Bis-Fe(IV): nature’s sniper for long-range oxidation

Geng, Jiafeng; Davis, Ian; Liu, Fange; Liu, Aimin

doi:10.1007/s00775-014-1123-8

Cited by 18 publications

(24 citation statements)

References 78 publications

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“…Even though bis -Fe(IV) MauG is electronically equivalent to the highly-reactive compound I of cytochrome P450 enzymes (an oxoferryl porphyrin cation radical), bis -Fe(IV) MauG is stable for several minutes at neutral pH [2, 8–10]. This unusual stability has been attributed to a type III charge-resonance phenomenon, by which the radical character of the high-valent species is shared over both hemes and with an intervening tryptophan residue [9, 10].…”

Section: Introductionmentioning

confidence: 99%

Radical Trapping Study of the Relaxation of bis-Fe(IV) MauG

Davis

Koto

Liu

2018

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The di-heme enzyme, MauG, utilizes a high-valent, charge-resonance stabilized bis-Fe(IV) state to perform protein radical-based catalytic chemistry. Though the bis-Fe(IV) species is able to oxidize remote tryptophan residues on its substrate protein, it does not rapidly oxidize its own residues in the absence of substrate. The slow return of bis-Fe(IV) MauG to its resting di-ferric state occurs via up to two intermediates, one of which has been previously proposed by Ma et al. (Biochem J 2016; 473:1769) to be a methionine-based radical in a recent study. In this work, we pursue intermediates involved in the return of high-valent MauG to its resting state in the absence of the substrate by EPR spectroscopy and radical trapping. The bis-Fe(IV) MauG is shown by EPR, HPLC, UV-Vis, and high-resolution mass spectrometry to oxidize the trapping agent, 5,5-dimethyl-1-pyrroline N-oxide (DMPO) to a radical species directly. Nitrosobenzene was also employed as a trapping agent and was shown to form an adduct with high-valent MauG species. The effects of DMPO and nitrosobenzene on the kinetics of the return to di-ferric MauG were both investigated. This work eliminates the possibility that a MauG-based methionine radical species accumulates during the self-reduction of bis-Fe(IV) MauG.

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Section: Introductionmentioning

confidence: 99%

Radical Trapping Study of the Relaxation of bis-Fe(IV) MauG

Davis

Koto

Liu

2018

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“…Each two‐electron oxidation cycle is suggested to be mediated by a unique bis‐Fe IV intermediate of MauG in which Heme 5C is in an oxyferryl state and Heme 6C is in a ferryl state with its two original axial ligands retained (Figure S2b) 15. 16…”

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Probing Bis‐Fe^IV MauG: Experimental Evidence for the Long‐Range Charge‐Resonance Model

2015

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The biosynthesis of tryptophan tryptophylquinone, a protein-derived cofactor, involves a longrange reaction mediated by a bis-Fe(IV) intermediate of a di-heme enzyme, MauG. Recently, a unique charge-resonance (CR) phenomenon was discovered in this intermediate, and a biological, long-distance CR model was proposed. This model suggests that the chemical nature of the bisFe(IV) species is not as simple as it appears; rather, it is composed of a collection of resonance structures in a dynamic equilibrium. Here, we experimentally evaluated the proposed CR model by introducing small molecules to, and measuring the temperature dependence of, bis-Fe(IV) MauG. Spectroscopic evidence was presented to demonstrate that the selected compounds increase the decay rate of the bis-Fe(IV) species via disrupting the equilibrium of the resonance structures that constitutes the proposed CR model. The results support this new CR model and bring a fresh concept to the classical CR theory. Keywords charge resonance; electronic structure; heme proteins; high-valence iron; near-infrared Since its first documentation by Brocklehurst and Badgers in 1968, [1] charge-resonance (CR) phenomena have been actively researched by organic chemists. [2] In a typical CR event, one-electron oxidation of an aromatic compound generates a cation radical which spontaneously associates with its neutral parent molecule or another molecule of the cation radical to form non-covalent "sandwich-like" dimeric complexes. The former scenario stabilizes an odd number of spin/charge in a mixed-valence species, (Π) 2•+ , and is classified as Type I CR; the latter one stabilizes an even number of spin/charge in a di-cation diradical, (Π 2 •+ ), and is classified as Type II CR. [3] Notably, unique electronic absorption bands in the near-infrared (NIR) region arise from resonance stabilization of spin/charge in the CR complexes and are thereby termed as CR bands (see Figure S1 for an MO-diagram illustration). [4][5][6][7] CR complexes represent the simplest intermolecular units that carry delocalized spin/charge. Investigation of these phenomena may provide the chemical basisCorrespondence to: Aimin Liu, Feradical@gsu.edu. Supporting information for this article is given via a link at the end of the document. HHS Public AccessAuthor manuscript Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript for electron transfer (ET), conductivity, and ferromagnetism in many organic materials and metalloporphyrin complexes.Like many classical chemical models adopted by nature, the utilization of CR in biological systems to transiently stabilize spin/charge was first suggested in a pair of chlorophyll molecules, known as the "special pair", in bacterial photosynthetic reaction centers. [8][9] Recently, a second example was revealed from a di-heme enzyme, MauG. [3] MauG is the terminal enzyme in the biogenesis pathway of a protein-derived cofactor, tryptophan tryptophylquinone (TTQ), [10] which is the catalytic center of methylamine dehydrogenase (MADH). [1...

