Structural basis for carbapenem-hydrolyzing mechanisms of carbapenemases conferring antibiotic resistance.
Carbapenems (imipenem, meropenem, biapenem, ertapenem, and doripenem) are β-lactam antimicrobial agents. Because carbapenems have the broadest spectra among all β-lactams and are primarily used to treat infections by multi-resistant Gram-negative bacteria, the emergence and spread of carbapenemases became a major public health concern. Carbapenemases are the most versatile family of β-lactamases that are able to hydrolyze carbapenems and many other β-lactams. According to the dependency of divalent cations for enzyme activation, carbapenemases can be divided into metallo-carbapenemases (zinc-dependent class B) and non-metallo-carbapenemases (zinc-independent classes A, C, and D). Many studies have provided various carbapenemase structures. Here we present a comprehensive and systematic review of three-dimensional structures of carbapenemase-carbapenem complexes as well as those of carbapenemases. We update recent studies in understanding the enzymatic mechanism of each class of carbapenemase, and summarize structural insights about regions and residues that are important in acquiring the carbapenemase activity.
National Leading Research Laboratory of Drug Resistance Proteomics, Department of Biological Sciences, Myongji University, 116 Myongjiro, Yongin, Gyeonggido 449-728, Korea. najashil@hanmail.net.
Jeong Ho
JH
Jeon
National Leading Research Laboratory of Drug Resistance Proteomics, Department of Biological Sciences, Myongji University, 116 Myongjiro, Yongin, Gyeonggido 449-728, Korea. leo102@naver.com.
Jung Hun
JH
Lee
National Leading Research Laboratory of Drug Resistance Proteomics, Department of Biological Sciences, Myongji University, 116 Myongjiro, Yongin, Gyeonggido 449-728, Korea. leo102@naver.com.
Jae Jin
JJ
Lee
National Leading Research Laboratory of Drug Resistance Proteomics, Department of Biological Sciences, Myongji University, 116 Myongjiro, Yongin, Gyeonggido 449-728, Korea. ryduses@naver.com.
Kwang Seung
KS
Park
National Leading Research Laboratory of Drug Resistance Proteomics, Department of Biological Sciences, Myongji University, 116 Myongjiro, Yongin, Gyeonggido 449-728, Korea. asadmustafa8@gmail.com.
Asad Mustafa
AM
Karim
National Leading Research Laboratory of Drug Resistance Proteomics, Department of Biological Sciences, Myongji University, 116 Myongjiro, Yongin, Gyeonggido 449-728, Korea. crlee@mju.ac.kr.
Chang-Ro
CR
Lee
National Leading Research Laboratory of Drug Resistance Proteomics, Department of Biological Sciences, Myongji University, 116 Myongjiro, Yongin, Gyeonggido 449-728, Korea. bcjeong@mju.ac.kr.
Byeong Chul
BC
Jeong
National Leading Research Laboratory of Drug Resistance Proteomics, Department of Biological Sciences, Myongji University, 116 Myongjiro, Yongin, Gyeonggido 449-728, Korea. sangheelee@mju.ac.kr.
Sang Hee
SH
Lee
D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism*; D004352:Drug Resistance, Microbial; D006868:Hydrolysis; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D015032:Zinc / Q000378:metabolism; D001618:beta-Lactamases / Q000737:chemistry* / Q000378:metabolism*
D001426:Bacterial Proteins; D001618:beta-Lactamases; C063912:carbapenemase; D015032:Zinc