Mechanisms of O Activation by Mononuclear Non-Heme Iron Enzymes

Overview

Journal Biochemistry

Specialty Biochemistry

Date 2021 Jul 16

PMID 34266238

Citations 12

Authors

Edward I Solomon

Dory E DeWeese

Jeffrey T Babicz Jr

Affiliations

Soon will be listed here.

Abstract

Two major subclasses of mononuclear non-heme ferrous enzymes use two electron-donating organic cofactors (α-ketoglutarate or pterin) to activate O to form Fe═O intermediates that further react with their substrates through hydrogen atom abstraction or electrophilic aromatic substitution. New spectroscopic methodologies have been developed, enabling the study of the active sites in these enzymes and their oxygen intermediates. Coupled to electronic structure calculations, the results of these spectroscopies provide fundamental insight into mechanism. This Perspective summarizes the results of these studies in elucidating the mechanism of dioxygen activation to form the Fe═O intermediate and the geometric and electronic structure of this intermediate that enables its high reactivity and selectivity in product formation.

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References

Mitchell A, Dunham N, Martinie R, Bergman J, Pollock C, Hu K . Visualizing the Reaction Cycle in an Iron(II)- and 2-(Oxo)-glutarate-Dependent Hydroxylase. J Am Chem Soc. 2017; 139(39):13830-13836. PMC: 5852378. DOI: 10.1021/jacs.7b07374. View

Solomon E, Light K, Liu L, Srnec M, Wong S . Geometric and electronic structure contributions to function in non-heme iron enzymes. Acc Chem Res. 2013; 46(11):2725-39. PMC: 3905672. DOI: 10.1021/ar400149m. View

Andersen O, Stokka A, Flatmark T, Hough E . 2.0A resolution crystal structures of the ternary complexes of human phenylalanine hydroxylase catalytic domain with tetrahydrobiopterin and 3-(2-thienyl)-L-alanine or L-norleucine: substrate specificity and molecular motions related to substrate.... J Mol Biol. 2003; 333(4):747-57. DOI: 10.1016/j.jmb.2003.09.004. View

Wong S, Srnec M, Matthews M, Liu L, Kwak Y, Park K . Elucidation of the Fe(IV)=O intermediate in the catalytic cycle of the halogenase SyrB2. Nature. 2013; 499(7458):320-3. PMC: 4123442. DOI: 10.1038/nature12304. View

Jaffe E, Stith L, Lawrence S, Andrake M, Dunbrack Jr R . A new model for allosteric regulation of phenylalanine hydroxylase: implications for disease and therapeutics. Arch Biochem Biophys. 2013; 530(2):73-82. PMC: 3580015. DOI: 10.1016/j.abb.2012.12.017. View

Iyer S, Tidemand K, Babicz Jr J, Jacobs A, Gee L, Haahr L . Direct coordination of pterin to Fe enables neurotransmitter biosynthesis in the pterin-dependent hydroxylases. Proc Natl Acad Sci U S A. 2021; 118(15). PMC: 8053929. DOI: 10.1073/pnas.2022379118. View

Goudarzi S, Iyer S, Babicz Jr J, Yan J, Peters G, Christensen H . Evaluation of a concerted vs. sequential oxygen activation mechanism in α-ketoglutarate-dependent nonheme ferrous enzymes. Proc Natl Acad Sci U S A. 2020; 117(10):5152-5159. PMC: 7071927. DOI: 10.1073/pnas.1922484117. View

Spector S, SJOERDSMA A, UDENFRIEND S . BLOCKADE OF ENDOGENOUS NOREPINEPHRINE SYNTHESIS BY ALPHA-METHYL-TYROSINE, AN INHIBITOR OF TYROSINE HYDROXYLASE. J Pharmacol Exp Ther. 1965; 147:86-95. View

Hillas P, FITZPATRICK P . A mechanism for hydroxylation by tyrosine hydroxylase based on partitioning of substituted phenylalanines. Biochemistry. 1996; 35(22):6969-75. DOI: 10.1021/bi9606861. View

10.

Srnec M, Solomon E . Frontier Molecular Orbital Contributions to Chlorination versus Hydroxylation Selectivity in the Non-Heme Iron Halogenase SyrB2. J Am Chem Soc. 2017; 139(6):2396-2407. PMC: 5310988. DOI: 10.1021/jacs.6b11995. View

11.

Hegg E, Que Jr L . The 2-His-1-carboxylate facial triad--an emerging structural motif in mononuclear non-heme iron(II) enzymes. Eur J Biochem. 1998; 250(3):625-9. DOI: 10.1111/j.1432-1033.1997.t01-1-00625.x. View

12.

England J, Guo Y, Farquhar E, Young Jr V, Munck E, Que Jr L . The crystal structure of a high-spin oxoiron(IV) complex and characterization of its self-decay pathway. J Am Chem Soc. 2010; 132(25):8635-44. PMC: 2903234. DOI: 10.1021/ja100366c. View

13.

Schofield C, Zhang Z . Structural and mechanistic studies on 2-oxoglutarate-dependent oxygenases and related enzymes. Curr Opin Struct Biol. 1999; 9(6):722-31. DOI: 10.1016/s0959-440x(99)00036-6. View

14.

Liu L, Bell 3rd C, Wong S, Wilson S, Kwak Y, Chow M . Definition of the intermediates and mechanism of the anticancer drug bleomycin using nuclear resonance vibrational spectroscopy and related methods. Proc Natl Acad Sci U S A. 2010; 107(52):22419-24. PMC: 3012509. DOI: 10.1073/pnas.1016323107. View

15.

Bell 3rd C, Wong S, Xiao Y, Klinker E, Tenderholt A, Smith M . A combined NRVS and DFT study of Fe(IV)=O model complexes: a diagnostic method for the elucidation of non-heme iron enzyme intermediates. Angew Chem Int Ed Engl. 2008; 47(47):9071-4. PMC: 2662738. DOI: 10.1002/anie.200803740. View

16.

Sturhahn , Toellner , Alp , Zhang , AnDo , Yoda . Phonon density of states measured by inelastic nuclear resonant scattering. Phys Rev Lett. 1995; 74(19):3832-3835. DOI: 10.1103/PhysRevLett.74.3832. View

17.

Komor A, Rivard B, Fan R, Guo Y, Que Jr L, Lipscomb J . Mechanism for Six-Electron Aryl-N-Oxygenation by the Non-Heme Diiron Enzyme CmlI. J Am Chem Soc. 2016; 138(23):7411-21. PMC: 4914076. DOI: 10.1021/jacs.6b03341. View

18.

Simurdiak M, Lee J, Zhao H . A new class of arylamine oxygenases: evidence that p-aminobenzoate N-oxygenase (AurF) is a di-iron enzyme and further mechanistic studies. Chembiochem. 2006; 7(8):1169-72. DOI: 10.1002/cbic.200600136. View

19.

Falnes P, Klungland A, Alseth I . Repair of methyl lesions in DNA and RNA by oxidative demethylation. Neuroscience. 2006; 145(4):1222-32. DOI: 10.1016/j.neuroscience.2006.11.018. View

20.

Martinez S, Hausinger R . Catalytic Mechanisms of Fe(II)- and 2-Oxoglutarate-dependent Oxygenases. J Biol Chem. 2015; 290(34):20702-20711. PMC: 4543632. DOI: 10.1074/jbc.R115.648691. View