5V4L

Cryptococcus neoformans adenylosuccinate lyase

Summary for 5V4L

• Entry DOI: 10.2210/pdb5v4l/pdb
• Descriptor: Adenylosuccinate lyase (2 entities in total)
• Functional Keywords: lyase, fumerase, adenylosuccinate, saicar
• Biological source: Cryptococcus neoformans
• Total number of polymer chains: 4
• Total formula weight: 214849.42

Authors

Chitty, J.,Williams, S.J.,Kobe, B.,Fraser, J.A. (deposition date: 2017-03-09, release date: 2017-06-07, Last modification date: 2023-10-04)

Primary citation

Chitty, J.L.,Blake, K.L.,Blundell, R.D.,Koh, Y.Q.A.E.,Thompson, M.,Robertson, A.A.B.,Butler, M.S.,Cooper, M.A.,Kappler, U.,Williams, S.J.,Kobe, B.,Fraser, J.A.
Cryptococcus neoformans ADS lyase is an enzyme essential for virulence whose crystal structure reveals features exploitable in antifungal drug design.
J. Biol. Chem., 292:11829-11839, 2017

PubMed Abstract: There is significant clinical need for new antifungal agents to manage infections with pathogenic species such as Because the purine biosynthesis pathway is essential for many metabolic processes, such as synthesis of DNA and RNA and energy generation, it may represent a potential target for developing new antifungals. Within this pathway, the bifunctional enzyme adenylosuccinate (ADS) lyase plays a role in the formation of the key intermediates inosine monophosphate and AMP involved in the synthesis of ATP and GTP, prompting us to investigate ADS lyase in Here, we report that encodes ADS lyase in We found that an Δ mutant is an adenine auxotroph and is unable to successfully cause infections in a murine model of virulence. Plate assays revealed that production of a number of virulence factors essential for dissemination and survival of in a host environment was compromised even with the addition of exogenous adenine. Purified recombinant ADS lyase shows catalytic activity similar to its human counterpart, and its crystal structure, the first fungal ADS lyase structure determined, shows a high degree of structural similarity to that of human ADS lyase. Two potentially important amino acid differences are identified in the crystal structure, in particular a threonine residue that may serve as an additional point of binding for a fungal enzyme-specific inhibitor. Besides serving as an antimicrobial target, ADS lyase inhibitors may also serve as potential therapeutics for metabolic disease; rather than disrupt ADS lyase, compounds that improve the stability the enzyme may be used to treat ADS lyase deficiency disease.

PubMed: 28559277
DOI: 10.1074/jbc.M117.787994

Experimental method

X-RAY DIFFRACTION (2.1 Å)