Dataset Information

D-?-aspartyl residue exhibiting uncommon high resistance to spontaneous peptide bond cleavage.

ABSTRACT: Although L-amino acids were selected as main constituents of peptides and proteins during chemical evolution, D-aspartyl (Asp) residue is found in a variety of living tissues. In particular, D-?-Asp is thought to be stable than any other Asp isomers, and this could be a reason for gradual accumulation in abnormal proteins and peptides to modify their structures and functions. It is predicted that D-?-Asp shows high resistance to biomolecular reactions. For instance, less reactivity of D-?-Asp is expected to bond cleavage, although such information has not been provided yet. In this work, the spontaneous peptide bond cleavage was compared between Asp isomers, by applying real-time solution-state NMR to eye lens ??-crystallin 51-60 fragment, S(51)LFRTVLD(58)SG(60) and ??-crystallin 61-67 analog, F(61)D(62)TGLSG(67) consisting of L-?- and D-?-Asp 58 and 62, respectively. Kinetic analysis showed how tough the uncommon D-?-Asp residue was against the peptide bond cleavage as compared to natural L-?-Asp. Differences in pKa and conformation between L-?- and D-?-Asp side chains were plausible factors to determine reactivity of Asp isomers. The present study, for the first time, provides a rationale to explain less reactivity of D-?-Asp to allow abnormal accumulation.

SUBMITTER: Aki K

PROVIDER: S-EPMC4753488 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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D-β-aspartyl residue exhibiting uncommon high resistance to spontaneous peptide bond cleavage.

Aki Kenzo K Okamura Emiko E

Scientific reports 20160215

Although L-amino acids were selected as main constituents of peptides and proteins during chemical evolution, D-aspartyl (Asp) residue is found in a variety of living tissues. In particular, D-β-Asp is thought to be stable than any other Asp isomers, and this could be a reason for gradual accumulation in abnormal proteins and peptides to modify their structures and functions. It is predicted that D-β-Asp shows high resistance to biomolecular reactions. For instance, less reactivity of D-β-Asp is ...[more]

PMID: 26876027

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Project description:Enterococcus faecalis, a Gram-positive bacterium, and Candida albicans, a polymorphic fungus, are common constituents of the microbiome as well as increasingly problematic causes of infections. Interestingly, we previously showed that these two species antagonize each other's virulence and that E. faecalis inhibition of C. albicans was specifically mediated by EntV. EntV is a bacteriocin encoded by the entV (ef1097) locus that reduces C. albicans virulence and biofilm formation by inhibiting hyphal morphogenesis. In this report, we studied the posttranslational modifications necessary for EntV antifungal activity. First, we show that the E. faecalis secreted enzyme gelatinase (GelE) is responsible for cleaving EntV into its 68-amino-acid, active form and that this process does not require the serine protease SprE. Furthermore, we demonstrate that a disulfide bond that forms within EntV is necessary for antifungal activity. Abrogating this bond by chemical treatment or genetic modification rendered EntV inactive against C. albicans Moreover, we identified the likely catalyst of this disulfide bond, a previously uncharacterized thioredoxin within the E. faecalis genome called DsbA. Loss of DsbA, or disruption of its redox-active cysteines, resulted in loss of EntV antifungal activity. Finally, we show that disulfide bond formation is not a prerequisite for cleavage; EntV cleavage proceeded normally in the absence of DsbA. In conclusion, we present a model in which following secretion, EntV undergoes disulfide bond formation by DsbA and cleavage by GelE in order to generate a peptide capable of inhibiting C. albicans IMPORTANCE Enterococcus faecalis and Candida albicans are among the most important and problematic pathobionts, organisms that normally are harmless commensals but can cause dangerous infections in immunocompromised hosts. In fact, both organisms are listed by the Centers for Disease Control and Prevention as serious global public health threats stemming from the increased prevalence of antimicrobial resistance. The rise in antifungal resistance is of particular concern considering the small arsenal of currently available therapeutics. EntV is a peptide with antifungal properties, and it, or a similar compound, could be developed into a therapeutic alternative, either alone or in combination with existing agents. However, to do so requires understanding what properties of EntV are necessary for its antifungal activity. In this work, we studied the posttranslational processing of EntV and what modifications are necessary for inhibition of C. albicans in order to fill this gap in knowledge.

Dataset Information

D-?-aspartyl residue exhibiting uncommon high resistance to spontaneous peptide bond cleavage.

Publications

D-β-aspartyl residue exhibiting uncommon high resistance to spontaneous peptide bond cleavage.

Similar Datasets

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