New DPYD variants causing DPD deficiency in patients treated with fluoropyrimidine

García-González, Xandra; Kaczmarczyk, B.; Abarca-Zabalía, Judith; Thomas, Fabienne; García‐Alfonso, Pilar; Robles, Luis; Pachón, Vanessa; Vaz, Ángeles; Salvador-Martín, Sara; Sanjurjo‐Sáez, María; López-Fernández, Luis Andrés

doi:10.1007/s00280-020-04093-1

Cited by 15 publications

(21 citation statements)

References 42 publications

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“…In addition to the nucleotide metabolizing function of the DPD metalloenzyme in humans, the dimeric protein also serves as an important anti-cancer drug target [4,5,6]. Deficiency or dysfunction of the enzyme as a result of mutations results to increased exposure to active fluoropyrimidines metabolites leading to severe toxicity effects.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, different methods such as identification of new mutants coupled with the structural analysis and clinical studies, i.e. phenotyping of DPD, has a great impact on understanding the structural and functional effects of these mutations [6]. Together, these results would be crucial not only towards understanding how mutations lead to 5-FU toxicities but also inform better the implementation of precision medicine in cancer treatment.…”

Section: The Studymentioning

confidence: 99%

“…The remaining 12-19 % unmetabolized 5-FU form is excreted through urine [4]. As such, deficiency or reduced levels of DPD enzyme as well as sequence variation due to mutations have been reported to cause fluoropyrimidine associated toxicity effects [5,6]. Thus, understanding the implication of mutations on the catalytic mechanism of DPD can improve treatment approaches for oncology patients.…”

Section: Introductionmentioning

confidence: 99%

“…DFT: density functional theory, 2 B3LYP: Becke, three-parameter, Lee Yang Parr,3 LSDA: local spin density approximation, 4 SD: standard deviation, 5 QM: quantum mechanics,6 MD: molecular dynamics…”

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confidence: 99%

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Force field parameters for Fe²⁺₄S^2-₄ clusters of dihydropyrimidine dehydrogenase, the 5-fluorouracil cancer drug deactivation protein: a step towards in silico pharmacogenomics studies

Tendwa¹,

Chebon²,

Lobb³

et al. 2021

Preprint

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The dimeric dihydropyrimidine dehydrogenase (DPD) metalloenzyme, an adjunct anti-cancer drug target contains highly specialized 4 x Fe2+4S2-4 clusters per chain. These clusters facilitate the catalysis of the rate-limiting step in the pyrimidine degradation pathway through a harmonized electron transfer cascade that triggers a redox catabolic reaction. In the process, majority of administered 5-fluorouracil (5-FU) cancer drug is inactivated while a small proportion is activated to nucleic acid antimetabolites. The occurrence of missense mutations in DPD protein within the general population, including those of African descent, has adverse toxicity effects due to altered 5-FU metabolism. Thus, deciphering mutation effects on protein structure and function is vital, especially for precision medicine purposes. We previously proposed combined molecular dynamics (MD) and dynamic residue network (DRN) analysis to decipher the molecular mechanisms of missense mutations in other proteins. However, the presence of Fe2+4S2-4 clusters in DPD poses a challenge for such in silico studies. The existing AMBER force field parameters cannot accurately describe the Fe2+ center coordination exhibited by this enzyme. Therefore, this study aimed to derive AMBER force field parameters for DPD enzyme Fe2+ centers, using the original Seminario method and collation features Visual Force Field Derivation Toolkit as a supportive approach. All-atom MD simulations were performed to validate the results. Both approaches generated similar force field parameters which accurately described the human DPD protein Fe2+4S2-4 clusters architecture. This information is crucial and opens new avenues for in silico cancer pharmacogenomics and drug discovery related research on 5-FU drug efficacy and toxicity issues.

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Section: Discussionmentioning

confidence: 99%

Section: The Studymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Force field parameters for Fe²⁺₄S^2-₄ clusters of dihydropyrimidine dehydrogenase, the 5-fluorouracil cancer drug deactivation protein: a step towards in silico pharmacogenomics studies

Tendwa¹,

Chebon²,

Lobb³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Comparison of average internal angles (°) calculated with X-ray, 2 DFT 4 (B3LYP), and 5 (LSDA) methods for the molecular cluster model ([Fe QM: quantum mechanics , 2 DFT: density functional theory,3 MD: molecular dynamics, 4 B3LYP: Becke, three-parameter, Lee Yang Parr,5 LSDA: local spin density approximation,6 SD: standard deviation.…”

mentioning

confidence: 99%

Force Field Parameters for Fe2+4S2−4 Clusters of Dihydropyrimidine Dehydrogenase, the 5-Fluorouracil Cancer Drug Deactivation Protein: A Step towards In Silico Pharmacogenomics Studies

