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Reactions of non-heme iron active si...

Stanford University.

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Reactions of non-heme iron active sites with dioxygen: Mechanistic insights through spectroscopy, kinetics and computations.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Reactions of non-heme iron active sites with dioxygen: Mechanistic insights through spectroscopy, kinetics and computations./
Author:	Chow, Marina Su Yin.
Description:	183 p.
Notes:	Adviser: Edward I. Solomon.
Contained By:	Dissertation Abstracts International69-05B.
Subject:	Chemistry, Inorganic. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3313556
ISBN:	9780549623960

Reactions of non-heme iron active sites with dioxygen: Mechanistic insights through spectroscopy, kinetics and computations.
Chow, Marina Su Yin.

Reactions of non-heme iron active sites with dioxygen: Mechanistic insights through spectroscopy, kinetics and computations. - 183 p.

Adviser: Edward I. Solomon.

Thesis (Ph.D.)--Stanford University, 2008.

Bleomycin is an antibiotic used in cancer chemotherapy for its ability to achieve both single- and double-strand cleavage of DNA through abstraction of the deoxyribose C4'-H.

ISBN: 9780549623960Subjects--Topical Terms:

517253
Chemistry, Inorganic.

Reactions of non-heme iron active sites with dioxygen: Mechanistic insights through spectroscopy, kinetics and computations.
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020 $a 9780549623960
035 $a (UMI)AAI3313556
035 $a AAI3313556
040 $a UMI $c UMI
100 1 $a Chow, Marina Su Yin. $3 1043557
245 1 0 $a Reactions of non-heme iron active sites with dioxygen: Mechanistic insights through spectroscopy, kinetics and computations.
300 $a 183 p.
500 $a Adviser: Edward I. Solomon.
500 $a Source: Dissertation Abstracts International, Volume: 69-05, Section: B, page: 2992.
502 $a Thesis (Ph.D.)--Stanford University, 2008.
520 $a Bleomycin is an antibiotic used in cancer chemotherapy for its ability to achieve both single- and double-strand cleavage of DNA through abstraction of the deoxyribose C4'-H.
520 $a This study provides experimental and theoretical evidence for direct H-atom abstraction by ABLM and proposes an attractive mechanism for the role of ABLM in double strand cleavage.
520 $a Mononuclear non-heme ferrous enzymes catalyze a wide variety of biologically-important reactions involving O2. This thesis focuses on the understanding of the mechanism of these O2 reactions at the non-heme ferrous sites in Bleomycin and Tyrosine Hydroxylase, and describes the methods by which this is achieved.
520 $a DNA binding to FeIIBLM significantly perturbs the Fe II active site, resulting in a change in intensity ratio of the d→d transitions and a decrease in excited-state orbital splitting (Delta 5Eg). Although this effect is somewhat dependent on length and composition of the oligonucleotide, it is not correlated to the presence of a 5'-G-pyrimidine-3' cleavage site. No effect is observed on the charge-transfer transitions, indicating that the H-bonding recognition between the pyrimidine and guanine base does not perturb Fe-pyrimidine back-bonding. Azide binding studies indicate that FeIIBLM bound to either oligomer has the same affinity for N3-. Parallel studies of BLM structural derivatives indicate that FeIIiso-PEPLM, in which the carbamoyl group is shifted on the mannose sugar, forms the same DNA-bound species as FeIIBLM. In contrast, FeIIDP-PEPLM, in which the beta-aminoalanine group is absent, forms a new species upon DNA binding.
520 $a Activated bleomycin (ABLM), a low-spin FeIII-OOH complex, is the last intermediate detected prior to DNA cleavage following hydrogen-atom abstraction from the C-4' of a deoxyribose sugar moiety. The mechanism of this C-H bond cleavage reaction and the nature of the active oxidizing species are still open issues. We have used kinetic measurements in combination with density functional calculations to study the reactivity of ABLM and the mechanism of the initial attack on DNA.
520 $a Our results show that the ABLM+DNA reaction is appreciably faster, and has a different kinetic isotope effect and a lower Arrhenius activation energy than ABLM decay. In the ABLM reaction with DNA, the small normal kH/k D is attributed, through DFT vibrational analysis of reactant and transition state frequencies, to a secondary solvent effect, and the lower Ea is attributed to the weaker bond involved in the abstraction reaction (C-H for DNA, and N-H for the decay in the absence of DNA). The DNA-dependence of the ABLM reaction indicates that DNA is involved in the transition state for ABLM decay, and thus reacts directly with BLM-FeIII-OOH instead of its decay product.
520 $a Tyrosine Hydroxylase (TH) is a pterin-dependent non-heme iron enzyme that catalyzes the hydroxylation of L-tyr to L-DOPA in the rate-limiting step of catecholamine neurotransmitter biosynthesis. When the FeII site is 6C, the two-electron reduction of O 2 to peroxide by FeII and pterin is favored over individual one-electron reactions. When the FeII is 5C, this O2 reaction is accelerated by at least 2 orders of magnitude. Comparison of the kinetics of WT TH, which produces FeIV=O + 4a-OH-pterin, and E332A TH, which does not, shows that the E332 residue plays an important role in directing the protonation of the bridged FeII-OO-pterin intermediate in WT to productively form FeIV=O, which is responsible for hydroxylating L-tyr to L-DOPA.
520 $a Using thiolate (RS-), sulfenate (RSO-) and sulfinate (RSO2-) ligated model complexes to provide benchmark spectral parameters, the results show that the S K-edge XAS is sensitive to the oxidation state of S-containing ligands and that the spectrum of the RSO- species changes upon protonation as the S-O bond is elongated (by &sim;0.1 A). These signature features are used to identify the three cysteine residues coordinated to the low-spin Fe III in the active site of NHase as CysS-, CysSOH and CysSO2- in both the NO-bound inactive form and in the photolyzed active form. These results are correlated to geometry optimized DFT calculations. The pre-edge region of the XAS spectrum is sensitive to the Zeff of the Fe and reveals that the Fe in {FeNO}6 NHase species has a very similar Zeff to that of its photolyzed FeIII counterpart. DFT calculations reveal that this results from the strong pi back-bonding in to the pi* anti-bonding orbital of NO, which shifts significant charge from the formally t2 6 low-spin metal to the coordinated NO. (Abstract shortened by UMI.)
590 $a School code: 0212.
650 4 $a Chemistry, Inorganic. $3 517253
690 $a 0488
710 2 $a Stanford University. $3 754827
773 0 $t Dissertation Abstracts International $g 69-05B.
790 $a 0212
790 1 0 $a Solomon, Edward I., $e advisor
791 $a Ph.D.
792 $a 2008
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3313556