title: Structure of a fungal form of aspartate-semialdehyde dehydrogenase from Aspergillus fumigatus.
abstract: Aspartate-semialdehyde dehydrogenase (ASADH) functions at a critical junction in the aspartate biosynthetic pathway and represents a validated target for antimicrobial drug design. This enzyme catalyzes the NADPH-dependent reductive dephosphorylation of β-aspartyl phosphate to produce the key intermediate aspartate semialdehyde. The absence of this entire pathway in humans and other mammals will allow the selective targeting of pathogenic microorganisms for antimicrobial development. Here, the X-ray structure of a new form of ASADH from the pathogenic fungal species Aspergillus fumigatus has been determined. The overall structure of this enzyme is similar to those of its bacterial orthologs, but there are some critical differences both in biological assembly and in secondary-structural features that can potentially be exploited for the development of species-selective drugs with selective toxicity against infectious fungal organisms.
authors.affiliation: Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, USA.
authors.forename: Gopal P
authors.initials: GP
authors.lastname: Dahal
authors.affiliation: Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, USA.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Viola
mesh_terms: D000595:Amino Acid Sequence; D001223:Aspartate-Semialdehyde Dehydrogenase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D001232:Aspergillus fumigatus / Q000737:chemistry* / Q000201:enzymology; D001665:Binding Sites; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005656:Fungal Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D007700:Kinetics; D008958:Models, Molecular; D009249:NADP / Q000737:chemistry / Q000378:metabolism; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D005656:Fungal Proteins; D011994:Recombinant Proteins; C032197:beta-aspartyl phosphate; D001224:Aspartic Acid; C006644:aspartic semialdehyde; D009249:NADP; D001223:Aspartate-Semialdehyde Dehydrogenase
keywords: Aspergillus fumigatus; aspartate-semialdehyde dehydrogenase; oligomeric arrangement; pathogenic fungi; structural comparison