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Crystal Structures of Vertebrate Dihydropyrimidinase and Complexes from Tetraodon nigroviridis with Lysine Carbamylation

Hsieh, Yin-Cheng and Chen, Mei-Chun and Hsu, Ching-Chen and Chan, Sunney I. and Yang, Yuh-Shyong and Chen, Chun-Jung (2013) Crystal Structures of Vertebrate Dihydropyrimidinase and Complexes from Tetraodon nigroviridis with Lysine Carbamylation. Journal of Biological Chemistry, 288 (42). pp. 30645-30658. ISSN 0021-9258. PMCID PMC3798535. doi:10.1074/jbc.M113.496778.

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Lysine carbamylation, a post-translational modification, facilitates metal coordination for specific enzymatic activities. We have determined structures of the vertebrate dihydropyrimidinase from Tetraodon nigroviridis (TnDhp) in various states: the apoenzyme as well as two forms of the holoenzyme with one and two metals at the catalytic site. The essential active-site structural requirements have been identified for the possible existence of four metal-mediated stages of lysine carbamylation. Only one metal is sufficient for stabilizing lysine carbamylation; however, the post-translational lysine carbamylation facilitates additional metal coordination for the regulation of specific enzymatic activities through controlling the conformations of two dynamic loops, Ala^(69)–Arg^(74) and Met^(158)–Met^(165), located in the tunnel for the substrate entrance. The substrate/product tunnel is in the “open form” in the apo-TnDhp, in the “intermediate state” in the monometal TnDhp, and in the “closed form” in the dimetal TnDhp structure, respectively. Structural comparison also suggests that the C-terminal tail plays a role in the enzymatic function through interactions with the Ala^(69)–Arg^(74) dynamic loop. In addition, the structures of the dimetal TnDhp in complexes with hydantoin, N-carbamyl-β-alanine, and N-carbamyl-β-amino isobutyrate as well as apo-TnDhp in complex with a product analog, N-(2-acetamido)-iminodiacetic acid, have been determined. These structural results illustrate how a protein exploits unique lysines and the metal distribution to accomplish lysine carbamylation as well as subsequent enzymatic functions.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Chan, Sunney I.0000-0002-5348-2723
Chen, Chun-Jung0000-0002-5157-4288
Additional Information:© 2013 American Society for Biochemistry and Molecular Biology, Inc. Received July 11, 2013; Revision received August 26, 2013. First Published on September 4, 2013. We are indebted to the supporting staffs at beamlines BL13B1 and BL13C1 of the National Synchrotron Radiation Research Center and to Masato Yoshimura and Hirofumi Ishii at Beamlines BL12B2 and BL44XU of SPring-8. This work was supported in part by National Science Council (NSC) Grants NSC 98-2311-B-213-MY3 and NSC 101-2628-B-213-MY4 and National Synchrotron Radiation Center Grants 1003RSB02 and 1013RSB02 (to C. J. C.) and NSC Grant NSC 99-2311-B-009-004-MY3 and the Aiming for the Top University and Elite Research Center Development Plan of Ministry of Education (MOE-ATU Plan) (to Y. S. Y.).
Funding AgencyGrant Number
National Science Council (Tapiei)NSC 98-2311-B-213-MY3
National Science Council (Taipei)NSC 101-2628-B-213-MY4
National Synchrotron Radiation Center1003RSB02
National Synchrotron Radiation Center1013RSB02
National Science Council (Taipei)NSC 99-2311-B-009-004-MY3
Ministry of Education (Taipei)UNSPECIFIED
Subject Keywords:Crystal Structure; Crystallography; Metalloenzymes Post-translational Modification; Protein Carboxylation; Protein Complexes
Issue or Number:42
PubMed Central ID:PMC3798535
Record Number:CaltechAUTHORS:20140214-093236082
Persistent URL:
Official Citation:Hsieh, Y.-C., Chen, M.-C., Hsu, C.-C., Chan, S. I., Yang, Y.-S., & Chen, C.-J. (2013). Crystal Structures of Vertebrate Dihydropyrimidinase and Complexes from Tetraodon nigroviridis with Lysine Carbamylation: METAL AND STRUCTURAL REQUIREMENTS FOR POST-TRANSLATIONAL MODIFICATION AND FUNCTION. Journal of Biological Chemistry, 288(42), 30645-30658. doi: 10.1074/jbc.M113.496778
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:43831
Deposited On:18 Feb 2014 15:41
Last Modified:10 Nov 2021 16:43

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