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“…A phenylalanine residue occupies the corresponding position. Interestingly, RoxA is the only member in the bCcP superfamily that utilizes molecular oxygen instead of H 2 O 2 as the oxidizing agent [23, 25]. Thus, it is not surprising that the corresponding glutamate residue is absent in the distal pocket of Heme 5C in RoxA as the reaction is completely different from those catalyzed by other enzymes in the bCcP superfamily.…”

Section: Resultsmentioning

confidence: 99%

“…2B, a complete cycle of TTQ biosynthesis requires three rounds of H 2 O 2 activation, and the bis -Fe(IV) species is generated in each round and subsequently consumed to complete one of the three consecutive two-electron oxidation steps on preMADH [25, 27]. In fact, this unique nature of the MauG-catalyzed reaction ( i.e ., multiple rounds of H 2 O 2 activation are required for each turnover) pronouncedly magnified the effect of the Glu-to-Gln mutation on the success rate of the overall reaction.…”

Section: Resultsmentioning

confidence: 99%

“…2A) [22, 24]. MauG catalyzes the final stage of the biosynthesis of a protein-derived redox cofactor, tryptophan tryptophylquinone (TTQ), which functions as the catalytic center of methylamine dehydrogenase (MADH) [25]. During this cofactor biogenesis process, H 2 O 2 is utilized as an oxidant to modify two adjacent tryptophan residues of the precursor protein, preMADH, through a radical mechanism (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Heterolytic OO bond cleavage: Functional role of Glu113 during bis-Fe(IV) formation in MauG

Geng

Huo

Liu

2017

Journal of Inorganic Biochemistry

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The diheme enzyme MauG utilizes H2O2 to perform oxidative posttranslational modification on a protein substrate. A bis-Fe(IV) species of MauG was previously identified as a key intermediate in this reaction. Heterolytic cleavage of the O-O bond of H2O2 drives the formation of the bis-Fe(IV) intermediate. In this work, we tested a hypothesis that a glutamate residue, Glu113 in the distal pocket of the pentacoordinate heme of MauG, facilitates heterolytic O-O bond cleavage, thereby leading to bis-Fe(IV) formation. This hypothesis was proposed based on sequence alignment and structural comparison with other H2O2-utilizing hemoenzymes, especially those from the diheme enzyme superfamily that MauG belongs to. Electron paramagnetic resonance characterization of the reaction between MauG and H2O2 revealed that mutation of Glu113 inhibited heterolytic O-O bond cleavage, in agreement with our hypothesis. This result was further confirmed by the HPLC study in which an analog of H2O2, cumene hydroperoxide, was used to probe the pattern of O-O bond cleavage. Together, our data suggest that Glu113 functions as an acid-base catalyst to assist heterolytic O-O bond cleavage during the early stage of the catalytic reaction. This work advances our mechanistic understanding of the H2O2-activation process during bis-Fe(IV) formation in MauG.

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Bis-Fe(IV): nature’s sniper for long-range oxidation

Cited by 18 publications

References 78 publications

Radical Trapping Study of the Relaxation of bis-Fe(IV) MauG

Radical Trapping Study of the Relaxation of bis-Fe(IV) MauG

Probing Bis‐Fe^IV MauG: Experimental Evidence for the Long‐Range Charge‐Resonance Model

Heterolytic OO bond cleavage: Functional role of Glu113 during bis-Fe(IV) formation in MauG

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Bis-Fe(IV): nature’s sniper for long-range oxidation

Cited by 18 publications

References 78 publications

Radical Trapping Study of the Relaxation of bis-Fe(IV) MauG

Radical Trapping Study of the Relaxation of bis-Fe(IV) MauG

Probing Bis‐FeIV MauG: Experimental Evidence for the Long‐Range Charge‐Resonance Model

Heterolytic OO bond cleavage: Functional role of Glu113 during bis-Fe(IV) formation in MauG

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Probing Bis‐Fe^IV MauG: Experimental Evidence for the Long‐Range Charge‐Resonance Model