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postgraduate thesis: Structural analysis of Zn-Zn distance in NDM-1's beta-lactam hydrolysis mechanism

TitleStructural analysis of Zn-Zn distance in NDM-1's beta-lactam hydrolysis mechanism
Authors
Issue Date2014
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Hui, K. A. [許家朗]. (2014). Structural analysis of Zn-Zn distance in NDM-1's beta-lactam hydrolysis mechanism. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5318938
AbstractIntroduction: The New Delhi metallo-β-lactamase (NDM-1) is an enzyme synthesized by bacterium which hydrolyses β-lactam antibiotics and inhibits their antibiotic effects. Its active site is highly diverse and the hydrolysis mechanism is not yet fully understood. So, there is currently no clinically useful inhibitor for this enzyme. Due to this β-lactam resistant characteristics and the ease of horizontal gene transfer between bacteria, NDM-1 producing bacteria poses a great threat to public health. Objective: Structural analysis on Zn-Zn distance in the active site of NDM-1 was carried out in order to gain a better insight on its hydrolysis mechanism. Method: Structures of NDM-1 were obtained from PDB database and were viewed on PyMOL. Out of 22 NDM-1 structures searched, 12 of them fulfilled the inclusion criterion and were included in this study. Zn-Zn distances were compared with different factors including pH and temperature during crystallization, presence of water in the active site and nature of ligand bound to active site. Results: A trend was observed when Zn-Zn distances were compared with pH. There was also a correlation between Zn-Zn distance and nature of ligand. Distance between the 2 zinc ions in the active site increased in acidic pH value of 6.5 or below and it favours substrate hydrolysis while neutral or alkaline pH shortened the distance between zinc ions leading to hydrolysis inhibition. Discussion: One NDM-1 structure can hydrolyse the substrate in the absence of water molecule. It suggested that there might be another alternative mechanism which does not involve water molecule as nucleophile. Future study can be carried out to verify this hypothesis. On the other hand, it was also suggested that a lower pH, likely to be a pH value of 6.5 or below, could lead to a relatively higher Zn-Zn distance, likely to be 4.00 Å or above. A Zn-Zn distance of 4.00 Å or above would facilitate the hydrolysis mechanism. In other words, a pH value lower than 6.5 might also promote the hydrolysis action against β-lactams. These give us a deeper understanding into the hydrolysis mechanism of NDM-1 and might be useful in future development of clinical inhibitor to tackle the public health threat brought by NDM-1.
DegreeMaster of Medical Sciences
SubjectBeta lactamases
Dept/ProgramPhysiology
Persistent Identifierhttp://hdl.handle.net/10722/206564

 

DC FieldValueLanguage
dc.contributor.authorHui, Ka-long, Aaron-
dc.contributor.author許家朗-
dc.date.accessioned2014-11-19T23:15:29Z-
dc.date.available2014-11-19T23:15:29Z-
dc.date.issued2014-
dc.identifier.citationHui, K. A. [許家朗]. (2014). Structural analysis of Zn-Zn distance in NDM-1's beta-lactam hydrolysis mechanism. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5318938-
dc.identifier.urihttp://hdl.handle.net/10722/206564-
dc.description.abstractIntroduction: The New Delhi metallo-β-lactamase (NDM-1) is an enzyme synthesized by bacterium which hydrolyses β-lactam antibiotics and inhibits their antibiotic effects. Its active site is highly diverse and the hydrolysis mechanism is not yet fully understood. So, there is currently no clinically useful inhibitor for this enzyme. Due to this β-lactam resistant characteristics and the ease of horizontal gene transfer between bacteria, NDM-1 producing bacteria poses a great threat to public health. Objective: Structural analysis on Zn-Zn distance in the active site of NDM-1 was carried out in order to gain a better insight on its hydrolysis mechanism. Method: Structures of NDM-1 were obtained from PDB database and were viewed on PyMOL. Out of 22 NDM-1 structures searched, 12 of them fulfilled the inclusion criterion and were included in this study. Zn-Zn distances were compared with different factors including pH and temperature during crystallization, presence of water in the active site and nature of ligand bound to active site. Results: A trend was observed when Zn-Zn distances were compared with pH. There was also a correlation between Zn-Zn distance and nature of ligand. Distance between the 2 zinc ions in the active site increased in acidic pH value of 6.5 or below and it favours substrate hydrolysis while neutral or alkaline pH shortened the distance between zinc ions leading to hydrolysis inhibition. Discussion: One NDM-1 structure can hydrolyse the substrate in the absence of water molecule. It suggested that there might be another alternative mechanism which does not involve water molecule as nucleophile. Future study can be carried out to verify this hypothesis. On the other hand, it was also suggested that a lower pH, likely to be a pH value of 6.5 or below, could lead to a relatively higher Zn-Zn distance, likely to be 4.00 Å or above. A Zn-Zn distance of 4.00 Å or above would facilitate the hydrolysis mechanism. In other words, a pH value lower than 6.5 might also promote the hydrolysis action against β-lactams. These give us a deeper understanding into the hydrolysis mechanism of NDM-1 and might be useful in future development of clinical inhibitor to tackle the public health threat brought by NDM-1.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.lcshBeta lactamases-
dc.titleStructural analysis of Zn-Zn distance in NDM-1's beta-lactam hydrolysis mechanism-
dc.typePG_Thesis-
dc.identifier.hkulb5318938-
dc.description.thesisnameMaster of Medical Sciences-
dc.description.thesislevelMaster-
dc.description.thesisdisciplinePhysiology-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5318938-

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