Structural analysis of substrate recognition loop flexibility in D-arabinose dehydrogenase from Candida auris

Area of Science:

• Mycology
• Structural Biology
• Antimicrobial Resistance

Background:

• Candida auris is a multidrug-resistant fungal pathogen causing global health concerns.
• Oxidative stress resistance is crucial for C. auris survival and virulence.
• d-arabinose dehydrogenase (CaAldO) is vital for synthesizing the antioxidant d-erythroascorbic acid (EASC) in C. auris.

Purpose of the Study:

• To determine the high-resolution crystal structure of C. auris d-arabinose dehydrogenase (CaAldO).
• To understand the structural basis of CaAldO's role in oxidative stress resistance.
• To compare CaAldO with its homolog for insights into antifungal strategies.

Main Methods:

• High-resolution crystal structure determination of CaAldO at 1.95 Å.
• Analysis of cofactor-binding pocket and substrate recognition loops.
• Structural comparison with homologous enzymes, such as ScAra1.

Main Results:

• The crystal structure of CaAldO reveals a TIM-barrel fold with a cofactor-binding pocket formed by four loop regions.
• Flexible Loops A and C in the substrate-binding pocket facilitate conformational changes.
• Significant structural differences were observed between CaAldO and ScAra1, particularly in substrate recognition and cofactor-binding pockets.

Conclusions:

• The structural flexibility of CaAldO contributes to its function in oxidative stress resistance.
• Distinct structural features of CaAldO compared to homologs provide potential targets for novel antifungal therapies.
• Understanding CaAldO's structure is key to developing strategies against the emerging pathogen Candida auris.