Zinc Thiolate Reactivity toward Nitrogen Oxides: Insights into the Interaction of Zn²⁺ with S-Nitrosothiols and Implications for Nitric Oxide Synthase

Abstract

Zinc thiolate complexes containing N2S tridentate ligands were prepared to investigate their reactivity toward reactive nitrogen species, chemistry proposed to occur at the zinc tetracysteine thiolate site of nitric oxide synthase (NOS). The complexes are unreactive toward nitric oxide in the absence of dioxygen, strongly indicating that NO cannot be the species directly responsible for S-nitrosothiol formation and loss of Zn2+ at the NOS dimer interface in vivo. S-Nitrosothiol formation does occur upon exposure of zinc thiolate solutions to NO in the presence of air, however, or to NO2 or NOBF4, indicating that these reactive nitrogen/oxygen species are capable of liberating zinc from the enzyme, possibly through generation of the S-nitrosothiol. Interaction between simple Zn2+ salts and pre-formed S-nitrosothiols leads to decomposition of the –SNO moiety, resulting in release of gaseous NO and N2O. The potential biological relevance of this chemistry is discussed.

A Fast and Selective Near-Infrared Fluorescent Sensor for Multicolor Imaging of Biological Nitroxyl (HNO)

“… 45 , 46 Mobilization of endogenous zinc induced by NO donors can be detected in live cells by fluorescent sensors, 47 but NO is unable to nitrosate thiolates directly. 48 HNO, however, reacts directly with thiols 16 and may be capable of releasing chelatable zinc. To investigate this possibility, we incubated HeLa cells with CuDHX1 and the green-fluorescent, zinc-selective, sensor ZP1.…”

Human sirtuins are differentially sensitive to inhibition by nitrosating agents and other cysteine oxidants

“…NO does not directly react with a thiol to form a nitrosothiol (58,59); however, in the presence of oxygen, S-nitrosation proceeds via a multistep process involving rate-limiting reaction of NO with molecular oxygen to form N 2 O 3 with NO 2 radical as an intermediate (rate constant 5 2 3 10 6 M 22 s 21 ) (60). Subsequent reaction of N 2 O 3 with a cysteine thiolate forms a nitrosothiol (rate constant 5 0.06-3 3 10 5 M 21 s 21 ) (58).…”

Zinc‐oxide nanoparticles act catalytically and synergistically with nitric oxide donors to enhance antimicrobial efficacy

“…After RSNO degradation to RS − +NO, residual RS − molecules end up forming disulfide RSSR compounds when in an aqueous environment. Zn is able to form a complex with these residual RS − ions to prevent disulfide bond formation, allowing for possible regeneration of RSH molecules after complete NO‐release and subsequent renitrosation into its original RSNO form . The presence of these thiols would also assist in the increased NO release of Zn incorporated SNAP films as RSH molecules have been demonstrated to have destabilizing effects to RSNOs …”

“…Zn is able to form a complex with these residual RS − ions to prevent disulfide bond formation, allowing for possible regeneration of RSH molecules after complete NO-release and subsequent renitrosation into its original RSNO form. 39 The presence of these thiols would also assist in the increased NO release of Zn incorporated SNAP films as RSH molecules have been demonstrated to have destabilizing effects to RSNOs. 40 The minimal leaching of Zn ions from the SNAP-ZnO samples (3.17%) shows how well encapsulated the nanoparticles were within the topcoats of the synthesized CarboSil polymer films and demonstrates the potential longevity of their catalytic activity.…”