Inhibition of the Oxygen-Sensing Asparaginyl Hydroxylase Factor Inhibiting Hypoxia-Inducible Factor: A Potential Hypoxia Response Modulating Strategy

Wu, Yue; Li, Zhihong; McDonough, M.A.; Schofield, Christopher J.; Zhang, Xiaojin

doi:10.1021/acs.jmedchem.1c00415

Cited by 23 publications

(19 citation statements)

References 118 publications

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“…Further, considering the pleiotropic effects that NOG and its derivatives exhibit in cellular studies, application of related 2-oxo acid derivatives to cells may trigger phenotypes useful in identifying previously overlooked 2OG oxygenase/2OG-utilizing enzyme functions. FIH 76 and AspH 22 – 26 are proposed medicinal chemistry targets and the use of (partially) selective 2OG derivatives, such as 13 or corresponding esters in cellular studies may help to improve the currently limited understanding on their biochemical roles and complement similar approaches using heterocyclic small-molecules 24 , 76 – 81 .…”

Section: Discussionmentioning

confidence: 99%

2-Oxoglutarate derivatives can selectively enhance or inhibit the activity of human oxygenases

et al. 2021

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Abstract2-Oxoglutarate (2OG) oxygenases are validated agrochemical and human drug targets. The potential for modulating their activity with 2OG derivatives has not been explored, possibly due to concerns regarding selectivity. We report proof-of-principle studies demonstrating selective enhancement or inhibition of 2OG oxygenase activity by 2-oxo acids. The human 2OG oxygenases studied, factor inhibiting hypoxia-inducible transcription factor HIF-α (FIH) and aspartate/asparagine-β-hydroxylase (AspH), catalyze C3 hydroxylations of Asp/Asn-residues. Of 35 tested 2OG derivatives, 10 enhance and 17 inhibit FIH activity. Comparison with results for AspH reveals that 2OG derivatives selectively enhance or inhibit FIH or AspH. Comparison of FIH structures complexed with 2OG derivatives to those for AspH provides insight into the basis of the observed selectivity. 2-Oxo acid derivatives have potential as drugs, for use in biomimetic catalysis, and in functional studies. The results suggest that the in vivo activity of 2OG oxygenases may be regulated by natural 2-oxo acids other than 2OG.

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Section: Discussionmentioning

confidence: 99%

2-Oxoglutarate derivatives can selectively enhance or inhibit the activity of human oxygenases

et al. 2021

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“…𝜇 s represents the average of the values of 𝐴 𝑛 minus 𝐴 0 in formula (1) when there is no inhibitor. 𝜇 c represents the average of the values of 𝐴 𝑖 minus 𝐴 0 in formula (1) when the inhibition rate is 100%. 𝜎 s represents the standard deviation of 𝐴 𝑛 minus 𝐴 0 in formula (1) when there is no inhibitor.…”

Section: Methods Validationmentioning

confidence: 99%

“…Hypoxia, a physiological process in which the relative demand for oxygen supply is insufficient, is one of the factors affecting human health [1]. Recently, it has been reported that hypoxia is closely related to the occurrence and evolution of various diseases, such as renal anemia, cancer, neovascular eye disease, and cardiovascular disease [2][3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Screening prolyl hydroxylase domain 2 inhibitory activity of traditional Chinese medicine by CZE‐UV

Zhang

Zhao²,

Wang

et al. 2022

Electrophoresis

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Prolyl hydroxylase domain 2 (PHD2) is a key enzyme regulating the expression of hypoxia inducible factor (HIF). Its inhibitors can improve the expression of HIF and downstream genes, which can treat hypoxia-related diseases. Therefore, the establishment of a reliable PHD2 inhibitors screening method is of great significance for the drug development of hypoxia-related diseases. In this work, an accurate, rapid, and simple screening method for PHD2 inhibitors was introduced by capillary zone electrophoresis (CZE). In order to improve the detection sensitivity, the derivative reaction of α-ketoglutaric acid (α-OG) and 1,2diaminobenzene (OPD) was used to enhance the UV absorption of α-OG (the substrate in the enzymatic reaction). The CZE method selected 20 mM Na 2 B 4 O 7 buffer (pH 9.0) as the separation buffer, +25 kV as the separation voltage, 25 • C as the cartridge temperature, and 210 nm as the detection wavelength. Under this condition, the analysis of a single sample can be realized within 9 min. Compared with the existing reported methods, the present work can directly screen the PHD2 inhibitory activity of traditional Chinese medicine (TCM) extracts, which is of significance for the target-purification of bioactive individual compounds from TCMs. Under the optimal conditions, the PHD2 inhibitor screening platform was successfully established, and it was found that 70% methanol/water extracts of Astragali Radix and Codonopsis pilosula had good PHD2 inhibitory activity. Furthermore, the present work provides a novel approach for screening the PHD2 inhibitory activity of TCM extracts and the discovery of anti-hypoxia bioactive compounds.

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“…The PHDs belong to a structural subfamily of prolyl hydroxylases which extends from humans to some bacteria 5 . A second type of human 2OG oxygenase, Factor Inhibiting HIF (FIH), also negatively regulates HIF activity by reducing its affinity for transcription promoting histone acetyl transferases 5 , 6 . FIH also plays a role in the context-dependent regulation of the sets of HIF target genes that are upregulated in response to hypoxia 6 .…”

Section: Introductionmentioning

confidence: 99%

“…A second type of human 2OG oxygenase, Factor Inhibiting HIF (FIH), also negatively regulates HIF activity by reducing its affinity for transcription promoting histone acetyl transferases 5 , 6 . FIH also plays a role in the context-dependent regulation of the sets of HIF target genes that are upregulated in response to hypoxia 6 . Crystallographic analyses have revealed that FIH belongs to the JmjC subfamily of 2OG oxygenases 2 , 3 .…”

Section: Introductionmentioning

confidence: 99%

Conservation of the unusual dimeric JmjC fold of JMJD7 from Drosophila melanogaster to humans

Chowdhury

Abboud

Wiley

et al. 2022

Sci Rep

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The JmjC family of 2-oxoglutarate dependent oxygenases catalyse a range of hydroxylation and demethylation reactions in humans and other animals. Jumonji domain-containing 7 (JMJD7) is a JmjC (3S)-lysyl-hydroxylase that catalyses the modification of Developmentally Regulated GTP Binding Proteins 1 and 2 (DRG1 and 2); JMJD7 has also been reported to have histone endopeptidase activity. Here we report biophysical and biochemical studies on JMJD7 from Drosophila melanogaster (dmJMJD7). Notably, crystallographic analyses reveal that the unusual dimerization mode of JMJD7, which involves interactions between both the N- and C-terminal regions of both dmJMJD7 monomers and disulfide formation, is conserved in human JMJD7 (hsJMJD7). The results further support the assignment of JMJD7 as a lysyl hydroxylase and will help enable the development of selective inhibitors for it and other JmjC oxygenases.

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Inhibition of the Oxygen-Sensing Asparaginyl Hydroxylase Factor Inhibiting Hypoxia-Inducible Factor: A Potential Hypoxia Response Modulating Strategy

Cited by 23 publications

References 118 publications

2-Oxoglutarate derivatives can selectively enhance or inhibit the activity of human oxygenases

2-Oxoglutarate derivatives can selectively enhance or inhibit the activity of human oxygenases

Screening prolyl hydroxylase domain 2 inhibitory activity of traditional Chinese medicine by CZE‐UV

Conservation of the unusual dimeric JmjC fold of JMJD7 from Drosophila melanogaster to humans

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