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  Redox regulation of Plasmodium falciparum ornithine δ-aminotransferase

Jortzik, E., Fritz-Wolf, K., Sturm, N., Hipp, M., Rahlfs, S., & Becker, K. (2010). Redox regulation of Plasmodium falciparum ornithine δ-aminotransferase. Journal of Molecular Biology (London), 402(2), 445-459. doi:10.1016/j.jmb.2010.07.039.

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Genre: Journal Article
Alternative Title : Redox regulation of Plasmodium falciparum ornithine delta-aminotransferase

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JMolBiol_402_2010_445.pdf (Any fulltext), 2MB
 
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Jortzik, Esther, Author
Fritz-Wolf, Karin1, Author              
Sturm, Nicole, Author
Hipp, Marieke, Author
Rahlfs, Stefan, Author
Becker, Katja, Author
Affiliations:
1Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society, ou_1497700              

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Free keywords: ornithine aminotransferase; thioredoxin; Plasmodium; redox regulation; crystal structure
 Abstract: Ornithine δ-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 Å 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.

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Language(s): eng - English
 Dates: 2010-07-162010-03-122010-07-202010-07-292010-09-17
 Publication Status: Published in print
 Pages: 15
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 664545
DOI: 10.1016/j.jmb.2010.07.039
URI: http://www.ncbi.nlm.nih.gov/pubmed/20673832
Other: 7642
 Degree: -

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Title: Journal of Molecular Biology (London)
  Other : J Mol Biol
Source Genre: Journal
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Publ. Info: London : Academic Press
Pages: - Volume / Issue: 402 (2) Sequence Number: - Start / End Page: 445 - 459 Identifier: ISSN: 0022-2836
CoNE: https://pure.mpg.de/cone/journals/resource/954922646042