Journal article

Publication year: 2010

Pages: 445-459

Journal: Journal of Molecular Biology

Volume number: 402

Issue number: 2

ISSN: 0022-2836

eISSN: 1089-8638

DOI Link: https://doi.org/10.1016/j.jmb.2010.07.039

Publisher: Elsevier

Abstract: 
Ornithine delta-aminotransferase (OAT) of the malaria parasite Plasmodium falciparum catalyzes the reversible conversion of ornithine into glutamate-5-semialdehyde and glutamate and is-in contrast to its human counterpart-activated by thioredoxin (Trx) by a factor of 10. Trx, glutaredoxin, and plasmoredoxin are redox-active proteins that play a crucial role in the maintenance and control of redox reactions, and were shown to interact with P. falciparum OAT. OAT, which is involved in ornithine homeostasis and proline biosynthesis, is essential for mitotic cell division in rapidly growing cells, thus representing a potential target for chemotherapeutic intervention. Here we report the three-dimensional crystal structure of P. falciparum OAT at 2.3 angstrom resolution. The overall structure is very similar to that of the human OAT. However, in plasmodial OAT, the loop involved in substrate binding contains two cysteine residues, which are lacking in human OAT. Site-directed mutagenesis of these cysteines and functional analysis demonstrated that Cys154 and Cys163 mediate the interaction with Trx. Interestingly, the Cys154 -> Ser mutant has a strongly reduced specific activity, most likely due to impaired binding of ornithine. Cys154 and Cys163 are highly conserved in Plasmodium but do not exist in other organisms, suggesting that redox regulation of OAT by Trx is specific for malaria parasites. Plasmodium might require a tight Trx-mediated control of OAT activity for coordinating ornithine homeostasis, polyamine synthesis, proline synthesis, and mitotic cell division. (C) 2010 Elsevier Ltd. All rights reserved.

Harvard Citation style: Jortzik, E., Fritz-Wolf, K., Sturm, N., Hipp, M., Rahlfs, S. and Becker, K. (2010) Redox Regulation of Plasmodium falciparum Ornithine delta-Aminotransferase, Journal of Molecular Biology, 402(2), pp. 445-459. https://doi.org/10.1016/j.jmb.2010.07.039

APA Citation style: Jortzik, E., Fritz-Wolf, K., Sturm, N., Hipp, M., Rahlfs, S., & Becker, K. (2010). Redox Regulation of Plasmodium falciparum Ornithine delta-Aminotransferase. Journal of Molecular Biology. 402(2), 445-459. https://doi.org/10.1016/j.jmb.2010.07.039