A short history of heme dioxygenases: rise, fall and rise again

Raven, E.L.

doi:10.1007/s00775-016-1412-5

Cited by 59 publications

(50 citation statements)

References 110 publications

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“…5–12 In the past decade, mechanistic studies have focused on the differentiation between a stepwise (through an epoxyindole) or a concerted (through a dioxetane) oxygen insertion mechanism. Recently, compelling evidence from multiple groups supports the stepwise oxygen insertion mechanism.…”

Section: Introductionmentioning

confidence: 99%

Stepwise O-Atom Transfer in Heme-Based Tryptophan Dioxygenase: Role of Substrate Ammonium in Epoxide Ring Opening

et al. 2018

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Heme-based tryptophan dioxygenases are established immunosuppressive metalloproteins with significant biomedical interest. Here, we synthesized two mechanistic probes to specifically test if the α-amino group of the substrate directly participates in a critical step of the O atom transfer during catalysis in human tryptophan 2,3-dioxygenase (TDO). Substitution of the nitrogen atom of the substrate to a carbon (probe 1) or oxygen (probe 2) slowed the catalytic step following the first O atom transfer such that transferring the second O atom becomes less likely to occur, although the dioxygenated products were observed with both probes. A monooxygenated product was also produced from probe 2 in a significant quantity. Analysis of this new product by HPLC coupled UV–vis spectroscopy, high-resolution mass spectrometry, 1H NMR, 13C NMR, HSQC, HMBC, and infrared (IR) spectroscopies concluded that this monooxygenated product is a furoindoline compound derived from an unstable epoxyindole intermediate. These results prove that small molecules can manipulate the stepwise O atom transfer reaction of TDO and provide a showcase for a tunable mechanism by synthetic compounds. The product analysis results corroborate the presence of a substrate-based epoxyindole intermediate during catalysis and provide the first substantial experimental evidence for the involvement of the substrate α-amino group in the epoxide ring-opening step during catalysis. This combined synthetic, biochemical, and biophysical study establishes the catalytic role of the α-amino group of the substrate during the O atom transfer reactions and thus represents a substantial advance to the mechanistic comprehension of the heme-based tryptophan dioxygenases.

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Section: Introductionmentioning

confidence: 99%

Stepwise O-Atom Transfer in Heme-Based Tryptophan Dioxygenase: Role of Substrate Ammonium in Epoxide Ring Opening

et al. 2018

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“…The hepatic hemoprotein tryptophan 2,3-dioxygenase (TDO; previously aka tryptophan pyrrolase) is the rate-limiting enzyme in the irreversible oxidative breakdown of the essential amino acid, L-tryptophan (L-Trp) to N-formylkynurenine (NFK) (1)(2)(3)(4)(5)(6)(7). This reaction is also carried out by indoleamine 2,3-dioxygenase (IDO) albeit with a much lesser substrate selectivity, as it also oxidizes many other indoles (4)(5)(6)8). Unlike TDO, which is relatively selectively localized in liver and brain, IDO exhibits a much broader tissue distribution (4)(5)(6)8).…”

Section: Introductionmentioning

confidence: 99%

“…This reaction is also carried out by indoleamine 2,3-dioxygenase (IDO) albeit with a much lesser substrate selectivity, as it also oxidizes many other indoles (4)(5)(6)8). Unlike TDO, which is relatively selectively localized in liver and brain, IDO exhibits a much broader tissue distribution (4)(5)(6)8). The product generated from either TDO-or IDO-mediated Trp/indole-breakdown is then further converted into various physiologically and pathologically relevant derivatives, including the cofactor NAD + (4)(5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Human hepatic tryptophan 2,3-dioxygenase ubiquitin-dependent protein degradation: The critical role of its exosite as the molecular lynchpin of its substrate-mediated protein stabilization

