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Structures of the N(omega)-hydroxy-L-arginine complex of inducible nitric oxide synthase oxygenase dimer with active and inactive pterins.

Crane BR, Arvai AS, Ghosh S, Getzoff ED, Stuehr DJ, Tainer JA
Biochemistry 39 4608-21 (2000)
Related entries: 1df1, 1dwv, 1dww, 1noc, 1nod, 1nos, 1qom, 2nod, 2nos, 3nod

Cited: 50 times
EuropePMC logo PMID: 10769116

Abstract

Nitric oxide synthases (NOSs) catalyze two mechanistically distinct, tetrahydrobiopterin (H(4)B)-dependent, heme-based oxidations that first convert L-arginine (L-Arg) to N(omega)-hydroxy-L-arginine (NHA) and then NHA to L-citrulline and nitric oxide. Structures of the murine inducible NOS oxygenase domain (iNOS(ox)) complexed with NHA indicate that NHA and L-Arg both bind with the same conformation adjacent to the heme iron and neither interacts directly with it nor with H(4)B. Steric restriction of dioxygen binding to the heme in the NHA complex suggests either small conformational adjustments in the ternary complex or a concerted reaction of dioxygen with NHA and the heme iron. Interactions of the NHA hydroxyl with active center beta-structure and the heme ring polarize and distort the hydroxyguanidinium to increase substrate reactivity. Steric constraints in the active center rule against superoxo-iron accepting a hydrogen atom from the NHA hydroxyl in their initial reaction, but support an Fe(III)-peroxo-NHA radical conjugate as an intermediate. However, our structures do not exclude an oxo-iron intermediate participating in either L-Arg or NHA oxidation. Identical binding modes for active H(4)B, the inactive quinonoid-dihydrobiopterin (q-H(2)B), and inactive 4-amino-H(4)B indicate that conformational differences cannot explain pterin inactivity. Different redox and/or protonation states of q-H(2)B and 4-amino-H(4)B relative to H(4)B likely affect their ability to electronically influence the heme and/or undergo redox reactions during NOS catalysis. On the basis of these structures, we propose a testable mechanism where neutral H(4)B transfers both an electron and a 3,4-amide proton to the heme during the first step of NO synthesis.

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  1. Substrate-ligand interactions in Geobacillus stearothermophilus nitric oxide synthase. Kabir M, Sudhamsu J, Crane BR, Yeh SR, Rousseau DL. Biochemistry 47 12389-12397 (2008)


Reviews citing this publication (13)

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Related citations provided by authors (4)

  1. N-terminal domain swapping and metal ion binding in nitric oxide synthase dimerization.. Crane BR, Rosenfeld RJ, Arvai AS, Ghosh DK, Ghosh S, Tainer JA, Stuehr DJ, Getzoff ED EMBO J 18 6271-81 (1999)
  2. Inducible nitric oxide synthase: role of the N-terminal beta-hairpin hook and pterin-binding segment in dimerization and tetrahydrobiopterin interaction.. Ghosh DK, Crane BR, Ghosh S, Wolan D, Gachhui R, Crooks C, Presta A, Tainer JA, Getzoff ED, Stuehr DJ EMBO J 18 6260-70 (1999)
  3. Structure of nitric oxide synthase oxygenase dimer with pterin and substrate.. Crane BR, Arvai AS, Ghosh DK, Wu C, Getzoff ED, Stuehr DJ, Tainer JA Science 279 2121-6 (1998)
  4. The structure of nitric oxide synthase oxygenase domain and inhibitor complexes.. Crane BR, Arvai AS, Gachhui R, Wu C, Ghosh DK, Getzoff ED, Stuehr DJ, Tainer JA Science 278 425-31 (1997)

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