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Structure of the First Fungal Enzyme Form of Aspartate β‐Semialdehyde Dehydrogenase
Author(s) -
Arachea Buenafe T,
Liu Xuying,
Pavlovsky Alexander,
Viola Ronald E
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.469.1
Subject(s) - enzyme , cofactor , biochemistry , dehydrogenase , dimer , oxidoreductase , active site , candida albicans , nad+ kinase , yeast , chemistry , stereochemistry , biology , antifungal drug , microbiology and biotechnology , organic chemistry
The enzyme aspartate semialdehyde dehydrogenase (ASADH) catalyzes the conversion of β‐aspartyl phosphate to aspartate β‐semialdehyde, a critical transformation step that is essential in microbial amino acid biosynthesis. This enzyme is found exclusively in bacteria, fungi and plants thus making it a potential target for drug development. Representative structures of bacterial and archael organisms have been previously determined; however no structural information on any fungal ASADH has been available. Here we report the first structure of ASADH purified from yeast Candida albicans and crystallized in the presence of its nucleotide cofactor. The fungal enzyme is a functional dimer with similar overall fold and domain organization with its bacterial counterparts. More detailed structural comparison between the fungal and bacterial ASADHs revealed differences in secondary structural elements and in the nucleotide cofactor binding that may explain the lower catalytic activity observed for the fungal enzyme. Moreover, alterations in the dimer interface through the deletion of a helical subdomain and the replacement of amino acids involved in critical hydrogen bonding network results in the disruption of intersubunit communication channels required to support an alternating site catalytic mechanism. Elucidation of the structural details of this fungal enzyme allows assessment of ASADH as a possible target for antifungal drug development. Crystallization studies of fungal ASADH‐inhibitor complexes are currently underway to provide additional information for inhibitor design.