5-Ethynyl-2(1H)-pyrimidinone: Aldehyde oxidase-activation to 5-ethynyluracil, a mechanism-based inactivator of dihydropyrimidine dehydrogenase

Porter, David; Harrington, Joan A.; Almond, Merrick R.; Lowen, Gregory T.; Zimmerman, Thomas P.; Spector, Thomas

doi:10.1016/0006-2952(94)90388-3

Cited by 19 publications

(10 citation statements)

References 13 publications

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“…5-Ethynyl-2(1H)-pyrimidinone was activated to 5-ethynyluracil by aldehyde oxidase purified from rabbit liver. The prodrug itself did not affect DPD activity (Porter et al, 1994) (Table 3). The catalytic efficiency (k cat /K m ) for 5-ethynyl-2(1H)-pyrimidinone oxidation was 60-fold higher than for N-methylnicotinamide, a well known aldehyde oxidase model substrate, and the K m value of aldehyde oxidase for 5-ethynyl-2(1H)-pyrimidinone was 50 M. After oral administration of 5-ethynyl-2(1H)-pyrimidinone to rats (2 or 20 g/kg), DPD activity was inhibited to a similar extent in liver, intestine, lung, spleen, and brain (Porter et al, 1994).…”

Section: A Class 1 Oxidoreductasesmentioning

confidence: 94%

“…The prodrug itself did not affect DPD activity (Porter et al, 1994) (Table 3). The catalytic efficiency (k cat /K m ) for 5-ethynyl-2(1H)-pyrimidinone oxidation was 60-fold higher than for N-methylnicotinamide, a well known aldehyde oxidase model substrate, and the K m value of aldehyde oxidase for 5-ethynyl-2(1H)-pyrimidinone was 50 M. After oral administration of 5-ethynyl-2(1H)-pyrimidinone to rats (2 or 20 g/kg), DPD activity was inhibited to a similar extent in liver, intestine, lung, spleen, and brain (Porter et al, 1994). Whether the lack of liver selectivity was due to a rapid distribution and/or clearance of 5-ethynyluracil or that other enzymes are involved in the bioactivation of 5-ethynyl-2(1H)-pyrimidinone remains unclear.…”

Section: A Class 1 Oxidoreductasesmentioning

confidence: 94%

“…However, the wide distribution of this enzyme does not make it an ideal candidate for organselective targeting. This is illustrated by the fact that after oral administration of 5-ethynyl-2(1H)-pyrimidinone to rats' DPD activity, inhibited by released 5-ethynyluracil, was inhibited to a similar extent in liver, intestine, lung, spleen, and brain (Porter et al, 1994). Another problem with aldehyde oxidase is the large difference in substrate specificity between species (Johns, 1967;Guo et al, 1995).…”

Section: A Class 1 Oxidoreductasesmentioning

confidence: 99%

See 2 more Smart Citations

Enzyme-Catalyzed Activation of Anticancer Prodrugs

Rooseboom

Commandeur

Vermeulen

2004

Pharmacological Reviews

447

297

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Section: A Class 1 Oxidoreductasesmentioning

confidence: 94%

Section: A Class 1 Oxidoreductasesmentioning

confidence: 94%

Section: A Class 1 Oxidoreductasesmentioning

confidence: 99%

See 1 more Smart Citation

Enzyme-Catalyzed Activation of Anticancer Prodrugs

Rooseboom

Commandeur

Vermeulen

2004

Pharmacological Reviews

447

297

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“…This is one of the first examples of the role exerted by aldehyde oxidases in the bioactivation of pro-drugs. Indeed, targeting of aldehyde oxidase metabolizing activity for the bioactivation of prodrugs has been proposed for other types of agents such as 5-fluoro-2-pyrimidone, a precursor of the antineoplastic agent 5-fluorouracil [128,129]. AOX1 is potentially useful in the bioactivation of pro-drugs in human liver and lung, given that the two tissues are the only ones reported to express significant amounts of this enzymatic activity.…”

Section: Anti-malarial and Anti-viral Drugsmentioning

confidence: 99%

Mammalian aldehyde oxidases: genetics, evolution and biochemistry

Garattini

Fratelli

Terao

2007

Cell. Mol. Life Sci.

