Work

Structural characterization and inhibition of carbonic anhydrase from Candida parapsilosis

Year: 2025

Type: article

Abstract: Fungal carbonic anhydrases (CAs) are metalloenzymes that catalyze the reversible hydration of carbon dioxide and play an essential role in fungal adaptation to environments with fluctuating CO₂ concentrations. The opportunistic pathogen Candida parapsilosis expresses a single β-class CA, CpNce103p, which is structurally distinct from human α-class CAs and therefore may represent a promising antifungal target. Here, we report the biochemical and structural characterization of CpNce103p, including its crystal structure in complex with the classical CA inhibitor acetazolamide. Mass photometry and X-ray crystallography revealed that CpNce103p forms a stable homotetramer, similar to its homolog CaNce103p from C. albicans. Inhibition constants (Ki) were measured for a panel of 16 sulfonamide derivatives. One compound attained single-digit micromolar inhibition of CpNce103p, similar to the Ki of acetazolamide. Docking suggested the compound’s binding mode, featuring zinc coordination and accommodation within the tight cavity. Our findings provide a structural basis for rational inhibitor design targeting fungal β-CAs and support CpNce103p as a viable target for the development of antifungal agents with selective activity.

Source: Journal of Structural Biology X

DOI: 10.1016/j.yjsbx.2025.100140