2-Oxoglutarate-Dependent Oxygenases

Islam, Md. Saiful; Leissing, T.M.; Chowdhury, Rasheduzzaman; Hopkinson, Richard J.; Schofield, Christopher J.

doi:10.1146/annurev-biochem-061516-044724

Cited by 337 publications

(389 citation statements)

References 167 publications

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“…Unlike the nucleotides, 2‐oxoglutarate is a key metabolite on the crossroad between energy production and nitrogen assimilation, possessing a number of signaling functions which are not necessarily coupled to diurnal rhythms, but may address other challenges (Bunik & Fernie, ). In fact, 2‐oxoglutarate takes part in the retrograde signaling between mitochondria and nucleus, is a substrate for a group of 2‐oxoglutarate‐dependent oxygenases participating, in particular, in hypoxic signaling (Islam et al, ), and an agonist of a G‐protein‐coupled receptor OXGR1 (He et al, ). In this regard, the constant level of 2‐oxoglutarate during the day may be required for organization of its signaling roles in the pathways mentioned earlier.…”

Section: Discussionmentioning

confidence: 99%

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Diurnal regulation of the function of the rat brain glutamate dehydrogenase by acetylation and its dependence on thiamine administration

Aleshin

Mkrtchyan

Kaehne

et al. 2020

Journal of Neurochemistry

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Glutamate dehydrogenase (GDH) is essential for the brain function and highly regulated, according to its role in metabolism of the major excitatory neurotransmitter glutamate. Here we show a diurnal pattern of the GDH acetylation in rat brain, associated with specific regulation of GDH function. Mornings the acetylation levels of K84 (near the ADP site), K187 (near the active site), and K503 (GTP‐binding) are highly correlated. Evenings the acetylation levels of K187 and K503 decrease, and the correlations disappear. These daily variations in the acetylation adjust the GDH responses to the enzyme regulators. The adjustment is changed when the acetylation of K187 and K503 shows no diurnal variations, as in the rats after a high dose of thiamine. The regulation of GDH function by acetylation is confirmed in a model system, where incubation of the rat brain GDH with acetyl‐CoA changes the enzyme responses to GTP and ADP, decreasing the activity at subsaturating concentrations of substrates. Thus, the GDH acetylation may support cerebral homeostasis, stabilizing the enzyme function during diurnal oscillations of the brain metabolome. Daytime and thiamine interact upon the (de)acetylation of GDH in vitro. Evenings the acetylation of GDH from control animals increases both IC50GTP and EC50ADP. Mornings the acetylation of GDH from thiamine‐treated animals increases the enzyme IC50GTP. Molecular mechanisms of the GDH regulation by acetylation of specific residues are proposed. For the first time, diurnal and thiamine‐dependent changes in the allosteric regulation of the brain GDH due to the enzyme acetylation are shown.

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Section: Discussionmentioning

confidence: 99%

“…The process is an important energy source for the brain, regulating energy homeostasis also in peripheral tissues (Karaca et al, ). Besides, 2‐oxoglutarate is a substrate of the 2‐oxoglutarate‐dependent oxygenases, having signaling importance (Bunik & Fernie, ; Islam, Leissing, Chowdhury, Hopkinson, & Schofield, ).…”

Section: Introductionmentioning

confidence: 99%

Diurnal regulation of the function of the rat brain glutamate dehydrogenase by acetylation and its dependence on thiamine administration

Aleshin

Mkrtchyan

Kaehne

et al. 2020

Journal of Neurochemistry

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“…69,70 Overall, there are 60-70 human enzymes belonging to the 2OG-dependent oxygenase superfamily, 66 which have important cellular roles, including in collagen biosynthesis, epigenetics, lipid metabolism, and DNA damage repair. 2,71 In principle, any of these could be inhibited by HIs competing with 2OG, though the available studies imply the clinically used compounds are at least partially selective. 25 In addition, any iron-containing enzyme may be affected by the used iron chelators, including those used for the treatment of Fe-overload diseases, 57 leading to a wide range of possible off-target mechanisms.…”

Section: Sulser Et Almentioning

confidence: 99%

“…In humans and other animals, chronic hypoxia/O 2 sensing occurs through the members of the 2-oxoglutarate (2OG) and Fe(II)dependent oxygenase superfamily. 1,2 The prolyl-4-hydroxylase domain (PHD1-3 in humans) enzymes utilize molecular oxygen for the hydroxylation of specific proline-residues of the α subunits of the transcription factor hypoxia-inducible factor (HIF). 3 Prolyl-4-hydroxylation primes HIFα subunits for poly-ubiquitination, resulting in their efficient proteasomal degradation.…”

