Inhibition of Murine Amido Phosphoribosyltransferase by Folate Derivatives

Schoettle, Sarah L.; Christopherson, Richard I.

doi:10.1007/978-1-4615-2584-4_34

Cited by 2 publications

(2 citation statements)

References 9 publications

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“…This is consistent with the interpretation that the enzyme being inhibited by MTX is amido phosphoribosyltransferase. Further in vitro assays performed with MTX-Glu 5 , the active metabolite of MTX in cells also showed that amido phosphoribosyltransferase is inhibited (32).…”

Section: Amido Phosphoribosyltransferasementioning

confidence: 95%

New targets for an old drug

Toledo-Sherman

DeSouza²,

Hosfield³

et al. 2004

Clin Proteom

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Methotrexate has been a clinical agent used in cancer, immunosuppression, rheumatoid arthritis and other highly proliferative diseases for many years, yet its underlying molecular mechanism of action in these therapeutic areas is still unclear. We present a chemical proteomics approach that uses ultra-sensitive mass spectrometry coupled to an inverse protein-ligand docking computational technique to unravel the mechanism of action of this drug. Using methotrexate tethered to a solid support we were able to isolate a significant number of proteins. We effectively captured a large portion of the de novo purine metabolome and propose a pathway architecture similar to that seen in signaling pathways and consistent with substrate channeling. More importantly, we were able to capture protein targets that could potentially provide new insights into the mechanism of action of methotrexate in rheumatoid arthritis and immunosuppression. The application of this approach to other drugs and drug candidates may facilitate the prediction of unknown and secondary therapeutic target proteins and those related to the side effects and toxicity. These results demonstrate that this proteomics technology could play an important role in drug discovery and development since it allows monitoring of the interactions between a drug and the protein content of a cell.

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Section: Amido Phosphoribosyltransferasementioning

confidence: 95%

New targets for an old drug

Toledo-Sherman

DeSouza²,

Hosfield³

et al. 2004

Clin Proteom

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“…There is also evidence from the literature indicating that HGPRT should be a direct target of methotrexate. For example, it is known that other enzymes that bind IMP can also be subject to inhibition by folates and methotrexate (21). Furthermore, it is also known from extensive medicinal chemistry work on antimetabolite drug research that the pterin group of methotrexate can be replaced with xanthine and xanthine-like moieties and vice versa.…”

Section: Hypoxanthine-guanine Amidophosphoribosyltransferasementioning

confidence: 99%

New targets for an old drug

Slon-Usakiewicz¹,

Pasternak²,

Reid³

et al. 2004

Clin Proteom

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Methotrexate has been a clinical agent used in cancer, immunosuppression, rheumatoid arthritis, and other highly proliferative diseases for many years, yet its underlying molecular mechanism of action in these therapeutic areas is still unclear. We have previously reported using a chemical proteomics technique on several other potential pharmacodynamic targets of methotrexate. Here, using a frontal affinity chromatography with mass spectrometry detection, we confirm one of these targets, hypoxanthine-guanine amidophosphoribosyltransferase, as a true binder of methotrexate with a K d of 4.2 M. These results complement and confirm our recent study, but more importantly, shed light into the mechanism of action of methotrexate in oncology and other highly proliferative diseases and may help explain some unaccounted for effects of this drug. For example, despite the fact that DNA salvage pathway enzymes are highly active, methotrexate can be effective if it only targets enzymes of the de novo pathway.

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Inhibition of Murine Amido Phosphoribosyltransferase by Folate Derivatives

Cited by 2 publications

References 9 publications

New targets for an old drug

New targets for an old drug

New targets for an old drug

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