Natural and synthetic 2-oxoglutarate derivatives are substrates for oncogenic variants of human isocitrate dehydrogenase 1 and 2

Liu, Xiao; Reinbold, Raphael; Liu, Shuang; Herold, Ryan A.; Rabe, Patrick; Duclos, Stéphanie; Yadav, Rahul B.; Abboud, Martine I.; Thieffine, Sandrine; Armstrong, Fräser A.; Brewitz, Lennart; Schofield, Christopher J.

doi:10.1016/j.jbc.2023.102873

“… [8] Figure 5A shows plots of absorbance (normalized) vs time after introducing different concentrations of Ivosidenib. A control experiment was carried out with an active‐site binding inhibitor, N‐oxalylglycine (NOG), a catalytically‐inactive 2OG analogue,[ 13 , 39 ] which manifested ≈90 % inhibition within seconds. The data were converted into the first derivative to obtain the rate of change of catalytic rate with time (Figure 5B ), giving a plot analogous to Figure 3A .…”

Section: Resultsmentioning

confidence: 99%

Electrochemical Nanoreactor Provides a Comprehensive View of Isocitrate Dehydrogenase Cancer‐drug Kinetics

Herold,

Schofield,

Armstrong

2023

Angewandte Chemie

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The ability to control enzyme cascades entrapped in a nanoporous electrode material (the “Electrochemical Leaf”, e‐Leaf) has been exploited to gain detailed kinetic insight into the mechanism of an anti‐cancer drug. Ivosidenib, used to treat acute myeloid leukemia, acts on a common cancer‐linked variant of isocitrate dehydrogenase 1 (IDH1 R132H) inhibiting its “gain‐of‐function” activity—the undesired reduction of 2‐oxoglutarate (2OG) to the oncometabolite 2‐hydroxyglutarate (2HG). The e‐Leaf quantifies the kinetics of IDH1 R132H inhibition across a wide and continuous range of conditions, efficiently revealing factors underlying the inhibitor residence time. Selective inhibition of IDH1 R132H by Ivosidenib and another inhibitor, Novartis 224, is readily resolved as a two‐stage process whereby initial rapid non‐inhibitory binding is followed by a slower step to give the inhibitory complex. These kinetic features are likely present in other allosteric inhibitors of IDH1/2. Such details, essential for understanding inhibition mechanisms, are not readily resolved in conventional steady‐state kinetics or by techniques that rely only on measuring binding. Extending the new method and analytical framework presented here to other enzyme systems will be straightforward and should rapidly reveal insight that is difficult or often impossible to obtain using other methods.

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“… [8] Figure 5A shows plots of absorbance (normalized) vs time after introducing different concentrations of Ivosidenib. A control experiment was carried out with an active‐site binding inhibitor, N‐oxalylglycine (NOG), a catalytically‐inactive 2OG analogue,[ 13 , 39 ] which manifested ≈90 % inhibition within seconds. The data were converted into the first derivative to obtain the rate of change of catalytic rate with time (Figure 5B ), giving a plot analogous to Figure 3A .…”

Section: Resultsmentioning

confidence: 99%

Electrochemical Nanoreactor Provides a Comprehensive View of Isocitrate Dehydrogenase Cancer‐drug Kinetics

Herold,

Schofield,

Armstrong

2023

Angew Chem Int Ed

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The ability to control enzyme cascades entrapped in a nanoporous electrode material (the “Electrochemical Leaf”, e‐Leaf) has been exploited to gain detailed kinetic insight into the mechanism of an anti‐cancer drug. Ivosidenib, used to treat acute myeloid leukemia, acts on a common cancer‐linked variant of isocitrate dehydrogenase 1 (IDH1 R132H) inhibiting its “gain‐of‐function” activity—the undesired reduction of 2‐oxoglutarate (2OG) to the oncometabolite 2‐hydroxyglutarate (2HG). The e‐Leaf quantifies the kinetics of IDH1 R132H inhibition across a wide and continuous range of conditions, efficiently revealing factors underlying the inhibitor residence time. Selective inhibition of IDH1 R132H by Ivosidenib and another inhibitor, Novartis 224, is readily resolved as a two‐stage process whereby initial rapid non‐inhibitory binding is followed by a slower step to give the inhibitory complex. These kinetic features are likely present in other allosteric inhibitors of IDH1/2. Such details, essential for understanding inhibition mechanisms, are not readily resolved in conventional steady‐state kinetics or by techniques that rely only on measuring binding. Extending the new method and analytical framework presented here to other enzyme systems will be straightforward and should rapidly reveal insight that is difficult or often impossible to obtain using other methods.

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“…4,4-dimethyl-2OG (9) inhibits AspH, but not JMJD5 or FIH (Table S2, ESI †). 37,44 It has also been reported that 4,4-dimethyl-2OG (9) does not inhibit human cancer-associated variants of isocitrate dehydrogenase (IDH); 60 these IDH variants employ 2OG as a substrate (but not 9 60 ), however, they are functionally and structurally unrelated to human 2OG oxygenases.…”

Section: Jmjd5 Inhibition Studiesmentioning

confidence: 99%

Kinetic and inhibition studies on human Jumonji-C (JmjC) domain-containing protein 5

Tumber

¹

,

Saleh

²

,

Brewitz

³

et al. 2023

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Natural and synthetic 2-oxoglutarate derivatives are substrates for oncogenic variants of human isocitrate dehydrogenase 1 and 2

Cited by 4 publications

References 75 publications

Electrochemical Nanoreactor Provides a Comprehensive View of Isocitrate Dehydrogenase Cancer‐drug Kinetics

Electrochemical Nanoreactor Provides a Comprehensive View of Isocitrate Dehydrogenase Cancer‐drug Kinetics

Electrochemical Nanoreactor Provides a Comprehensive View of Isocitrate Dehydrogenase Cancer‐drug Kinetics

Kinetic and inhibition studies on human Jumonji-C (JmjC) domain-containing protein 5

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