A Parsimony Approach to Biological Pathway Reconstruction/Inference for Genomes and Metagenomes

A common biological pathway reconstruction approach—as implemented by many automatic biological pathway services (such as the KAAS and RAST servers) and the functional annotation of metagenomic sequences—starts with the identification of protein functions or families (e.g., KO families for the KEGG database and the FIG families for the SEED database) in the query sequences, followed by a direct mapping of the identified protein families onto pathways. Given a predicted patchwork of individual biochemical steps, some metric must be applied in deciding what pathways actually exist in the genome or metagenome represented by the sequences. Commonly, and straightforwardly, a complete biological pathway can be identified in a dataset if at least one of the steps associated with the pathway is found. We report, however, that this naïve mapping approach leads to an inflated estimate of biological pathways, and thus overestimates the functional diversity of the sample from which the DNA sequences are derived. We developed a parsimony approach, called MinPath (Minimal set of Pathways), for biological pathway reconstructions using protein family predictions, which yields a more conservative, yet more faithful, estimation of the biological pathways for a query dataset. MinPath identified far fewer pathways for the genomes collected in the KEGG database—as compared to the naïve mapping approach—eliminating some obviously spurious pathway annotations. Results from applying MinPath to several metagenomes indicate that the common methods used for metagenome annotation may significantly overestimate the biological pathways encoded by microbial communities

Characterization of a Gene Family Encoding SEA (Sea-urchin Sperm Protein, Enterokinase and Agrin)-Domain Proteins with Lectin-Like and Heme-Binding Properties from Schistosoma japonicum

BackgroundWe previously identified a novel gene family dispersed in the genome of Schistosoma japonicum by retrotransposon-mediated gene duplication mechanism. Although many transcripts were identified, no homolog was readily identifiable from sequence information.Methodology/Principal FindingsHere, we utilized structural homology modeling and biochemical methods to identify remote homologs, and characterized the gene products as SEA (sea-urchin sperm protein, enterokinase and agrin)-domain containing proteins. A common extracellular domain in this family was structurally similar to SEA-domain. SEA-domain is primarily a structural domain, known to assist or regulate binding to glycans. Recombinant proteins from three members of this gene family specifically interacted with glycosaminoglycans with high affinity, with potential implication in ligand acquisition and immune evasion. Similar approach was used to identify a heme-binding site on the SEA-domain. The heme-binding mode showed heme molecule inserted into a hydrophobic pocket, with heme iron putatively coordinated to two histidine axial ligands. Heme-binding properties were confirmed using biochemical assays and UV-visible absorption spectroscopy, which showed high affinity heme-binding (KD = 1.605×10?6 M) and cognate spectroscopic attributes of hexa-coordinated heme iron. The native proteins were oligomers, antigenic, and are localized on adult worm teguments and gastrodermis; major host-parasite interfaces and site for heme detoxification and acquisition.ConclusionsThe results suggest potential role, at least in the nucleation step of heme crystallization (hemozoin formation), and as receptors for heme uptake. Survival strategies exploited by parasites, including heme homeostasis mechanism in hemoparasites, are paramount for successful parasitism. Thus, assessing prospects for application in disease intervention is warranted

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