Mercury BLASTP

Jacob, Arpith C.; Lancaster, Joseph M.; Buhler, Jeremy; Harris, Brandon; Chamberlain, Roger D.

doi:10.1145/1371579.1371581

Cited by 74 publications

(13 citation statements)

References 20 publications

(27 reference statements)

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“…Sequences of putative aldehyde dehydrogenases were retrieved from a BLASTp [ 62 ] search using Homo sapiens ALDH proteins as query against the genomes of the selected Opisthokont and Trypanosomatida species (BLOSUM62, Existence: 11 Extension: 1 Conditional compositional score matrix adjustment). The subsequent hits were analysed and outliers excluded from the phylogenetic assembly based on protein alignment generated using EMB-EBI Clustal Omega.…”

Section: Methodsmentioning

confidence: 99%

Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles

et al. 2018

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Recent development of benzoxaborole-based chemistry gave rise to a collection of compounds with great potential in targeting diverse infectious diseases, including human African Trypanosomiasis (HAT), a devastating neglected tropical disease. However, further medicinal development is largely restricted by a lack of insight into mechanism of action (MoA) in pathogenic kinetoplastids. We adopted a multidisciplinary approach, combining a high-throughput forward genetic screen with functional group focused chemical biological, structural biology and biochemical analyses, to tackle the complex MoAs of benzoxaboroles in Trypanosoma brucei. We describe an oxidative enzymatic pathway composed of host semicarbazide-sensitive amine oxidase and a trypanosomal aldehyde dehydrogenase TbALDH3. Two sequential reactions through this pathway serve as the key underlying mechanism for activating a series of 4-aminomethylphenoxy-benzoxaboroles as potent trypanocides; the methylamine parental compounds as pro-drugs are transformed first into intermediate aldehyde metabolites, and further into the carboxylate metabolites as effective forms. Moreover, comparative biochemical and crystallographic analyses elucidated the catalytic specificity of TbALDH3 towards the benzaldehyde benzoxaborole metabolites as xenogeneic substrates. Overall, this work proposes a novel drug activation mechanism dependent on both host and parasite metabolism of primary amine containing molecules, which contributes a new perspective to our understanding of the benzoxaborole MoA, and could be further exploited to improve the therapeutic index of antimicrobial compounds.

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Section: Methodsmentioning

confidence: 99%

Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles

et al. 2018

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“…First, all of the known Arabidopsis PAT gene sequences were used as query sequences to perform multiple database searches against proteome and genome files downloaded from the Phytozome database (www.phytozome.net/) [31] and PlantGDB database (www.plantgdb.org/) [32]. Stand-alone versions of BLASTP [33] and TBLASTN (http://blast.ncbi.nlm.nih.gov), which are available from NCBI, were used with an e-value cut-off of 1e-003 [34]. All protein sequences derived from the collected candidate PAT genes were examined using the domain analysis programs PFAM (http://pfam.sanger.ac.uk/) and SMART (http://smart.embl-heidelberg.de/) with the default cut-off parameters.…”

Section: Methodsmentioning

confidence: 99%

Putative DHHC-Cysteine-Rich Domain S-Acyltransferase in Plants

et al. 2013

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Protein S-acyltransferases (PATs) containing Asp-His-His-Cys within a Cys-rich domain (DHHC-CRD) are polytopic transmembrane proteins that are found in eukaryotic cells and mediate the S-acylation of target proteins. S-acylation is an important secondary and reversible modification that regulates the membrane association, trafficking and function of target proteins. However, little is known about the characteristics of PATs in plants. Here, we identified 804 PATs from 31 species with complete genomes. The analysis of the phylogenetic relationships suggested that all of the PATs fell into 8 groups. In addition, we analysed the phylogeny, genomic organization, chromosome localisation and expression pattern of PATs in Arabidopsis, Oryza sative, Zea mays and Glycine max. The microarray data revealed that PATs genes were expressed in different tissues and during different life stages. The preferential expression of the ZmPATs in specific tissues and the response of Zea mays to treatments with phytohormones and abiotic stress demonstrated that the PATs play roles in plant growth and development as well as in stress responses. Our data provide a useful reference for the identification and functional analysis of the members of this protein family.

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“…The genome structure was annotated using Glimmer version 3.02 (10). To obtain the protein function annotation, the predicted protein sequences were compared with those in the nonredundant protein (NR), Cluster of Orthologous Groups (COG), KEGG, Gene Ontology (GO), and Swiss-Prot databases in NCBI using BLASTP with an E value of 1e−5 (11).…”

Section: Announcementmentioning

confidence: 99%