Abstract
BackgroundCytochrome P450 monooxygenases (CYPs) represent a large and diverse family of enzymes involved in various biological processes in humans. Individual genome sequencing has revealed multiple mutations in human CYPs, and many missense mutations have been associated with variety of diseases. Since 3D structures are not resolved for most human CYPs, there is a need for a reliable sequence-based prediction that discriminates benign and disease causing mutations.MethodsA new prediction method (MutaCYP) has been developed for scoring de novo missense mutations to have a deleterious effect. The method utilizes only five features, all of which are sequence-based: predicted relative solvent accessibility (RSA), variance of predicted RSA among the residues in close sequence proximity, Z-score of Shannon entropy for a given position, difference in similarity scores and weighted difference in size between wild type and new amino acids. The method is based on a single neural network.ResultsMutaCYP achieves MCC = 0.70, Q2 = 88.52%, Recall = 93.40% with Precision = 91.09%, and AUC = 0.909. Comparative evaluation with other existing methods indicates that MutaCYP outperforms SIFT and PolyPhen-2. Predictions by MutaCYP appear to be orthogonal to predictions by the evaluated methods. Potential issues on reliability of annotations of mutations in the existing databases are discussed.ConclusionsA new accurate method, MutaCYP, for classification of missense mutations in human CYPs is presented. The prediction model consists of only five sequence-based features, including a real-valued predicted relative solvent accessibility. The method is publicly available at http://research.cchmc.org/MutaSense/.
Highlights
Cytochrome P450 monooxygenases (CYPs) represent a large and diverse family of enzymes involved in various biological processes in humans
Feature selection Missense mutations in CYPs may cause a disease phenotype due to many reasons including impediment of heme binding; misfolding or destabilizing of the protein; a change in the binding affinity to a substrate leading to reduced or increased enzymatic activity; alteration of the substrate/product turnaround in and out of the active site cavity; hindrance or abolishment of the binding to a redox partner; and an altered ability to reside at the membrane such that the protein cannot properly localize within the cell
The protein-protein interaction interface with a redox partner is not defined for human CYPs and cannot be mapped directly from remote homologs
Summary
Cytochrome P450 monooxygenases (CYPs) represent a large and diverse family of enzymes involved in various biological processes in humans. CYPs participate in various innate metabolic pathways, e.g., steroid hormone biosynthesis or fatty acid metabolism, and are involved in biotransformation of xenobiotics, such as drugs and environmental pollutants [2]. Such considerable involvement in a wide array of biological processes Not all missense mutations in CYPs have functional implications and result in a disease phenotype To this end, individual genome sequencing has revealed a considerable number of variants in CYP genes (see below), and this number is expected to grow with time.
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