Related Experiment Videos
The x-ray crystal structure of phosphomannose isomerase from Candida albicans at 1.7 angstrom resolution
A Cleasby1, A Wonacott, T Skarzynski
1Glaxo Wellcome Research and Development, Department of Biomolecular Structure, Stevenage, UK.
Abstract:
Phosphomannose isomerase (PMI) catalyses the reversible isomerization of fructose-6-phosphate (F6P) and mannose-6-phosphate (M6P). Absence of PMI activity in yeasts causes cell lysis and thus the enzyme is a potential target for inhibition and may be a route to antifungal drugs. The 1.7 A crystal structure of PMI from Candida albicans shows that the enzyme has three distinct domains. The active site lies in the central domain, contains a single essential zinc atom, and forms a deep, open cavity of suitable dimensions to contain M6P or F6P The central domain is flanked by a helical domain on one side and a jelly-roll like domain on the other.
Insights
Phosphomannose isomerase (PMI) is crucial for yeast survival. Inhibiting this enzyme, essential for mannose-6-phosphate and fructose-6-phosphate conversion, offers a promising antifungal drug strategy.
Area of Science:
- Biochemistry
- Structural Biology
- Medicinal Chemistry
Background:
- Phosphomannose isomerase (PMI) catalyzes the interconversion of fructose-6-phosphate (F6P) and mannose-6-phosphate (M6P).
- PMI deficiency in yeasts leads to cell lysis, identifying it as a potential antifungal drug target.
- Understanding PMI's structure is key to developing novel antifungal agents.
Purpose of the Study:
- To elucidate the crystal structure of Phosphomannose isomerase (PMI) from Candida albicans.
- To identify the active site characteristics and potential inhibition mechanisms.
- To provide structural insights for the rational design of antifungal drugs targeting PMI.
Main Methods:
- X-ray crystallography was employed to determine the 1.7 Å resolution structure of Candida albicans PMI.
- Structural analysis focused on identifying the enzyme's domains and active site features.
- Computational modeling may be used to assess substrate binding within the active site cavity.
Main Results:
- The crystal structure reveals PMI comprises three distinct domains: a central domain, a helical domain, and a jelly-roll like domain.
- The active site is located in the central domain and contains a single essential zinc atom.
- The active site forms a deep, open cavity capable of accommodating M6P or F6P.
Conclusions:
- The determined structure of Candida albicans PMI provides a detailed molecular blueprint.
- The active site's architecture, including the essential zinc ion, offers specific targets for inhibitor design.
- This structural information facilitates the development of new antifungal therapies by targeting PMI.