The mitochondrial amidoxime reducing component—from prodrug-activation mechanism to drug-metabolizing enzyme and onward to drug target

Struwe, Michel A.; Scheidig, Axel J.; Clement, Bernd

doi:10.1016/j.jbc.2023.105306

Cited by 5 publications

(2 citation statements)

References 183 publications

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“…cPMP is then converted outside the mitochondria via MOCS2 to molybdopterin (MPT), which in turn is further converted to the MOlybdenum COfactor (MOCO) by gephyrin (GPHN). MOCO is the central element of the four human molybdenum enzymes: i) sulfite oxidase (SUOX) that transforms sulfites into sulfates (Mendel and Schwarz 2023); ii) xanthine dehydrogenase (XDH) and aldehyde oxidase (AOX) that catalyse the two-step reaction from hypoxanthine to xanthine and from xanthine to uric acid in purine metabolism (Bortolotti et al 2021); iii), and is involved in the metabolism of retinaldehyde, respectively, and the mitochondrial amidoxime-reducing component (mARC), a key factor in the N-hydroxylation of prodrugsor N-oxygenated compounds (Struwe, Scheidig, and Clement 2023).…”

Section: Introductionmentioning

confidence: 99%

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Autism spectrum disorders: an impaired glycolysis induces an ATP deficiency and a reduced cell respiration

Féron,

Caillol,

Fourel

et al. 2024

Preprint

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In two previous studies, based on human olfactory ecto-mesenchymal stem cells (OEMSC) of 11 patients with autism spectrum disorders (ASD) and 11 healthy individuals, we demonstrated that the lower abundance of the enzyme MOCOS (MOlybdenum COfactor Sulfurase) and its associated lower expression of the long non-coding RNA, COSMOC, induces neurotransmission and synaptic defects as well as an exacerbated oxidative stress sensitivity. To move a step further, we assessed whether these defects were associated to a disturbed mitochondrial homeostasis. For that purpose, we used cellular and molecular techniques to quantify mitochondrial metabolism and biogenesis, ATP production and cell respiration in OEMSCs from the 8 ASD patients of the cohort that display the most severe symptoms. We show here that OEMSCs from ASD patients, when compared to control individuals, display i) a reduced expression/abundance of glycolysis-associated transcripts and metabolites, ii) an overall reduced ATP, mainly due to the impaired glycolysis, iii) a reduced basal cell respiration and iv) a modified mitochondrial network. These results are in accordance with some of our previously published data and may explain some of the symptoms (stress, overarousal, seizures, increased or decreased muscle tone, fatigue) observed in autism spectrum disorders.

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Section: Introductionmentioning

confidence: 99%

“…The copyright holder for this this version posted January 24, 2024. ; https://doi.org/10.1101/2024.01.22.576644 doi: bioRxiv preprint reQnaldehyde, respecQvely, and the mitochondrial amidoxime-reducing component (mARC), a key factor in the N-hydroxylaQon of prodrugsor N-oxygenated compounds (Struwe, Scheidig, and Clement 2023).…”

Section: Introduconmentioning

confidence: 99%

Autism spectrum disorders: an impaired glycolysis induces an ATP deficiency and a reduced cell respiration

Féron,

Caillol,

Fourel

et al. 2024

Preprint

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Exploring the nature’s discriminating factors behind the selection of molybdoenzymes and tungstoenzymes depending on the biological environment

Das,

Das

2025

Coordination Chemistry Reviews

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Second-Coordination-Sphere Effects Reveal Electronic Structure Differences between the Mitochondrial Amidoxime Reducing Component and Sulfite Oxidase

Struwe,

Yang,

Kolanji

et al. 2024

Inorg. Chem.

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A combination of X-ray absorption and low-temperature electronic absorption spectroscopies has been used to probe the geometric and electronic structures of the human mitochondrial amidoxime reducing component enzyme (hmARC1) in the oxidized Mo(VI) and reduced Mo(IV) forms. Extended X-ray absorption fine structure analysis revealed that oxidized enzyme possesses a 5-coordinate [MoO2(SCys)(PDT)]− (PDT = pyranopterin dithiolene) active site with a cysteine coordinated to Mo. A 5-coordinate geometry is retained in the reduced state, with the equatorial oxo being protonated. Low-temperature electronic absorption spectroscopy of hmARC1 reveals a spectrum for the oxidized enzyme that is significantly different from what has been reported for sulfite oxidase family enzymes. Time-dependent density functional theory computations on oxidized and reduced hmARC1, and a small molecule analogue for hmARC1ox, have been used to assist us in making detailed band assignments and developing a greater understanding of enzyme electronic structure contributions to reactivity. Our understanding of the hmARCred HOMO and the LUMO of the benzamidoxime substrate reveal a potential π-bonding interaction between these redox orbitals, with two-electron occupation of the substrate LUMO along the reaction coordinate activating the O–N bond for cleavage and promoting oxygen atom transfer to the Mo site.

show abstract

The mitochondrial amidoxime reducing component—from prodrug-activation mechanism to drug-metabolizing enzyme and onward to drug target

Cited by 5 publications

References 183 publications

Autism spectrum disorders: an impaired glycolysis induces an ATP deficiency and a reduced cell respiration

Autism spectrum disorders: an impaired glycolysis induces an ATP deficiency and a reduced cell respiration

Exploring the nature’s discriminating factors behind the selection of molybdoenzymes and tungstoenzymes depending on the biological environment

Second-Coordination-Sphere Effects Reveal Electronic Structure Differences between the Mitochondrial Amidoxime Reducing Component and Sulfite Oxidase

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