ArticleScientific reports2019
A robust bacterial assay for high-throughput screening of human 4-hydroxyphenylpyruvate dioxygenase inhibitors.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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9 citing papers in PubMed, 19 citations in OpenAlex.
- A Comprehensive In Vitro and In Silico Approach for Targeting 4-Hydroxyphenyl Pyruvate Dioxygenase: Towards New Therapeutics for Alkaptonuria.International journal of molecular sciences · 2025Article
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- A robust bacterial high-throughput screening system to evaluate single nucleotide polymorphisms of human homogentisate 1,2-dioxygenase in the context of alkaptonuria.Scientific reports · 2022Article
- New insights and advances on pyomelanin production: from microbial synthesis to applications.Journal of industrial microbiology & biotechnology · 2022Review
- Predicting plasmid persistence in microbial communities by coarse-grained modeling.BioEssays : news and reviews in molecular, cellular and developmental biology · 2021Article
- Discovery and characterization of small molecule inhibitors of cystathionine gamma-synthase with in planta activity.Plant biotechnology journal · 2021Article
- Production and properties of non-cytotoxic pyomelanin by laccase and comparison to bacterial and synthetic pigments.Scientific reports · 2021Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hereditary tyrosinemia type 1 (HT1) and alkaptonuria (AKU) are inherited metabolic disorders caused by defective enzymes involved in tyrosine catabolism. Nitisinone, an ex-herbicide and member of the β-triketone family, is therapeutically applied to prevent accumulation of toxic metabolites in patients by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD). Here, we developed a colorimetric bacterial whole-cell screening system that allows quantifying the inhibitory effects of human HPD inhibitors in a high-throughput and a robust fashion. The principle of our screening system is based on the degradation of tyrosine through 4-hydroxyphenylpyruvate into homogentisate by human HPD expressed in E. coli and subsequent production of a soluble melanin-like pigment. With the aim to optimise the assay, we tested different E. coli strains, expression and reaction temperatures, and time-points for supplementing the substrate. We found that in our assay the addition of prototypical β-triketone HPD inhibitors decreases pigment production in a dose-dependent manner with increasing inhibitor concentrations. In addition, plate uniformity, signal variability and spatial uniformity assessment showed that we have developed a robust high-throughput screening assay that is simple to use, cost-effective and enables identification and evaluation of novel therapeutic human HPD inhibitors for the treatment of tyrosine-related metabolic disorders.
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