Structural studies on 2-oxoglutarate oxygenases and related double-stranded β-helix fold proteins

Clifton, I.J.; McDonough, Michael A.; Ehrismann, Dominic; Kershaw, Nadia J.; Granatino, Nicolas; Schofield, Christopher J.

doi:10.1016/j.jinorgbio.2006.01.024

Cited by 399 publications

(459 citation statements)

References 160 publications

(266 reference statements)

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“…The structure of the three HIF PHD isoforms share a common motif, a double-stranded b-helix core fold also known as jelly-roll fold consists of eight b-strands (Clifton et al, 2006;Ozer and Bruick, 2007). They require Fe (II) for catalytic activity, which binds to a His1-X-Asp/Glu-Xn-His2 motif, these residues being His313, Asp315, and His374 for human HIF PHD's (McDonough et al, 2006).…”

Section: Hypoxia-inducible Factor Family Transcription Factorsmentioning

confidence: 99%

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Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition: Robust New Target or Another Big Bust for Stroke Therapeutics?

Karuppagounder

Ratan

2012

J Cereb Blood Flow Metab

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A major challenge in developing stroke therapeutics that augment adaptive pathways to stress has been to identify targets that can activate compensatory programs without inducing or adding to the stress of injury. In this regard, hypoxia-inducible factor prolyl hydroxylases (HIF PHDs) are central gatekeepers of posttranscriptional and transcriptional adaptation to hypoxia, oxidative stress, and excitotoxicity. Indeed, some of the known salutary effects of putative 'antioxidant' iron chelators in ischemic and hemorrhagic stroke may derive from their abilities to inhibit this family of iron, 2-oxoglutarate, and oxygen-dependent enzymes. Evidence from a number of laboratories supports the notion that HIF PHD inhibition can improve histological and functional outcomes in ischemic and hemorrhagic stroke models. In this review, we discuss this evidence and highlight important gaps in our understanding that render HIF PHD inhibition a promising but not yet preclinically validated target for protection and repair after stroke.

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Section: Hypoxia-inducible Factor Family Transcription Factorsmentioning

confidence: 99%

“…They require Fe (II) for catalytic activity, which binds to a His1-X-Asp/Glu-Xn-His2 motif, these residues being His313, Asp315, and His374 for human HIF PHD's (McDonough et al, 2006). All three PHD isozymes can hydroxylate the motif LXXLAP in HIF.…”

Section: Hypoxia-inducible Factor Family Transcription Factorsmentioning

confidence: 99%

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition: Robust New Target or Another Big Bust for Stroke Therapeutics?

Karuppagounder

Ratan

2012

J Cereb Blood Flow Metab

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“…The HIF hydroxylases are Fe(II) and 2OG-dependent dioxygenases (16,17); their requirement for dioxygen has led to their characterization as cellular oxygen sensors (refs. 9 -11, 18, and 19; Fig.…”

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confidence: 99%

Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2)

McDonough

Flashman

et al. 2006

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

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332

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Cellular and physiological responses to changes in dioxygen levels in metazoans are mediated via the posttranslational oxidation of hypoxia-inducible transcription factor (HIF). Hydroxylation of conserved prolyl residues in the HIF-␣ subunit, catalyzed by HIF prolyl-hydroxylases (PHDs), signals for its proteasomal degradation. The requirement of the PHDs for dioxygen links changes in dioxygen levels with the transcriptional regulation of the gene array that enables the cellular response to chronic hypoxia; the PHDs thus act as an oxygen-sensing component of the HIF system, and their inhibition mimics the hypoxic response. We describe crystal structures of the catalytic domain of human PHD2, an important prolyl-4-hydroxylase in the human hypoxic response in normal cells, in complex with Fe(II) and an inhibitor to 1.7 Å resolution. PHD2 crystallizes as a homotrimer and contains a double-stranded ␤-helix core fold common to the Fe(II) and 2-oxoglutarate-dependant dioxygenase family, the residues of which are well conserved in the three human PHD enzymes (PHD 1-3). The structure provides insights into the hypoxic response, helps to rationalize a clinically observed mutation leading to familial erythrocytosis, and will aid in the design of PHD selective inhibitors for the treatment of anemia and ischemic disease.erythropoietin ͉ dioxygenase ͉ hypoxic response ͉ 2-oxoglutarate I n metazoans the ␣͞␤ heterodimeric hypoxia-inducible transcription factor (HIF) (1) regulates the transcription of an array of genes including those coding for glycolytic enzymes, erythropoietin, and VEGF. The levels and transcriptional activity of the HIF-␣, but not the HIF-␤, subunit are regulated by oxygen. Hydroxylation of either Pro-402 or Pro-564 in human HIF-1␣ (2, 3) within the C-terminal oxygen-dependent degradation domain (CODDD) enables its binding to the von Hippel-Lindau protein (pVHL), a targeting element of the E3-ubiquitin ligase; subsequent ubiquitylation leads to proteasomal degradation of HIF-␣ (for reviews, see refs. 4 -7). In humans, this mechanism is augmented by hydroxylation of an asparagine residue in the C-terminal transcriptional activation domain (8); this modification blocks interaction of HIF-1␣ with the CBP͞p300 coactivator, thereby disabling HIFmediated transcription.Hydroxylation of HIF-1␣ is catalyzed by four 2-oxoglutarate (2OG) dioxygenases: three prolyl hydroxlyases (PHD 1, 2, and 3) (also known as HPH 3, 2, and 1 and EGLN 2, 1, and 3; refs. 9-11) and an asparaginyl hydroxylase [factor inhibiting HIF (FIH); refs. 12 and 13]. The available evidence implicates PHD2 as the most important HIF hydroxylase in down-regulating the hypoxic response during normoxia (5,7,14,15).The HIF hydroxylases are Fe(II) and 2OG-dependent dioxygenases (16, 17); their requirement for dioxygen has led to their characterization as cellular oxygen sensors (refs. 9 -11, 18, and 19; Fig. 1a). The first 2OG dioxygenase to be identified was procollagen prolyl-hydroxylase, which like the PHDs catalyzes trans-4-hydroxylation reactions. Pro...

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“…The majority of KDMs belong to the Jumonji C (JmjC) family of enzymes, which contain a catalytically‐active Fe II ion in the active site and require a 2‐oxoglutarate (2‐OG) cofactor for demethylation in the catalytic JmjC domain 6. The JmjC KDMs may be divided into six sub‐families (KDM2–KDM7) based on substrate specificity, with KDM2 and KDM7 being closely related 7.…”

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confidence: 99%

Discovery of a Highly Selective Cell‐Active Inhibitor of the Histone Lysine Demethylases KDM2/7

et al. 2017

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Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell‐permeable inhibitors or suitable tool compounds for these enzymes. We describe the discovery of a new class of inhibitor that is highly potent towards the histone lysine demethylases KDM2A/7A. A modular synthetic approach was used to explore the chemical space and accelerate the investigation of key structure–activity relationships, leading to the development of a small molecule with around 75‐fold selectivity towards KDM2A/7A versus other KDMs, as well as cellular activity at low micromolar concentrations.

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Structural studies on 2-oxoglutarate oxygenases and related double-stranded β-helix fold proteins

Cited by 399 publications

References 160 publications

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition: Robust New Target or Another Big Bust for Stroke Therapeutics?

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition: Robust New Target or Another Big Bust for Stroke Therapeutics?

Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2)

Discovery of a Highly Selective Cell‐Active Inhibitor of the Histone Lysine Demethylases KDM2/7

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