The Chemical Biology of Human Metallo-β-Lactamase Fold Proteins

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) Vol. 41; no. 4; pp. 338 - 355
• Main Authors: Pettinati, Ilaria, Brem, Jürgen, Lee, Sook Y., McHugh, Peter J., Schofield, Christopher J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2016; Elsevier Trends Journals
• Subjects: Arabidopsis - enzymology; Arabidopsis - genetics; Bacteria - enzymology; Bacteria - genetics; beta-Lactamases - chemistry; beta-Lactamases - genetics; beta-Lactamases - metabolism; beta-Lactams - chemistry; beta-Lactams - metabolism; DNA repair; DNA Repair Enzymes - chemistry; DNA Repair Enzymes - genetics; DNA Repair Enzymes - metabolism; Exodeoxyribonucleases; Gene Expression; Humans; hydrogen sulphide metabolism; Hydrolysis; metallo β-lactamase fold protein; Mitochondrial Proteins - chemistry; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Muscle Proteins - chemistry; Muscle Proteins - genetics; Muscle Proteins - metabolism; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; nuclease; Nucleocytoplasmic Transport Proteins - chemistry; Nucleocytoplasmic Transport Proteins - genetics; Nucleocytoplasmic Transport Proteins - metabolism; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Folding; Protein Interaction Domains and Motifs; Review; RNA processing; Thiolester Hydrolases - chemistry; Thiolester Hydrolases - genetics; Thiolester Hydrolases - metabolism; Zinc - chemistry; Zinc - metabolism; β-lactam antibiotic and cancer drug resistance; metallo β-lactamase fold protein; β-lactam antibiotic and cancer drug resistance; hydrogen sulphide metabolism; RNA processing; nuclease; DNA repair
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2015.12.007

The αββα metallo β-lactamase (MBL) fold (MBLf) was first observed in bacterial enzymes that catalyze the hydrolysis of almost all β-lactam antibiotics, but is now known to be widely distributed. The MBL core protein fold is present in human enzymes with diverse biological roles, including cell detoxification pathways and enabling resistance to clinically important anticancer medicines. Human (h)MBLf enzymes can bind metals, including zinc and iron ions, and catalyze a range of chemically interesting reactions, including both redox (e.g., ETHE1) and hydrolytic processes (e.g., Glyoxalase II, SNM1 nucleases, and CPSF73). With a view to promoting basic research on MBLf enzymes and their medicinal targeting, here we summarize current knowledge of the mechanisms and roles of these important molecules. MBLs are mono- or di-zinc ion-dependent hydrolases that enable bacterial resistance to almost all β-lactam antibiotics. The αββα MBL core fold is widely distributed and supports a range of catalytic activities, including redox reactions. hMBL proteins are a small family of approximately 18 zinc- and iron-dependent proteins with roles in metabolism and/or detoxification and nucleic acid modification. In a notable parallel with the role of bacterial MBLs in antibiotic resistance, some hMBLf enzymes enable resistance to chemotherapy drugs, such as cisplatin and mitomycin C.