Kim

Liu

Wang

et al. 2019

Preprint

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Hepatic tryptophan 2,3-dioxygenase (TDO) is a cytoplasmic homotetrameric hemoprotein and the rate-limiting enzyme in the irreversible degradation of the essential amino acid L-tryptophan (L-Trp) to N-formylkynurenine, thus controlling the flux of L-Trp into its serotonergic and kynureninic/NAD pathways. TDO has long been recognized to be substrate-inducible via protein stabilization, but the molecular mechanism of this stabilization has remained elusive. Recent elucidation of human TDO (hTDO) crystal structure has identified a high-affinity (Kd ≈ 0.5 µM)Trp-binding exosite in each of its 4 monomeric subunits. Mutation of the Glu105, Trp208 and Arg211 comprising this exosite not only abolished the high-affinity L-Trp binding, but also accelerated the ubiquitin-dependent proteasomal degradation of hTDO. We have further characterized this hTDO degradation by documenting that its ubiquitination by gp78/AMFR and CHIP E2/E3 ligase complexes occurs on external Lys-residues within or vicinal to acidic Asp/Glu and phosphorylated pSer/pThr (DEpSpT)-clusters. Furthermore, we have identified the unstructured hTDO N-and C-termini as imparting relatively high proteolytic instability, as their deletion (DNC) markedly prolonged hTDO t1/2. Additionally, although previous studies reported that upon hepatic heme-depletion, the heme-free apoTDO turns over with a t1/2 ≈ 2.2 h relative to the t1/2 of 7.7 h of holoTDO, mutating the axial heme-ligating His328 to Ala has the opposite effect of prolonging hTDO t1/2. Most importantly, introducing the exosite mutation into the DNC-deleted or H328A-mutant completely abolished their prolonged half-lives irrespective of L-Trp presence or absence, thereby revealing that the exosite is the molecular lynchpin that defines L-Trpmediated TDO induction via protein stabilization.

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“…Iron-dependent dioxygenases can employ either heme and nonheme cofactors in the active site. The heme-dependent dioxygenases are discussed in our recent review [5] and by Raven in this volume [6] and thus will not be included here.…”

Section: Introductionmentioning

confidence: 99%

Oxygen activation by mononuclear nonheme iron dioxygenases involved in the degradation of aromatics

Wang

Liu

2017

J Biol Inorg Chem

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Molecular oxygen is utilized in numerous metabolic pathways fundamental for life. Mononuclear nonheme iron-dependent oxygenase enzymes are well-known for their involvement in some of these pathways, activating O2 so that oxygen atoms can be incorporated into their primary substrates. These reactions often initiate pathways that allow organisms to use stable organic molecules as sources of carbon and energy for growth. From the myriad of reactions in which these enzymes are involved, this perspective recounts the general mechanisms of aromatic dihydroxylation and oxidative ring cleavage, both of which are ubiquitous chemical reactions found in life-sustaining processes. The organic substrate provides all four electrons required for oxygen activation and insertion in the reactions mediated by extradiol and intradiol ring-cleaving catechol dioxygenases. In contrast, two of the electrons are provided by NADH in the cis-dihydroxylation mechanism of Rieske dioxygenases. The catalytic nonheme Fe center, with the aid of active site residues, facilitates these electron transfers to O2 as key elements of the activation processes. This review discusses some general questions for the catalytic strategies of oxygen activation and insertion into aromatic compounds employed by mononuclear nonheme iron-dependent dioxygenases. These include: (1) how oxygen is activated, (2) whether there are common intermediates before oxygen transfer to the aromatic substrate, and (3) are these key intermediates unique to mononuclear nonheme iron dioxygenases?

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A short history of heme dioxygenases: rise, fall and rise again

Cited by 59 publications

References 110 publications

Stepwise O-Atom Transfer in Heme-Based Tryptophan Dioxygenase: Role of Substrate Ammonium in Epoxide Ring Opening

Stepwise O-Atom Transfer in Heme-Based Tryptophan Dioxygenase: Role of Substrate Ammonium in Epoxide Ring Opening

Human hepatic tryptophan 2,3-dioxygenase ubiquitin-dependent protein degradation: The critical role of its exosite as the molecular lynchpin of its substrate-mediated protein stabilization

Oxygen activation by mononuclear nonheme iron dioxygenases involved in the degradation of aromatics

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