oxidative phosphorylation that yield the central energy-rich molecules used throughout metabolism. The second, no less important role is to serve as the source for many of the oxygen atoms found in the essential molecules of biological systems such as steroid hormones, aromatic amino acids, neurotransmitters, signalling molecules, and regulatory factors 1 . Also, processes operating on a global scale, such as the recovery of the enormous quantities of carbon sequestered as lignin in plant life or the oxidation of the billions of tons of methane generated by anaerobes before it can enter the atmosphere, also involve oxygen incorporation from O 2 2 ,3 . On a more local scale, biodegradation of both aliphatic and aromatic toxic compounds often begins with the incorporation of oxygen 4 . The third, and least appreciated role played by dioxygen in aerobic organisms involves neither energy conversion nor oxygen incorporation. Rather, some enzymes can convert dioxygen to alternative forms that are, in effect, highly specialized reagents that are used to catalyze the synthesis of important biomolecules. An excellent example of the latter role for O 2 is the biosynthesis of penicillintype antibiotics 5,6 , which is discussed in more detail later in this review.Dioxygen is an attractive reagent for use in a biological system because its high potential reactivity is held in check by its molecular structure. The triplet ground state of O 2 that results from the presence of two unpaired electrons in degenerate molecular orbitals makes the direct reaction with singlet molecules, the spin-paired state of most potential reaction partners, a forbidden process 7 . The central question that has faced chemists and biochemists for the half Competing Interests StatementThe authors declare no competing financial interests. Of course, the answers to this question are of fundam...

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Role of the nonheme Fe(II) center in the biosynthesis of the plant hormone ethylene

Cited by 111 publications

References 43 publications

Non-Heme Fe(IV)–Oxo Intermediates

Non-Heme Fe(IV)–Oxo Intermediates

VTVH-MCD and DFT Studies of Thiolate Bonding to {FeNO}⁷/{FeO₂}⁸ Complexes of Isopenicillin N Synthase: Substrate Determination of Oxidase versus Oxygenase Activity in Nonheme Fe Enzymes

Versatility of biological non-heme Fe(II) centers in oxygen activation reactions

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Role of the nonheme Fe(II) center in the biosynthesis of the plant hormone ethylene

Cited by 111 publications

References 43 publications

Non-Heme Fe(IV)–Oxo Intermediates

Non-Heme Fe(IV)–Oxo Intermediates

VTVH-MCD and DFT Studies of Thiolate Bonding to {FeNO}7/{FeO2}8 Complexes of Isopenicillin N Synthase: Substrate Determination of Oxidase versus Oxygenase Activity in Nonheme Fe Enzymes

Versatility of biological non-heme Fe(II) centers in oxygen activation reactions

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VTVH-MCD and DFT Studies of Thiolate Bonding to {FeNO}⁷/{FeO₂}⁸ Complexes of Isopenicillin N Synthase: Substrate Determination of Oxidase versus Oxygenase Activity in Nonheme Fe Enzymes