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Journal article
Crystal Structure of Arginase from Plasmodium falciparum and Implications for L-Arginine Depletion in Malarial Infection
Biochemistry (Easton), v 49(26), pp 5600-5608
06 Jul 2010
PMID: 20527960
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Abstract
The 2.15 angstrom resolution crystal structure of arginase from Plasmodium falciparum, the parasite that causes cerebral malaria, is reported in complex with the boronic acid inhibitor 2(S)-amino-6-boronohexanoic acid (ABEL) (K-d = 11 mu M). This is the first crystal structure of a parasitic arginase. Various protein constructs were explored to identify an optimally active enzyme form for inhibition and structural studies and to probe the structure and function of two polypeptide insertions unique to malarial arginase: a 74-residue low-complexity region contained in loop L2 and an 11-residue segment contained in loop L8. Structural studies indicate that the low-complexity region is largely disordered and is oriented away from the trimer interface; its deletion does not significantly compromise enzyme activity. The loop L8 insertion is located at the trimer interface and makes several intra- and intermolecular interactions important for enzyme function. In addition, we also demonstrate that arg- Plasmodium herghei sporozoites show significantly decreased liver infectivity in vivo. Therefore, inhibition of malarial arginase may serve as a possible candidate for antimalarial therapy against liver-stage infection, and ABH may serve as a lead for the development of inhibitors.
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Details
- Title
- Crystal Structure of Arginase from Plasmodium falciparum and Implications for L-Arginine Depletion in Malarial Infection
- Creators
- Daniel P. Dowling - University of PennsylvaniaMonica Ilies - University of PennsylvaniaKellen L. Olszewski - Princeton UniversitySilvia Portugal - University of LisbonMaria M. Mota - University of LisbonManuel Llinas - Center for Disease Dynamics, Economics & PolicyDavid W. Christianson - University of PennsylvaniaArgonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Publication Details
- Biochemistry (Easton), v 49(26), pp 5600-5608
- Publisher
- American Chemical Society; Washington, DC
- Number of pages
- 9
- Grant note
- Fundacao para a Ciencia e Tecnologia (FCT, Portugal); Fundacao para a Ciencia e a Tecnologia (FCT) GM49758; 1DP2OD001315-01 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA National Science Foundation; National Science Foundation (NSF) Howard Hughes Medical Institute RR-15301 / National Center for Research Resources at the National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) DE-AC02-06CH11357 / U.S. Department of Energy, Office of Basic Energy Sciences; United States Department of Energy (DOE) Burroughs Wellcome Fund
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemistry
- Web of Science ID
- WOS:000279197300022
- Scopus ID
- 2-s2.0-77954199478
- Other Identifier
- 991020545127204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology