Crystal structure of betaine aldehyde dehydrogenase from Burkholderia pseudomallei
Dylan K. Beard, Sandhya Subramanian, Jan Abendroth, Thomas E. Edwards, Peter J. Myler, and Oluwatoyin A. Asojo [1]
Molecular Tour
Burkholderia pseudomallei is a rod-shaped, motile, flagellated, soil-dwelling gram-negative proteobacterium of the Burkholderiaceae family that thrives in tropical and subtropical regions. B. pseudomallei causes melioidosis, a deadly emerging opportunistic infection mainly of the immunocompromised. B. pseudomallei is transmitted through open wounds, contact with contaminated soil and water, ingestion, or inhalation, and is also a potential biological warfare agent. The Seattle Structural Genomics Center for Infectious Disease (SSGCID) has determined and solved X-ray structures of a potential drug target betaine aldehyde dehydrogenase (BADH) from B. pseudomallei (BpBADH):
- , colored in rainbow from blue (N-terminus) to red (C-terminus); 6wsa.
- , monomers are shown as green and cyan ribbons, with NAD shown as ball-and-sticks; 6wsb.
BpBADH has a prototypical BADH topology and shares considerable structure and sequence similarity with the ortholog from P. aeruginosa (PaBADH); see static image below:
Figure 3. Proposed reaction steps of the conversion of PUT to HSP by the bacterial HSS. Relevant residues, NAD(H), PUT, HSP and intermediates are shown as two-dimensional structure representations. Hydrogen bonds are depicted as blue dotted lines, delocalized electrons as dashed lines, cation-π interactions as orange dash-dotted lines and electron transfers as red arrows. Atom numbering is given for PUT and HSP in green. For simplicity, steps 5 and 6 are shown in combined depictions with correspondingly labeled electron transfers. A more detailed sequence of reaction steps was described before
[2] and additional intervening reaction steps are proposed in Fig. S2 of Helfrich & Scheidig, 2021
[3].
The structures are similar to those of BADH from Pseudomonas aeruginosa (PaBADH). The co-factor binding domains of BpBADH (6wsb) and PaBADH (4caz) are well conserved (identical residues of both structures are labeled in green, while non-identical in red):
- (6wsb).
- (4caz).
- (BpBADH is colored in green, PaBADH is in olive).
PaBADH is inhibited by the drug disulfiram which is an approved drug. Both structures show the irreversibly inhibited by disulfiram. Our preliminary analysis could facilitate drug repurposing studies for melioidosis. This project is an educational collaboration between the SSGCID and Hampton University. The SSGCID consortium is directed by Dr. Peter Myler (principal investigator) and comprises many different scientists working at multiple centers towards determining the three-dimensional structures of proteins from biodefense organisms and emerging infectious diseases. Dylan K. Beard was part of a pilot Hampton University Chemistry Education and Mentorship Course-based undergraduate research (HU-ChEM CURES) funded by the NIGMS.
References
- ↑ Beard DK, Subramanian S, Abendroth J, Dranow DM, Edwards TE, Myler PJ, Asojo OA. Crystal structure of betaine aldehyde dehydrogenase from Burkholderia pseudomallei. Acta Crystallogr F Struct Biol Commun. 2022 Feb 1;78(Pt 2):45-51. doi:, 10.1107/S2053230X21013455. Epub 2022 Jan 27. PMID:35102892 doi:http://dx.doi.org/10.1107/S2053230X21013455
- ↑ Krossa S, Faust A, Ober D, Scheidig AJ. Comprehensive Structural Characterization of the Bacterial Homospermidine Synthase-an Essential Enzyme of the Polyamine Metabolism. Sci Rep. 2016 Jan 18;6:19501. doi: 10.1038/srep19501. PMID:26776105 doi:http://dx.doi.org/10.1038/srep19501
- ↑ Helfrich F, Scheidig AJ. Structural and catalytic characterization of Blastochloris viridis and Pseudomonas aeruginosa homospermidine synthases supports the essential role of cation-pi interaction. Acta Crystallogr D Struct Biol. 2021 Oct 1;77(Pt 10):1317-1335. doi:, 10.1107/S2059798321008937. Epub 2021 Sep 23. PMID:34605434 doi:http://dx.doi.org/10.1107/S2059798321008937
