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Design of Artificial Glycosidases: Metallopeptides that Remove H?Antigen from Human Erythrocytes.

ABSTRACT: Catalysts that promote carbohydrate degradation have a wide range of potential applications, but the use of either enzyme glycosidases or small-molecule catalysts in biological systems raises significant challenges. Herein, we demonstrate a novel strategy for the design of synthetic agents that mimic natural glycosidases and address current problems for biological use. This strategy is illustrated by application to the development of potential blood substitutes for the rare Bombay blood type that is characterized by a deficiency of H2 antigen. Metallopeptides with 16 to 20 amino acids were constructed as artificial fucosidases that exhibit selective carbohydrate cleavage reactivity toward l-fucose over d-glucose. Selective fucose cleavage from the H2-antigen saccharide enables efficient removal of H2 antigen from erythrocytes and thereby accomplishes the conversion of regular human type-O blood into a potential blood substitute for the rare Bombay blood type.

SUBMITTER: Yu Z

PROVIDER: S-EPMC5455340 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Design of Artificial Glycosidases: Metallopeptides that Remove H Antigen from Human Erythrocytes.

Yu Zhen Z Cowan James Allan JA

Angewandte Chemie (International ed. in English) 20170127 10

Catalysts that promote carbohydrate degradation have a wide range of potential applications, but the use of either enzyme glycosidases or small-molecule catalysts in biological systems raises significant challenges. Herein, we demonstrate a novel strategy for the design of synthetic agents that mimic natural glycosidases and address current problems for biological use. This strategy is illustrated by application to the development of potential blood substitutes for the rare Bombay blood type tha ...[more]

PMID: 28128528

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Project description:Using de novo protein design, we incorporated a copper metal binding site within the three-helix bundle ?3D (Walsh et al. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 5486-5491) to assess whether a cupredoxin center within an ?-helical domain could mimic the spectroscopic, structural, and redox features of native type-1 copper (CuT1) proteins. We aimed to determine whether a CuT1 center could be realized in a markedly different scaffold rather than the native ?-barrel fold and whether the characteristic short Cu-S bond (2.1-2.2 Å) and positive reduction potentials could be decoupled from the spectroscopic properties (?600 nm = 5000 M(-1) cm(-1)) of such centers. We incorporated 2HisCys(Met) residues in three distinct ?3D designs designated core (CR), chelate (CH), and chelate-core (ChC). XAS analysis revealed a coordination environment similar to reduced CuT1 proteins, producing Cu-S(Cys) bonds ranging from 2.16 to 2.23 Å and Cu-N(His) bond distances of 1.92-1.99 Å. However, Cu(II) binding to the CR and CH constructs resulted in tetragonal type-2 copper-like species, displaying an intense absorption band between 380 and 400 nm (>1500 M(-1) cm(-1)) and A|| values of (150-185) × 10(-4) cm(-4). The ChC construct, which possesses a metal-binding site deeper in its helical bundle, yielded a CuT1-like brown copper species, with two absorption bands at 401 (4429 M(-1) cm(-1)) and 499 (2020 M(-1) cm(-1)) nm and an A|| value ?30 × 10(-4) cm(-4) greater than its native counterparts. Electrochemical studies demonstrated reduction potentials of +360 to +460 mV (vs NHE), which are within the observed range for azurin and plastocyanin. These observations showed that the designed metal binding sites lacked the necessary rigidity to enforce the appropriate structural constraints for a Cu(II) chromophore (EPR and UV-vis); however, the Cu(I) structural environment and the high positive potential of CuT1 centers were recapitulated within the ?-helical bundle of ?3D.

Dataset Information

Design of Artificial Glycosidases: Metallopeptides that Remove H?Antigen from Human Erythrocytes.

Publications

Design of Artificial Glycosidases: Metallopeptides that Remove H Antigen from Human Erythrocytes.

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