4ZHS: Crystal Structure of Aspartate Semialdehyde Dehydrogenase from Trichophyton rubrum

Aspartate-beta-semialdehyde dehydrogenase (ASADH) catalyzes the second reaction in the aspartate pathway, a pathway required for the biosynthesis of one fifth of the essential amino acids in plants and microorganisms. Microarray analysis of a fungal pathogen T. rubrum responsible for most human dermatophytoses identified the upregulation of ASADH (trASADH) expression when the fungus is exposed to human skin, underscoring its potential as a drug target. Here we report the crystal structure of trASADH, revealing a tetrameric ASADH with a GAPDH-like fold. The tetramerization of trASADH was confirmed by sedimentation and SAXS experiments. Native PAGE demonstrated that this ASADH tetramerization is apparently universal in fungal species, unlike the functional dimer that is observed in all bacterial ASADHs. The helical subdomain in dimeric bacteria ASADH is replaced by the cover loop in archaeal/fungal ASADHs, presenting the determinant for this altered oligomerization. Mutations that disrupt the tetramerization of trASADH also abolish the catalytic activity, suggesting that the tetrameric state is required to produce the active fungal enzyme form. Our findings provide a basis to categorize ASADHs into dimeric and tetrameric enzymes, adopting a different orientation for NADP binding and offer a structural framework for designing drugs that can specifically target the fungal pathogens.
PDB ID: 4ZHSDownload
MMDB ID: 136917
PDB Deposition Date: 2015/4/27
Updated in MMDB: 2018/07
Experimental Method:
x-ray diffraction
Resolution: 2.603  Å
Source Organism:
Similar Structures:
Biological Unit for 4ZHS: tetrameric; determined by author and by software (PISA)
Molecular Components in 4ZHS
Label Count Molecule
Proteins (4 molecules)
Aspartate Semialdehyde Dehydrogenase
Molecule annotation
Chemicals (4 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB