Inhibition of human arginase I by substrate and product analogues

Journal Article · Mon Jun 21 04:00:00 EDT 2010 · Arch. Biochem. Biophys.

DOI:https://doi.org/10.1016/j.abb.2010.02.004· OSTI ID:1002373

Di Costanzo, Luigi; Ilies, Monica; Thorn, Katherine J; Christianson, David W ^[1]

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1. UPENN

Human arginase I is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to generate l-ornithine and urea. We demonstrate that N-hydroxy-l-arginine (NOHA) binds to this enzyme with K{sub d} = 3.6 {micro}M, and nor-N-hydroxy-l-arginine (nor-NOHA) binds with K{sub d} = 517 nM (surface plasmon resonance) or K{sub d} {approx} 50 nM (isothermal titration calorimetry). Crystals of human arginase I complexed with NOHA and nor-NOHA afford 2.04 and 1.55 {angstrom} resolution structures, respectively, which are significantly improved in comparison with previously-determined structures of the corresponding complexes with rat arginase I. Higher resolution structures clarify the binding interactions of the inhibitors. Finally, the crystal structure of the complex with l-lysine (K{sub d} = 13 {micro}M) is reported at 1.90 {angstrom} resolution. This structure confirms the importance of hydrogen bond interactions with inhibitor {alpha}-carboxylate and {alpha}-amino groups as key specificity determinants of amino acid recognition in the arginase active site.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1002373
• Journal Information: Arch. Biochem. Biophys., Journal Name: Arch. Biochem. Biophys. Journal Issue: (2) ; 04, 2010 Vol. 496; ISSN ABBIA4; ISSN 0003-9861
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

08 HYDROGEN
36 MATERIALS SCIENCE
AMINO ACIDS
ARGINASE
CALORIMETRY
CRYSTAL STRUCTURE
ENZYMES
HYDROGEN
HYDROLYSIS
MANGANESE
PLASMONS
RESOLUTION
RESONANCE
SPECIFICITY
SUBSTRATES
TITRATION
UREA