166

184

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Mammalian aldehyde oxidases are a small group of proteins belonging to the larger family of molybdo-flavoenzymes along with xanthine oxidoreductase and other bacterial enzymes. The two general types of reactions catalyzed by aldehyde oxidases are the hydroxylation of heterocycles and the oxidation of aldehydes into the corresponding carboxylic acids. Different animal species are characterized by a different complement of aldehyde oxidase genes. Humans contain a single active gene, while marsupials and rodents are characterized by four such genes clustering at a short distance on the same chromosome. At present, little is known about the physiological relevance of aldehyde oxidases in humans and other mammals, although these enzymes are known to play a role in the metabolism of drugs and compounds of toxicological importance in the liver. The present article provides an overview of the current knowledge of genetics, evolution, structure, enzymology, tissue distribution and regulation of mammalian aldehyde oxidases.

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“…DPD has considerable medical relevance as it rapidly detoxifies ( t 1/2 ∼ 20 min) the antineoplastic agent 5-fluorouracil (5FU). − Net DPD activity varies between individuals (30-fold) , and is therefore both a therapeutic complication in dosing and a primary determinant of 5FU toxicity and/or efficacy. ,,,− Inhibition of DPD has long been recognized as a means of improving outcomes of chemotherapeutic regiments for numerous cancers. , The chemistry catalyzed by DPD is typical of numerous flavin-dependent dehydrogenases, − but its architecture is atypical. DPD exists as a homodimer of 113 kDa protomers that each contain six redox cofactors: an FAD, an FMN, and four Fe 4 S 4 clusters (Figure ).…”

mentioning

confidence: 99%

Perturbing the Movement of Hydrogens to Delineate and Assign Events in the Reductive Activation and Turnover of Porcine Dihydropyrimidine Dehydrogenase

et al. 2021

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The native function of dihydropyrimidine dehydrogenase (DPD) is to reduce the 5,6-vinylic bond of pyrimidines uracil and thymine with electrons obtained from NADPH. NADPH and pyrimidines bind at separate active sites separated by ∼60 Å that are bridged by four Fe4S4 centers. We have shown that DPD undergoes reductive activation, taking up two electrons from NADPH [Beaupre, B. A., et al. (2020) Biochemistry 59, 2419–2431]. pH studies indicate that the rate of turnover is not controlled by the protonation state of the general acid, cysteine 671. The activation of the C671 variants is delineated into two phases particularly at low pH values. Spectral deconvolution of the delineated reductive activation reaction reveals that the initial phase results in the accumulation of charge transfer absorption added to the binding difference spectrum for NADPH. The second phase results in reduction of one of the two flavins. X-ray crystal structure analysis of the C671S variant soaked with NADPH and the slow substrate, thymine, in a low-oxygen atmosphere resolved the presumed activated form of the enzyme that has the FMN cofactor reduced. These data reveal that charge transfer arises from the proximity of the NADPH and FAD bases and that the ensuing flavin is a result of rapid transfer of electrons to the FMN without accumulation of reduced forms of the FAD or Fe4S4 centers. These data suggest that the slow rate of turnover of DPD is governed by the movement of a mobile structural feature that carries the C671 residue.

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5-Ethynyl-2(1H)-pyrimidinone: Aldehyde oxidase-activation to 5-ethynyluracil, a mechanism-based inactivator of dihydropyrimidine dehydrogenase

Cited by 19 publications

References 13 publications

Enzyme-Catalyzed Activation of Anticancer Prodrugs

Enzyme-Catalyzed Activation of Anticancer Prodrugs

Mammalian aldehyde oxidases: genetics, evolution and biochemistry

Perturbing the Movement of Hydrogens to Delineate and Assign Events in the Reductive Activation and Turnover of Porcine Dihydropyrimidine Dehydrogenase

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