Modelling of molybdopterin-dependent enzymes

Research output: ThesisDoctoral Thesis (compilation)

Abstract

The thesis deals with models for molybdopterin-dependent enzymes. Several model systems containing molybdenum or tungsten have been prepared and characterised, and their reactivity with oxygen atom acceptors and donors have been investigated. Oxygen atom transfer reactions involving oxomolybdenum bis-dithiolene complexes have been modelled using density functional calculations.

The first molybdenum(VI) complexes containing unperturbed <i>cis</i>-MoOS moieties, [MoOS(OSiPh<sub>3</sub>)<sub>2</sub>(L)] where L is bidentate nitrogen ligand, have been prepared as models for the xanthine oxidase family of mononuclear molybdenum enzymes. Spectroscopic measurements (<sup>1</sup>H-NMR, IR, XAS, and X-ray crystallography) confirm the integrity of the <i>cis</i>-MoOS moiety both in solution and in the solid state. When [MoOS(OSiPh<sub>3</sub>)<sub>2</sub>(Me<sub>4</sub>phen)] is reacted with PPh<sub>3</sub>, a good oxo acceptor, the complex does not undergo oxygen atom transfer but instead sulfur atom transfer to form Ph<sub>3</sub>PS and [Mo<sup>V</sup>OCl(OSiPh<sub>3</sub>)<sub>2</sub>(Me<sub>4</sub>phen)].

Two dioxotungsten(VI) complexes, [WO<sub>2</sub>(<sup>t</sup>BuL-NS)<sub>2</sub>] (<sup>t</sup>BuL-NS<sup>-</sup> = bis(4-tert-butylphenyl)-2-pyridylmethanethiolate(1-)) and [WO<sub>2</sub>(<sup>t</sup>BuL-NO)<sub>2</sub>] (<sup>t</sup>BuL-NO<sup>-</sup> = bis(4-tert-butylphenyl)-2-pyridylmethanolate(1-)) have been prepared as models for mononuclear tungsten enzymes. They have been spectroscopically and structurally characterised. The dioxomolybdenum(VI) analogue of [WO<sub>2</sub>(<sup>t</sup>BuL-NS)<sub>2</sub>] can be reduced to a mono-oxomolybdenum(IV) complex by phosphines and the molybdenum(IV) complex can reduce a range of oxygen atom donors. In contrast [WO<sub>2</sub>(<sup>t</sup>BuL-NS)<sub>2</sub>] does not undergo the corresponding oxygen atom transfer chemistry with phoshines, which may be attributed to a larger thermodymic barrier for reduction of tungsten(VI) compared to molybdenum(VI).

A dioxomolybdenum(VI) complex, [MoO<sub>2</sub>(L-O)]PF<sub>6</sub> (L-OH = N-(2-hydroxybenzyl)-N,N-bis(2-pyridylmethyl)amine) has been synthesised as a functional model for molybdenum oxotransferases. When the complex is reacted with phosphines in methanol, phosphine oxides are formed together with a red, air-sensitive, molybdenum complex. The identity of the red complex is not established but it is proposed to be a Mo(V) complex. The red molybdenum complex can be oxidised to [MoO<sub>2</sub>(L-O)]<sup>+</sup> by addition of oxygen atom donors such as DMSO or nitrate, thereby mimicking the activity of molybdenum oxotransferases. Attempts at isolating the red complex leads to the formation of a dark purple m-oxo-bridged Mo(V) dimer, [(L-O)OMo(m-O)MoO(L-O)]<sup>2+</sup>.

Computer modelling of the reaction of [MoO<sub>2</sub>(mnt)<sub>2</sub>]<sup>2-</sup> (mnt<sup>2-</sup> = 1,2-dicyano-ethylene-1,2-dithiolate(2-)) with hydrogen sulfite shows that the reaction mechanism is likely to involve a direct attack of the sulfur lone pair on one of the oxo ligands. The reaction proceeds <i>via</i> an oxygen atom transfer reaction where the substrate is oxidised to hydrogen sulfate, this is in good agreement with proposed mechanisms from other model systems and with the proposed mechanism for sulfite oxidase itself.

Density functional modelling of the reduction of Me<sub>3</sub>NO by [MoO(mnt)<sub>2</sub>]<sup>2-</sup> shows that the reaction proceeds via an intermediate containing coordinated Me<sub>3</sub>NO to formation of the products, [MoO<sub>2</sub>(mnt)<sub>2</sub>]<sup>2-</sup> and NMe<sub>3</sub>. In the final transition state, one of the Mo-S bonds of one mnt ligand is elongated due to the trans influence of the spectator oxo ligand. Modelling of the reduction of DMSO by [Mo(OCH<sub>3</sub>)(mnt)<sub>2</sub>]<sup>-</sup> shows that the methoxy group may be beneficial for the reaction in two ways: i) by lowering the energy of the products ([MoO(OCH<sub>3</sub>)(mnt)<sub>2</sub>]<sup>-</sup> and DMS) relative to the reactants, and ii) by offering an alternative reaction pathway with a twisted trigonal prismatic geometry in the transition state. This finding may have implications for the enzymes in the DMSO reductase family of mononuclear molybdenum enzymes where an amino acid residue (serine, cysteine or seleneocysteine) is found in the active site.

Details

Authors
  • Anders Thapper
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Inorganic Chemistry

Keywords

  • Inorganic chemistry, enzymes, transition state, intermediate, mechanism, molybdopterin, density functional theory, model systems, oxygen atom transfer, molybdenum, tungsten, Oorganisk kemi, Chemistry, Kemi
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2001 May 18
Publisher
  • Anders Thapper, Inorganic Chemistry 1, Chemical Center, Lund University
Print ISBNs91-628-4800-3
Publication statusPublished - 2001
Publication categoryResearch

Bibliographic note

Defence details Date: 2001-05-18 Time: 10:15 Place: Lecture hall D, Chemical Center External reviewer(s) Name: Garner, C. D. Title: Prof Affiliation: Nottingham, England --- Article: The Unperturbed Oxo-Sulfido Functional Group cis-MoVIOS Related to That in the Xanthine Oxidase Family of Molybdoenzymes: Synthesis, Structural Characterization, and Reactivity AspectsThapper, A.; Donahue, J. P.; Musgrave, K. B.; Willer, M. W.; Nordlander, E.; Hedman, B.; Hodgson, K. O.; Holm, R. H.Inorg. Chem. 1999, 38, 4104 Article: Synthesis and Structural Characterization of Two Tungsten(VI) Dioxo Complexes With N,O- and N,S-Coordinating LigandsThapper, A.; Balmes, O.; Lorber, C.; Svensson, P. H.; Holm, R. H.; Nordlander, E.Accepted for publication in Inorg. Chim. Acta Article: Synthesis, Characterization and Reactivity Studies of a Functional Model for Molybdenum OxotransferasesThapper, A.; Fryxelius, J.; Johansson, M. H.; Prestopino, F., Behrens, A.; Nordlander, E.Manuscript Article: Computer Modelling of the Oxygen-atom Transfer Reaction between Hydrogen Sulfite and a Molybdenum(VI) Dioxo Complex.Thapper A.; Deeth, R. J.; Nordlander. E.Inorg. Chem. 1999, 38, 1015 Article: A Density Functional Study of Oxygen Atom Transfer Reactions Between Biological Oxygen Atom Donors and Molybdenum(IV) bis-Dithiolene ComplexesThapper, A.; Deeth, R. J.; Nordlander, E.Submitted to Inorg. Chem. The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Inorganic chemistry (ceased) (LUR000010)