Crystal Structure of Phosphoserine BlaC from Mycobacterium tuberculosis Inactivated by Bis(Benzoyl) Phosphate

• Published in: International journal of molecular sciences 2019-07, Vol.20 (13), p.3247
• Main Authors: Moural, Timothy W, White, Dawanna Shar-Day, Choy, Cindy J, Kang, Chulhee, Berkman, Clifford E
• Format: Article
• Language: English
• Subjects: Amides; Amino Acid Sequence; Antibiotic resistance; Antibiotics; Bacterial infections; Benzoates - chemistry; Benzoates - pharmacology; beta-Lactam Resistance - drug effects; beta-Lactamase Inhibitors - chemistry; beta-Lactamase Inhibitors - pharmacology; beta-Lactamases - chemistry; beta-Lactamases - metabolism; Carbon; Crystal structure; Crystallography, X-Ray; Enzymes; Humans; Infections; Infectious diseases; Inhibitors; Models, Molecular; Mycobacterium tuberculosis; Mycobacterium tuberculosis - chemistry; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - enzymology; Mycobacterium tuberculosis - metabolism; Organophosphates - chemistry; Organophosphates - pharmacology; Phosphates; Phosphonates; Phosphorylation; Phosphoserine; Protein Conformation - drug effects; Sequence Alignment; Tuberculosis; Tuberculosis - drug therapy; Tuberculosis - microbiology; β-lactam antibiotic resistance; β-Lactam antibiotics; β-lactamase
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20133247

, the pathogen responsible for tuberculosis (TB), is the leading cause of death from infectious disease worldwide. The class A serine β-lactamase BlaC confers resistance to conventional β-lactam antibiotics. As the primary mechanism of bacterial resistance to β-lactam antibiotics, the expression of a β-lactamase by results in hydrolysis of the β-lactam ring and deactivation of these antibiotics. In this study, we conducted protein X-ray crystallographic analysis of the inactivation of BlaC, upon exposure to the inhibitor bis(benzoyl) phosphate. Crystal structure data confirms that serine β-lactamase is phosphorylated at the catalytic serine residue (Ser-70) by this phosphate-based inactivator. This new crystallographic evidence suggests a mechanism for phosphorylation of BlaC inhibition by bis(benzoyl) phosphate over acylation. Additionally, we confirmed that bis(benzoyl) phosphate inactivated BlaC in a time-dependent manner.