et al. 2021

View full text Add to dashboard Cite

The dimeric dihydropyrimidine dehydrogenase (DPD), metalloenzyme, an adjunct anti-cancer drug target, contains highly specialized 4 × Fe2+4S2−4 clusters per chain. These clusters facilitate the catalysis of the rate-limiting step in the pyrimidine degradation pathway through a harmonized electron transfer cascade that triggers a redox catabolic reaction. In the process, the bulk of the administered 5-fluorouracil (5-FU) cancer drug is inactivated, while a small proportion is activated to nucleic acid antimetabolites. The occurrence of missense mutations in DPD protein within the general population, including those of African descent, has adverse toxicity effects due to altered 5-FU metabolism. Thus, deciphering mutation effects on protein structure and function is vital, especially for precision medicine purposes. We previously proposed combining molecular dynamics (MD) and dynamic residue network (DRN) analysis to decipher the molecular mechanisms of missense mutations in other proteins. However, the presence of Fe2+4S2−4 clusters in DPD poses a challenge for such in silico studies. The existing AMBER force field parameters cannot accurately describe the Fe2+ center coordination exhibited by this enzyme. Therefore, this study aimed to derive AMBER force field parameters for DPD enzyme Fe2+ centers, using the original Seminario method and the collation features Visual Force Field Derivation Toolkit as a supportive approach. All-atom MD simulations were performed to validate the results. Both approaches generated similar force field parameters, which accurately described the human DPD protein Fe2+4S2−4 cluster architecture. This information is crucial and opens new avenues for in silico cancer pharmacogenomics and drug discovery related research on 5-FU drug efficacy and toxicity issues.

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Consensus of experts from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology for the genotyping of DPYD in cancer patients who are candidates for treatment with fluoropyrimidines

et al. 2021

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Abstract5-Fluorouracil (5-FU) and oral fluoropyrimidines, such as capecitabine, are widely used in the treatment of cancer, especially gastrointestinal tumors and breast cancer, but their administration can produce serious and even lethal toxicity. This toxicity is often related to the partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which causes a reduction in clearance and a longer half-life of 5-FU. It is advisable to determine if a DPD deficiency exists before administering these drugs by genotyping DPYD gene polymorphisms. The objective of this consensus of experts, in which representatives from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology participated, is to establish clear recommendations for the implementation of genotype and/or phenotype testing for DPD deficiency in patients who are candidates to receive fluoropyrimidines. The genotyping of DPYD previous to treatment classifies individuals as normal, intermediate, or poor metabolizers. Normal metabolizers do not require changes in the initial dose, intermediate metabolizers should start treatment with fluoropyrimidines at doses reduced to 50%, and poor metabolizers are contraindicated for fluoropyrimidines.

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New DPYD variants causing DPD deficiency in patients treated with fluoropyrimidine

Cited by 15 publications

References 42 publications

Force field parameters for Fe²⁺₄S^2-₄ clusters of dihydropyrimidine dehydrogenase, the 5-fluorouracil cancer drug deactivation protein: a step towards in silico pharmacogenomics studies

Force field parameters for Fe²⁺₄S^2-₄ clusters of dihydropyrimidine dehydrogenase, the 5-fluorouracil cancer drug deactivation protein: a step towards in silico pharmacogenomics studies

Force Field Parameters for Fe2+4S2−4 Clusters of Dihydropyrimidine Dehydrogenase, the 5-Fluorouracil Cancer Drug Deactivation Protein: A Step towards In Silico Pharmacogenomics Studies

Consensus of experts from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology for the genotyping of DPYD in cancer patients who are candidates for treatment with fluoropyrimidines

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New DPYD variants causing DPD deficiency in patients treated with fluoropyrimidine

Cited by 15 publications

References 42 publications

Force field parameters for Fe2+4S2-4 clusters of dihydropyrimidine dehydrogenase, the 5-fluorouracil cancer drug deactivation protein: a step towards in silico pharmacogenomics studies

Force field parameters for Fe2+4S2-4 clusters of dihydropyrimidine dehydrogenase, the 5-fluorouracil cancer drug deactivation protein: a step towards in silico pharmacogenomics studies

Force Field Parameters for Fe2+4S2−4 Clusters of Dihydropyrimidine Dehydrogenase, the 5-Fluorouracil Cancer Drug Deactivation Protein: A Step towards In Silico Pharmacogenomics Studies

Consensus of experts from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology for the genotyping of DPYD in cancer patients who are candidates for treatment with fluoropyrimidines

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Force field parameters for Fe²⁺₄S^2-₄ clusters of dihydropyrimidine dehydrogenase, the 5-fluorouracil cancer drug deactivation protein: a step towards in silico pharmacogenomics studies

Force field parameters for Fe²⁺₄S^2-₄ clusters of dihydropyrimidine dehydrogenase, the 5-fluorouracil cancer drug deactivation protein: a step towards in silico pharmacogenomics studies