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Crystal structures of Bacillus caldovelox arginase in complex with substrate and inhibitors reveal new insights into activation, inhibition and catalysis in the arginase superfamily.

Bewley MC, Jeffrey PD, Patchett ML, Kanyo ZF, Baker EN
Structure 7 435-48 (1999)
Related entries: 1cev, 2cev, 4cev, 5cev

Cited: 74 times
EuropePMC logo PMID: 10196128

Abstract

Background

Arginase is a manganese-dependent enzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. In ureotelic animals arginase is the final enzyme of the urea cycle, but in many species it has a wider role controlling the use of arginine for other metabolic purposes, including the production of creatine, polyamines, proline and nitric oxide. Arginase activity is regulated by various small molecules, including the product L-ornithine. The aim of these structural studies was to test aspects of the catalytic mechanism and to investigate the structural basis of arginase inhibition.

Results

We report here the crystal structures of arginase from Bacillus caldovelox at pH 5.6 and pH 8.5, and of binary complexes of the enzyme with L-arginine, L-ornithine and L-lysine at pH 8.5. The arginase monomer comprises a single compact alpha/beta domain that further associates into a hexameric quaternary structure. The binary complexes reveal a common mode of ligand binding, which places the substrate adjacent to the dimanganese centre. We also observe a conformational change that impacts on the active site and is coupled with the occupancy of an external site by guanidine or arginine.

Conclusion

The structures reported here clarify aspects of the active site and indicate key features of the catalytic mechanism, including substrate coordination to one of the manganese ions and an orientational role for a neighboring histidine residue. Stereospecificity for L-amino acids is found to depend on their precise recognition at the active-site rim. Identification of a second arginine-binding site, remote from the active site, and associated conformational changes lead us to propose a regulatory role for this site in substrate hydrolysis.

Articles - 3cev mentioned but not cited (4)

  1. Replacing Mn(2+) with Co(2+) in human arginase i enhances cytotoxicity toward l-arginine auxotrophic cancer cell lines. Stone EM, Glazer ES, Chantranupong L, Cherukuri P, Breece RM, Tierney DL, Curley SA, Iverson BL, Georgiou G. ACS Chem Biol 5 333-342 (2010)
  2. Crystal structures of TM0549 and NE1324--two orthologs of E. coli AHAS isozyme III small regulatory subunit. Petkowski JJ, Chruszcz M, Zimmerman MD, Zheng H, Skarina T, Onopriyenko O, Cymborowski MT, Koclega KD, Savchenko A, Edwards A, Minor W. Protein Sci 16 1360-1367 (2007)
  3. The second-shell metal ligands of human arginase affect coordination of the nucleophile and substrate. Stone EM, Chantranupong L, Georgiou G. Biochemistry 49 10582-10588 (2010)
  4. A synthetic peptide as an allosteric inhibitor of human arginase I and II. Gao K, Lunev S, van den Berg MPM, Al-Dahmani ZM, Evans S, Mertens DALJ, Meurs H, Gosens R, Groves MR. Mol Biol Rep 48 1959-1966 (2021)


Reviews citing this publication (5)

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  5. Polyamine Deacetylase Structure and Catalysis: Prokaryotic Acetylpolyamine Amidohydrolase and Eukaryotic HDAC10. Shinsky SA, Christianson DW. Biochemistry 57 3105-3114 (2018)

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