Please use this identifier to cite or link to this item:
https://hdl.handle.net/10216/120442
Author(s): | Santos M.M. Ruivo R. Lopes-Marques M. Torres T. de los Santos C.B. Castro L.F.C. Neuparth T. |
Title: | Statins: An undesirable class of aquatic contaminants? |
Publisher: | Elsevier |
Issue Date: | 2016 |
Abstract: | Emerging pollutants, such as pharmaceuticals, may pose a considerable environment risk. Hypocholesterolaemic drugs such as statins are among the most prescribed human pharmaceuticals in western European countries. In vertebrates, this therapeutic class disrupts the cholesterol synthesis by inhibiting the enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), responsible for the limiting step in the mevalonate pathway. Recently, functional studies have shown that statins competitively inhibit HMGR in vertebrates and arthropods, two taxa that have diverged over 450 million years ago. Importantly, chronic simvastatin exposure disrupts crustacean reproduction and development at environmentally relevant concentrations. Hence, a fundamental question emerges: what is the taxonomic scope of statins-induced HMGR inhibition across metazoans? Here, we address this central question in a large sampling of metazoans using comparative genomics, homology modelling and molecular docking. Sequence alignment of metazoan HMGRs allowed the annotation of highly conserved catalytic, co-factor and substrate binding sites, including residues highjacked for statin binding. Furthermore, molecular docking shows that the catalytic domains of metazoan HMGRs are highly conserved regarding interactions, not only with HMG-CoA, but also with both simvastatin and atorvastatin, the top prescribed statins in Europe and USA. Hence, the data indicates that both statins are expected to competitively inhibit metazoan's HMGRs, and therefore all metazoan taxa might be at risk. The environmental relevance of these findings are discussed and research priorities established. We believe that the conceptual framework used in this study can be applied to other emerging pollutants and assist in the design of toxicity testing and risk assessment. © 2016 Elsevier |
Subject: | atorvastatin hydroxymethylglutaryl coenzyme A reductase hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin 3-hydroxy-3-methylglutaryl-coenzyme A acyl coenzyme A hydroxymethylglutaryl coenzyme A reductase hydroxymethylglutaryl coenzyme A reductase inhibitor water pollutant chemical pollutant drug metazoan pollution exposure risk assessment taxonomy toxicity test Article competitive inhibition conceptual framework developmental toxicity embryotoxicity genomics human molecular docking nonhuman phylogeny priority journal reproductive toxicity sequence alignment structure analysis water pollutant animal binding site chemistry genetics metabolism protein tertiary structure toxicity water pollutant Europe Arthropoda Crustacea Metazoa Vertebrata Acyl Coenzyme A Animals Atorvastatin Calcium Binding Sites Hydroxymethylglutaryl CoA Reductases Hydroxymethylglutaryl-CoA Reductase Inhibitors Molecular Docking Simulation Protein Structure, Tertiary Simvastatin Water Pollutants, Chemical |
URI: | https://hdl.handle.net/10216/120442 |
Source: | Aquatic Toxicology, vol. 174, p. 1-9 |
Related Information: | info:eu-repo/grantAgreement/FCT/5876/147268/PT |
Document Type: | Artigo em Revista Científica Internacional |
Rights: | restrictedAccess |
Appears in Collections: | CIIMAR - Artigo em Revista Científica Internacional |
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File | Description | Size | Format | |
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Santos MM_2016.pdf Restricted Access | 4.75 MB | Adobe PDF | Request a copy |
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