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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