The iron(II) and 2-oxoacid-dependent dioxygenases and their role in metabolism (1967 to 1999)

Prescott, Andy G.; Lloyd, Matthew D.

doi:10.1039/a902197c

Cited by 176 publications

(157 citation statements)

References 295 publications

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“…It has been established that three prolyl hydroxylases, PHD1, PHD2, and PHD3, can each hydroxylate the HIF␣ subunit (13,33). These enzymes belong to the superfamily of iron(II)-and 2OG-dependent dioxygenases (34). To function, they all require ascorbate, which is bound to the enzyme and serves to reduce iron following the hydroxylation reaction (35).…”

Section: Discussionmentioning

confidence: 99%

Depletion of Intracellular Ascorbate by the Carcinogenic Metals Nickel and Cobalt Results in the Induction of Hypoxic Stress

Salnikow

Donald

Bruick

et al. 2004

Journal of Biological Chemistry

288

234

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Nickel and cobalt have wide industrial usage, which leads to environmental pollution by these metals and their by-products at all stages of production, recycling, and disposal (1, 2). Additionally, burning of fossil fuels pollutes the air with metalcontaining particles, up to 35% of which could be composed of nickel (3). Environmental or occupational exposure to particles containing nickel or cobalt causes various forms of lung injury including pneumonitis, asthma, and fibrosis (4). Both metals are carcinogenic in animals (5, 6), and nickel has been recognized as a human carcinogen (7). The mechanisms of their toxicity and carcinogenicity are not fully understood. An interesting feature of nickel or cobalt exposure is the induction of hypoxia-like stress, which is manifested in cells by the activation of the HIF-1 1 transcription factor and hypoxia-inducible genes (8 -10). It has been suggested that the induction of the hypoxia-like stress by these metals is based on their ability to substitute for an iron atom in an "oxygen sensor" (11). No direct evidence supporting this interesting hypothesis is available, although several studies have demonstrated that Co(II) can inhibit activity of recombinant asparaginyl (12) or prolyl (13) hydroxylase in vitro, presumably because of competition with Fe(II). The induction of hypoxia-like stress by nickel or cobalt has numerous implications. It is well established that HIFinducible genes are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism, and invasion (14, 15).Recently, using HIF-1␣ normal and knock-out cells, we have shown that nickel promotes soft agar growth via the HIF-1 transcription factor (16). These data indicate that HIF-1 induction may play an important role in nickel-mediated malignant transformation of cells. The HIF-1 transcription factor is a heterodimer composed of ␣ and ␤ subunits (17). The activity of HIF-1 depends on the accumulation of short lived HIF␣. Under normoxic conditions, hydroxylation of proline residues 402 and 564 in the ODD of HIF-1␣ leads to its interaction with the VHL tumor suppressor protein, a part of the ubiquitin⅐ligase complex, followed by ubiquitylation and rapid proteosomal degradation of . Under hypoxic conditions, limiting oxygen decreases hydroxylation, which prevents VHL binding and leads to the accumulation of HIF-1␣ protein. Nickel(II) or cobalt(II) exposure even in the presence of oxygen causes increased accumulation of HIF-1␣ protein and induction of HIF-1 transcriptional activity (17,21,22). The accumulation of HIF-1␣ protein observed in cells after cobalt(II) exposure resulted from the inability of HIF␣ to complex with the VHL protein (18). This inability, as we found here, is associated with inhibition of HIF-1␣ hydroxylation, manifested by both cobalt(II) and nickel(II) exposure. HIF activity can also be affected by the asparaginyl hydroxylation of the C-terminal transactivation domain, which is regulated by FIH-1 (23). Like the prolyl hydroxylase, this enzyme

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Section: Discussionmentioning

confidence: 99%

Depletion of Intracellular Ascorbate by the Carcinogenic Metals Nickel and Cobalt Results in the Induction of Hypoxic Stress

Salnikow

Donald

Bruick

et al. 2004

Journal of Biological Chemistry

288

234

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“…The 2OG oxygenases are found in organisms ranging from bacteria to mammals and play a wide variety of biological roles [4]. All require ferrous iron, dioxygen, and 2OG for full activity; in some cases L L-ascorbic acid also is required or beneficial for activity, at least in vitro [5].…”

Section: Introductionmentioning

confidence: 99%

Incorporation of oxygen into the succinate co‐product of iron(II) and 2‐oxoglutarate dependent oxygenases from bacteria, plants and humans

et al. 2005

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The ferrous iron and 2-oxoglutarate (2OG) dependent oxygenases catalyse two electron oxidation reactions by coupling the oxidation of substrate to the oxidative decarboxylation of 2OG, giving succinate and carbon dioxide coproducts. The evidence available on the level of incorporation of one atom from dioxygen into succinate is inconclusive. Here, we demonstrate that five members of the 2OG oxygenase family, AlkB from Escherichia coli, anthocyanidin synthase and flavonol synthase from Arabidopsis thaliana, and prolyl hydroxylase domain enzyme 2 and factor inhibiting hypoxia-inducible factor-1 from Homo sapiens all incorporate a single oxygen atom, almost exclusively derived from dioxygen, into the succinate co-product.