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confidence: 99%

HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity

et al. 2019

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factor; HRB5rl, human hepatoma Hep3B cells stably transfected with the HIF-dependent Firefly luciferase reporter pH3SVL followed by the Renilla reporter construct pRL-SV40; JNJ-1935, JNJ-42041935; OTUB1, ovarian tumor domain-containing ubiquitin aldehyde binding protein 1; PHD, prolyl-4-hydroxylase domain; SDR, SensorDish Reader; SV40, simian virus 40; 2OG, 2-oxoglutarate. AbstractPharmacologic HIF hydroxylase inhibitors (HIs) are effective for the treatment of anemia in chronic kidney disease patients and may also be beneficial for the treatment of diseases such as chronic inflammation and ischemia-reperfusion injury. The selectivities of many HIs for HIF hydroxylases and possible off-target effects in cellulo are unclear, delaying the translation from preclinical studies to clinical trials. We developed a novel assay that discriminates between the inhibition of HIF-α prolyl-4-hydroxylase domain (PHD) enzymes and HIF-α asparagine hydroxylase factor inhibiting HIF (FIH). We characterized 15 clinical and preclinical HIs, categorizing them into pan-HIF-α hydroxylase (broad spectrum), PHD-selective, and FIHselective inhibitors, and investigated their effects on HIF-dependent transcriptional regulation, erythropoietin production, and cellular energy metabolism. While energy homeostasis was generally maintained following HI treatment, the pan-HIs led to a stronger increase in pericellular pO 2 than the PHD/FIH-selective HIs. Combined knockdown of FIH and PHD-selective inhibition did not further increase pericellular pO 2 . Hence, the additional increase in pericellular pO 2 by pan-over PHD-selective HIs likely reflects HIF hydroxylase independent off-target effects. Overall, these analyses demonstrate that HIs can lead to oxygen redistribution within the cellular microenvironment, which should be considered as a possible contributor to HI effects in the treatment of hypoxia-associated diseases. K E Y W O R D Sanemia, hypoxia, 2-oxoglutarate oxygenase inhibitor, prolyl hydroxylase inhibitor, Roxadustat

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“…The α-ketoglutarate (α-KG) dioxygenases are a diverse enzyme superfamily, whose primary biochemical function is the addition of hydroxyl (-OH) to protein or nucleic acid substrates. 1 The family includes the TET 5-methylcytosine hydroxylases, the EGLN prolyl-hydroxylases that regulate hypoxia inducible factor (HIF), and the JmjC domain-containing histone demethylases. All α-KG dioxygenases use α-KG and O2 as biochemical substrates and generate succinate as product.…”

Section: Introductionmentioning

confidence: 99%

ALKBH7 mediates necrosis via rewiring of glyoxal metabolism

Kulkarni

Nadtochiy

Kennedy³

et al. 2020

Preprint

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Alkb homolog 7 (ALKBH7) is a mitochondrial α-ketoglutarate dioxygenase required for necrotic cell death in response to DNA alkylating agents, but its physiologic role within tissues remains unclear.Herein, we show that ALKBH7 plays a key role in the regulation of dialdehyde metabolism, which impacts cardiac survival in response to ischemia-reperfusion (IR) injury. Using a multi-omics approach, we do not find evidence that ALKBH7 functions as a prolyl-hydroxylase. However, we do find that mice lacking ALKBH7 exhibit a significant increase in glyoxalase I (GLO-1), a dialdehyde detoxifying enzyme. Consistent with increased dialdehyde production, metabolomics analysis reveals rewiring of metabolic pathways related to the toxic glycolytic by-product methylglyoxal (MGO), as well as accelerated glycolysis and elevated levels of MGO protein adducts, in mice lacking ALKBH7. Consistent with roles for both necrosis and glycative stress in cardiac IR injury, hearts from male but not female Alkbh7 -/mice are protected against IR, although somewhat unexpectedly this protection does not appear to involve modulation of the mitochondrial permeability transition pore. Highlighting the importance of MGO metabolism for the observed protection, removal of glucose as a metabolic substrate or pharmacologic inhibition of GLO-1 both abrogate cardioprotection in ALKBH7 deficient mice. Integrating these observations, we propose that ALKBH7 plays a role in the regulation of glyoxal metabolism, and that protection against necrosis and IR injury bought on by ALKBH7 deficiency originates from hormetic signaling in response to elevated MGO stress.

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2-Oxoglutarate-Dependent Oxygenases

Cited by 337 publications

References 167 publications

Diurnal regulation of the function of the rat brain glutamate dehydrogenase by acetylation and its dependence on thiamine administration

Diurnal regulation of the function of the rat brain glutamate dehydrogenase by acetylation and its dependence on thiamine administration

HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity

ALKBH7 mediates necrosis via rewiring of glyoxal metabolism

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