Abstract
BackgroundBacterial tyrosine-kinases (BY-kinases), which play an important role in numerous cellular processes, are characterized as a separate class of enzymes and share no structural similarity with their eukaryotic counterparts. However, in silico methods for predicting BY-kinases have not been developed yet. Since these enzymes are involved in key regulatory processes, and are promising targets for anti-bacterial drug design, it is desirable to develop a simple and easily interpretable predictor to gain new insights into bacterial tyrosine phosphorylation. This study proposes a novel SCMBYK method for predicting and characterizing BY-kinases.ResultsA dataset consisting of 797 BY-kinases and 783 non-BY-kinases was established to design the SCMBYK predictor, which achieved training and test accuracies of 97.55 and 96.73%, respectively. Furthermore, the leave-one-phylum-out method was used to predict specific bacterial phyla hosts of target sequences, gaining 97.39% average test accuracy. After analyzing SCMBYK-derived propensity scores, four characteristics of BY-kinases were determined: 1) BY-kinases tend to be composed of α-helices; 2) the amino-acid content of extracellular regions of BY-kinases is expected to be dominated by residues such as Val, Ile, Phe and Tyr; 3) BY-kinases structurally resemble nuclear proteins; 4) different domains play different roles in triggering BY-kinase activity.ConclusionsThe SCMBYK predictor is an effective method for identification of possible BY-kinases. Furthermore, it can be used as a part of a novel drug repurposing method, which recognizes putative BY-kinases and matches them to approved drugs. Among other results, our analysis revealed that azathioprine could suppress the virulence of M. tuberculosis, and thus be considered as a potential antibiotic for tuberculosis treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-016-1371-4) contains supplementary material, which is available to authorized users.
Highlights
Bacterial tyrosine-kinases (BY-kinases), which play an important role in numerous cellular processes, are characterized as a separate class of enzymes and share no structural similarity with their eukaryotic counterparts
Our results, according to which AZA may interact with BY-kinases and suppress the virulence of M. tuberculosis, suggest that it was the removal of AZA, and not the introduction of mycophenolate, that led to the appearance of tuberculosis in the patients that switched medication. Since their discovery BY-kinases have been receiving a growing amount of attention. This is especially true for the biomedical field, where they are seen as promising targets for anti-bacterial drug design
Our physicochemical properties (PCPs) mining method revealed a high correlation between the propensity scores of 20 amino acids and such PCPs as: MAXF760106, RACS820107, NAKH920103, CEDJ970105, and CEDJ970102
Summary
Bacterial tyrosine-kinases (BY-kinases), which play an important role in numerous cellular processes, are characterized as a separate class of enzymes and share no structural similarity with their eukaryotic counterparts. Bacterial tyrosine-kinases (BY-kinases) are enzymes that perform protein phosphorylation and autophosphorylation, and have been identified in the majority of sequenced bacterial genomes [1,2,3] They transfer phosphate groups from ATP to reactive side chains of Tyr residues, regulating processes of cellular signaling [3]. In the C-terminal tail, BY-kinases possess a tyrosine-rich region called the YC-cluster [1,2,3] It varies in length (10 to 20 amino acids) and contains several tyrosine residues that correspond to the BY-kinase-autophosphorylation sites [3, 4]. The presence of these four motifs (Walker A, Walker A’, Walker B, and YC) is a typical signature of BY-kinases [4]. BY-kinases of Proteobacteria are characterized by the existence of a short region rich in Arg and Lys residues, called the “RK cluster”, in the Nterminal part of their cytoplasmic domain [5]
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