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“…This Escherichia coli protein is a member of a rapidly expanding enzyme superfamily that utilizes mononuclear Fe(II) active sites to catalyze a diverse range of chemical transformations, usually coupled to the oxidative decarboxylation of an ␣-keto acid (2)(3)(4). Other family members include enzymes that modify protein side chains (5,6), repair alkylation-damaged DNA (7), degrade compounds in the environment (8)(9)(10)(11), and synthesize antibiotics (12)(13)(14), plant metabolites (15,16), or other small molecules (17,18).…”

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confidence: 99%

Interconversion of two oxidized forms of taurine/α-ketoglutarate dioxygenase, a non-heme iron hydroxylase: Evidence for bicarbonate binding

Ryle

Koehntop

Liu

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Taurine͞␣-ketoglutarate (␣KG) dioxygenase, or TauD, is a mononuclear non-heme iron hydroxylase that couples the oxidative decarboxylation of ␣KG to the decomposition of taurine, forming sulfite and aminoacetaldehyde. Prior studies revealed that taurine-free TauD catalyzes an O 2-and ␣KG-dependent selfhydroxylation reaction involving Tyr-73, yielding an Fe(III)-catecholate chromophore with a max of 550 nm. Here, a chromophore ( max 720 nm) is described and shown to arise from O2-dependent self-hydroxylation of TauD in the absence of ␣KG, but requiring the product succinate. A similar chromophore rapidly develops with the alternative oxidant H 2O2. Resonance Raman spectra indicate that the Ϸ700-nm chromophore also arises from an Fe(III)-catecholate species, and site-directed mutagenesis studies again demonstrate Tyr-73 involvement. The Ϸ700-nm and 550-nm species are shown to interconvert by the addition or removal of bicarbonate, consistent with the ␣KG-derived CO2 remaining tightly bound to the oxidized metal site as bicarbonate. The relevance of the metal-bound bicarbonate in TauD to reactions of other members of this enzyme family is discussed.T aurine͞␣-ketoglutarate (␣KG) dioxygenase, or TauD, catalyzes the conversion of taurine (2-aminoethanesulfonic acid) to sulfite and aminoacetaldehyde in the presence of O 2 , ␣KG, and Fe(II) as shown in Scheme 1 (1). This Escherichia coli protein is a member of a rapidly expanding enzyme superfamily that utilizes mononuclear Fe(II) active sites to catalyze a diverse range of chemical transformations, usually coupled to the oxidative decarboxylation of an ␣-keto acid (2-4). Other family members include enzymes that modify protein side chains (5, 6), repair alkylation-damaged DNA (7), degrade compounds in the environment (8-11), and synthesize antibiotics (12-14), plant metabolites (15, 16), or other small molecules (17,18). Most representatives carry out specific hydroxylation reactions, but examples of enzymes catalyzing desaturations, ring closures, and ring expansion reactions have also been documented (19). Regardless of their overall chemistry, these enzymes generally are thought to form a highvalent iron-oxo intermediate; however, such an intermediate has never been directly observed.Recent studies of TauD and the herbicide-degrading enzyme TfdA, which share Ϸ30% sequence identity, have provided important insights into the reactivity of this group of enzymes (e.g., refs. 20-28). In the absence of substrates, Fe(II) is coordinated by three amino acid side chains in a two-His-one-carboxylate motif [His-99, Asp-101, and His-255 in TauD; and His-114, Asp-116, and His-262 in TfdA (23, 26)] and three water molecules to afford a six-coordinate metal center. ␣KG chelates to the Fe(II) and displaces two water molecules, binding through the 1-carboxylate and 2-keto moieties. The primary substrate binds near, but not directly to, the Fe(II), promoting loss of the final water ligand to yield a five-coordinate metal center (26), as illustrated in Fig. 1. The site vacated by wate...

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The iron(II) and 2-oxoacid-dependent dioxygenases and their role in metabolism (1967 to 1999)

Cited by 176 publications

References 295 publications

Depletion of Intracellular Ascorbate by the Carcinogenic Metals Nickel and Cobalt Results in the Induction of Hypoxic Stress

Depletion of Intracellular Ascorbate by the Carcinogenic Metals Nickel and Cobalt Results in the Induction of Hypoxic Stress

Incorporation of oxygen into the succinate co‐product of iron(II) and 2‐oxoglutarate dependent oxygenases from bacteria, plants and humans

Interconversion of two oxidized forms of taurine/α-ketoglutarate dioxygenase, a non-heme iron hydroxylase: Evidence for bicarbonate binding

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