Inhibition of Human Arginase I by Substrate adn Product Analogues
Journal Article
·
· Archives of Biochemistry and Biophysics
OSTI ID:1041810
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(d)=3.6 microM, and nor-N-hydroxy-L-arginine (nor-NOHA) binds with K(d)=517 nM (surface plasmon resonance) or K(d) approximately 50 nM (isothermal titration calorimetry). Crystals of human arginase I complexed with NOHA and nor-NOHA afford 2.04 and 1.55 A 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(d)=13 microM) is reported at 1.90 A 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:
- BROOKHAVEN NATIONAL LABORATORY (BNL)
- Sponsoring Organization:
- USDOE SC OFFICE OF SCIENCE (SC)
- DOE Contract Number:
- AC02-98CH10886
- OSTI ID:
- 1041810
- Report Number(s):
- BNL--97488-2012-JA
- Journal Information:
- Archives of Biochemistry and Biophysics, Journal Name: Archives of Biochemistry and Biophysics Journal Issue: 2 Vol. 496; ISSN ABBIA4; ISSN 0003-9861
- Country of Publication:
- United States
- Language:
- English
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