Control of nitric oxide synthase dimer assembly by a heme-NO-dependent mechanism

Biochemistry
Yishi ChenDennis J Stuehr

Abstract

Homodimer formation is a key step that follows heme incorporation during assembly of an active inducible nitric oxide synthase (iNOS). In cells, heme incorporation into iNOS becomes limited due to interaction between self-generated NO and cellular heme [Albakri, Q., and Stuehr, D. J. (1996) J. Biol. Chem. 271, 5414-5421]. Here we investigated if NO can regulate at points downstream in the process by inhibiting dimerization of heme-containing iNOS monomer. Heme-containing monomers were generated by treating iNOS dimer or iNOS oxygenase domain dimer (iNOSoxy) with urea. Both monomers dimerized when incubated with Arg and 6R-tetrahydrobiopterin (H4B), as shown previously [Abu-Soud, H. M., Loftus, M., and Stuehr, D. J. (1995) Biochemistry 34, 11167-11175]. The NO-releasing drug S-nitrosyl-N-acetyl-D,L-penicillamine (SNAP; 0-0.5 mM) inhibited dimerization of iNOS monomer in a dose- and time-dependent manner, without causing heme release. SNAP-pretreated monomer also did not dimerize in response to H4B plus Arg. SNAP converted Arg- and H4B-free iNOS dimer into monomer that could not redimerize, but had no effect on iNOS dimer preincubated with Arg and H4B. Anaerobic spectral analysis showed that NO from SNAP bound to the ferric heme ...Continue Reading

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Citations

Jul 28, 2010·The Journal of Biological Chemistry·Robin J RosenfeldElizabeth D Getzoff
Jun 3, 2004·Life Sciences·Fugen Aktan
Aug 30, 2005·Journal of Molecular Biology·Kartikeya Pant, Brian R Crane
Aug 16, 2005·Brain Research. Developmental Brain Research·Mark S WainwrightStephen M Black
Apr 7, 2004·The Journal of Biological Chemistry·David LiDenis L Rousseau
Nov 8, 2018·British Journal of Pharmacology·Dennis J Stuehr, Mohammad Mahfuzul Haque
Jan 20, 2006·The Journal of Biological Chemistry·David LiSyun-Ru Yeh
Jun 3, 2015·The Journal of Biological Chemistry·Veena M BhopaleStephen R Thom
Feb 14, 2017·Israel Journal of Chemistry·Jacob M GoldbergStephen J Lippard
Aug 30, 2018·Frontiers in Oncology·Emmanuelle BignonElena Papaleo
Mar 1, 2019·Journal of Natural Products·Cui-Yun ZhangLi-Xia Chen

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