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  • Chen, Xiabin  (3)
  • Yao, Weixuan  (3)
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  • 1
    Online Resource
    Online Resource
    Computational Design and Crystal Structure of a Highly Efficient Benzoylecgonine Hydrolase
    Wiley ; 2021
    In:  Angewandte Chemie International Edition Vol. 60, No. 40 ( 2021-09-27), p. 21959-21965
    Details
    In: Angewandte Chemie International Edition, Wiley, Vol. 60, No. 40 ( 2021-09-27), p. 21959-21965
    Abstract: Benzoylecgonine (BZE) is the major toxic metabolite of cocaine and is responsible for the long‐term cocaine‐induced toxicity owing to its long residence time in humans. BZE is also the main contaminant following cocaine consumption. Here, we identified the bacterial cocaine esterase (CocE) as a BZE‐metabolizing enzyme (BZEase), which can degrade BZE into biological inactive metabolites (ecgonine and benzoic acid). CocE was redesigned by a reactant‐state‐based enzyme design theory. An encouraging mutant denoted as BZEase2, presented a 〉 400‐fold improved catalytic efficiency against BZE compared with wild‐type (WT) CocE. In vivo, a single dose of BZEase2 (1 mg kg −1 , IV) could eliminate nearly all BZE within only two minutes, suggesting the enzyme has the potential for cocaine overdose treatment and BZE elimination in the environment by accelerating BZE clearance. The crystal structure of a designed BZEase was also determined.
    Type of Medium: Online Resource
    ISSN: 1433-7851 , 1521-3773
    URL: Issue
    URL: Article
    DOI: 10.1002/anie.v60.40
    DOI: 10.1002/anie.202108559
    RVK:
    VA 2100
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2011836-3
    detail.hit.zdb_id: 123227-7
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    The protonation state of Glu202 in acetylcholinesterase
    Wiley ; 2022
    In:  Proteins: Structure, Function, and Bioinformatics Vol. 90, No. 2 ( 2022-02), p. 485-492
    Details
    In: Proteins: Structure, Function, and Bioinformatics, Wiley, Vol. 90, No. 2 ( 2022-02), p. 485-492
    Abstract: Acetylcholinesterase (AChE) is the crucial enzyme in the central nervous system. It is the target of various organophosphorus nerve agents and pesticides, and the inhibition of AChE is a therapeutic strategy for the treatment of various neurological‐related diseases. The Glu202 is a key residue adjacent to the catalytic His447 and plays important role in catalysis. Although the Glu202 has long been considered as negatively charged in many studies, more and more evidences support a protonated Glu202. However, Glu202 is freely accessible by solvent, and thus it seems more reasonable for Glu202 to majorly take the deprotonated state. In the present work, we carried out a series of molecular dynamics simulations with the Glu202 adopting different protonation states. Our results show that the protonated Glu202 is important in maintaining the key hydrogen bond network that supports the catalytic triad, whereas the deprotonated Glu202 results in the collapse of the key hydrogen bond network which consequently destabilizes the catalytic His447. We also notice that different protonation states of Glu202 merely alters the binding mode of ACh. However, since the catalytic His447 is disrupted if Glu202 is deprotonated, His447 cannot facilitate the nucleophilic attack performed by Ser203. Therefore, the catalytic efficiency of ACh hydrolysis should be remarkably decreased if Glu202 is deprotonated. Our findings suggest that, when designing and developing highly active AChE inhibitors or proposing mechanistic hypotheses for AChE‐catalyzed reactions, the protonated state of Glu202 should be considered.
    Type of Medium: Online Resource
    ISSN: 0887-3585 , 1097-0134
    URL: Issue
    URL: Article
    DOI: 10.1002/prot.v90.2
    DOI: 10.1002/prot.26243
    RVK:
    WA 15000
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 1475032-6
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Computational Design and Crystal Structure of a Highly Efficient Benzoylecgonine Hydrolase
    Wiley ; 2021
    In:  Angewandte Chemie Vol. 133, No. 40 ( 2021-09-27), p. 22130-22136
    Details
    In: Angewandte Chemie, Wiley, Vol. 133, No. 40 ( 2021-09-27), p. 22130-22136
    Abstract: Benzoylecgonine (BZE) is the major toxic metabolite of cocaine and is responsible for the long‐term cocaine‐induced toxicity owing to its long residence time in humans. BZE is also the main contaminant following cocaine consumption. Here, we identified the bacterial cocaine esterase (CocE) as a BZE‐metabolizing enzyme (BZEase), which can degrade BZE into biological inactive metabolites (ecgonine and benzoic acid). CocE was redesigned by a reactant‐state‐based enzyme design theory. An encouraging mutant denoted as BZEase2, presented a 〉 400‐fold improved catalytic efficiency against BZE compared with wild‐type (WT) CocE. In vivo, a single dose of BZEase2 (1 mg kg −1 , IV) could eliminate nearly all BZE within only two minutes, suggesting the enzyme has the potential for cocaine overdose treatment and BZE elimination in the environment by accelerating BZE clearance. The crystal structure of a designed BZEase was also determined.
    Type of Medium: Online Resource
    ISSN: 0044-8249 , 1521-3757
    URL: Issue
    URL: Article
    DOI: 10.1002/ange.v133.40
    DOI: 10.1002/ange.202108559
    RVK:
    VA 2100
    RVK:
    VN 5020
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 505868-5
    detail.hit.zdb_id: 506609-8
    detail.hit.zdb_id: 514305-6
    detail.hit.zdb_id: 505872-7
    detail.hit.zdb_id: 1479266-7
    detail.hit.zdb_id: 505867-3
    detail.hit.zdb_id: 506259-7
    Location Call Number Limitation Availability
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    Online Resource
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