Probing the heme-thiolate oxygenase domain of inducible nitric oxide synthase with<font>Ru</font>(II) and<font>Re</font>(I) electron tunneling wires

Whited, Charlotte A.; Belliston-Bittner, Wendy; Dunn, Alexander R.; Winkler, Jay R.

doi:10.1142/s1088424608000352

Cited by 4 publications

(3 citation statements)

References 34 publications

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“…Here, we report on another class of synthetic photoactivatable nanoswitches that alter cell membrane potentials. Ruthenium-diimine complexes, which have previously been used to facilitate light-activated electron transfer in redox metalloproteins, can be excited in the blue region of the visible spectrum. − The complex employed here is [Ru(bpy) 2 (bpy-C17)] 2+ ,where bpy is 2,2′-bipyridine and bpy-C17 is 4-heptadecyl-4′-methyl-2,2′-bipyridine, which will be referred to as RubpyC17. Illumination generates a photoexcited complex that can either accept or donate an electron, depending on whether a sacrificial reductant (e.g., ascorbate) or oxidant (e.g., ferricyanide) is present .…”

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confidence: 99%

Light-Triggered Modulation of Cellular Electrical Activity by Ruthenium Diimine Nanoswitches

Rohan

Citron

Durrell³

et al. 2013

ACS Chem. Neurosci.

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Ruthenium diimine complexes have previously been used to facilitate light-activated electron transfer in the study of redox metalloproteins. Excitation at 488 nm leads to a photoexcited state, in which the complex can either accept or donate an electron, respectively, in the presence of a soluble sacrificial reductant or oxidant. Here, we describe a novel application of these complexes in mediating light-induced changes in cellular electrical activity. We demonstrate that RubpyC17 ([Ru(bpy) 2 (bpy-C17)] 2+ , where bpy is 2,2′-bipyridine and bpy-C17 is 2,2′-4-heptadecyl-4′-methyl-bipyridine), readily incorporates into the plasma membrane of cells, as evidenced by membrane-confined luminescence. Excitable cells incubated in RubpyC17 and then illuminated at 488 nm in the presence of the reductant ascorbate undergo membrane depolarization leading to firing of action potentials. In contrast, the same experiment performed with the oxidant ferricyanide, instead of ascorbate, leads to hyperpolarization. These experiments suggest that illumination of membrane-associated RubpyC17 in the presence of ascorbate alters the cell membrane potential by increasing the negative charge on the outer face of the cell membrane capacitor, effectively depolarizing the cell membrane. We rule out two alternative explanations for light-induced membrane potential changes, using patch clamp experiments: (1) lightinduced direct interaction of RubpyC17 with ion channels and (2) light-induced membrane perforation. We show that incorporation of RubpyC17 into the plasma membrane of neuroendocrine cells enables light-induced secretion as monitored by amperometry. While the present work is focused on ruthenium diimine complexes, the findings point more generally to broader application of other transition metal complexes to mediate light-induced biological changes.

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confidence: 99%

Light-Triggered Modulation of Cellular Electrical Activity by Ruthenium Diimine Nanoswitches

Rohan

Citron

Durrell³

et al. 2013

ACS Chem. Neurosci.

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“…In several of these and other studies, the photoexcited metal center could be competitively displaced by the natural binder or synthetic inhibitors, providing light-up probes for inhibitors. Photoinduced electron transfer from the metal centers to the heme allowed for the direct creation of reactive heme redox states [57,59,60].…”

Section: Binding Of Metal-containing "Wires" With P450 Proteinsmentioning

confidence: 99%

The Impact of Inorganic Systems and Photoactive Metal Compounds on Cytochrome P450 Enzymes and Metabolism: From Induction to Inhibition

Havrylyuk,

Heidary,

Glazer

2024

Biomolecules

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While cytochrome P450 (CYP; P450) enzymes are commonly associated with the metabolism of organic xenobiotics and drugs or the biosynthesis of organic signaling molecules, they are also impacted by a variety of inorganic species. Metallic nanoparticles, clusters, ions, and complexes can alter CYP expression, modify enzyme interactions with reductase partners, and serve as direct inhibitors. This commonly overlooked topic is reviewed here, with an emphasis on understanding the structural and physiochemical basis for these interactions. Intriguingly, while both organometallic and coordination compounds can act as potent CYP inhibitors, there is little evidence for the metabolism of inorganic compounds by CYPs, suggesting a potential alternative approach to evading issues associated with rapid modification and elimination of medically useful compounds.

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“…Toward this end, we and others have developed photoactive electron tunneling wires to deliver electrons and holes to and from the deeply buried heme active sites in P450cam [10-12] and NOS [13-16]. Importantly, one of the NOS wires, tmRu-F 9 bp (Chart 1), can potentially probe the catalytic cycle, since it binds tightly and specifically to the oxidase domain of the inducible form of the enzyme (iNOSoxy) in a region that is distant from the active site [17].…”

Section: Introductionmentioning

confidence: 99%

Nanosecond photoreduction of inducible nitric oxide synthase by a Ru-diimine electron tunneling wire bound distant from the active site

Whited

Belliston-Bittner

Dunn

et al. 2009

Journal of Inorganic Biochemistry

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A Ru-diimine wire, [(4,4’,5,5’-tetramethylbipyridine)2Ru(F9bp)]2+ (tmRu-F9bp, where F9bp is 4-methyl-4’-methylperfluorobiphenylbipyridine), binds tightly to the oxidase domain of inducible nitric oxide synthase (iNOSoxy). The binding of tmRu-F9bp is independent of tetrahydrobiopterin, arginine, and imidazole, indicating that the wire resides on the surface of the enzyme, distant from the active-site heme. Photoreduction of an imidazole-bound active-site heme iron in the enzyme-wire conjugate (kET = 2(1) × 107 s-1) is fully seven orders of magnitude faster than the in vivo process.

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Probing the heme-thiolate oxygenase domain of inducible nitric oxide synthase withRu(II) andRe(I) electron tunneling wires

Cited by 4 publications

References 34 publications

Light-Triggered Modulation of Cellular Electrical Activity by Ruthenium Diimine Nanoswitches

Light-Triggered Modulation of Cellular Electrical Activity by Ruthenium Diimine Nanoswitches

The Impact of Inorganic Systems and Photoactive Metal Compounds on Cytochrome P450 Enzymes and Metabolism: From Induction to Inhibition

Nanosecond photoreduction of inducible nitric oxide synthase by a Ru-diimine electron tunneling wire bound distant from the active site

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