Bacterial metalloenzymes and other zinc-binding enzymes

Bacterial metalloenzymes and other zinc-binding enzymes constitute a diverse group of proteins that require zinc ions (Zn2+) for their catalytic activity, structural stability, or regulatory functions (Maret, 2013, Metallomics) [4]. This category includes several high-priority therapeutic targets such as metallo-beta-lactamases (MBLs), which are responsible for resistance against carbapenem antibiotics, and peptide deformylase (PDF), an enzyme essential for the removal of the N-formyl group from newly synthesized proteins (Bush & Bradford, 2019, Nat Rev Microbiol; Sangshetti et al., 2015, Curr Med Chem) [1, 2]. Other significant members include LpxC, which catalyzes the rate-limiting step in Lipid A biosynthesis in Gram-negative bacteria, and various bacterial carbonic anhydrases and proteases (Liang et al., 2016, Curr Top Med Chem) [3]. These enzymes are critical for bacterial survival, pathogenesis, and the evasion of the host immune system or antibiotic treatment. Because many of these enzymes have distinct active site architectures compared to their human counterparts, they offer opportunities for the development of selective antimicrobial agents. However, the design of such inhibitors is complicated by the need to avoid cross-reactivity with essential human zinc-dependent enzymes like matrix metalloproteinases (MMPs) and histone deacetylases (HDACs) (Maret, 2013) [4]. Current drug discovery efforts focus on small molecules that utilize zinc-binding groups to coordinate with the metal center, effectively neutralizing the enzyme's function in multi-drug resistant infections.

Other names

Bacterial zinc-dependent enzymesBacterial metalloproteinsZinc-binding bacterial enzymes

Inhibition of enzymatic activity through coordination with the active-site zinc ion or competitive binding at the substrate pocket (Bush & Bradford, 2019; Sangshetti et al., 2015).