Sinan Sabuncu

Oregon Health & Science University

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Pierre Moënne‐Loccoz

Oregon Health & Science University

Therese Albert

Oregon Health & Science University

David P. Goldberg

Johns Hopkins University

Maxime A. Siegler

Johns Hopkins University

Adem Yıldırım

Oregon Health & Science University

Aniruddha Dey

Johns Hopkins University

Jesse B. Gordon

Johns Hopkins University

FÇ

Fehmi Çivitçi

Oregon Health & Science University

Jared M. Fischer

Oregon Health & Science University

Eckhard Bill

Max Planck Institute for Chemical Energy Conversion

Cooperative Institutions

Oregon Health & Science University

University of Kansas

Johns Hopkins University

OHSU Knight Cancer Institute

University of California, Irvine

University of California, San Diego

University of Illinois Urbana-Champaign

Carnegie Mellon University

University of Minnesota

University of California System

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A Nonheme Mononuclear {FeNO}⁷ Complex that Produces N₂O in the Absence of an Exogenous Reductant

Angewandte Chemie International Edition (2021)

Aniruddha Dey Jesse B. Gordon Therese Albert Sinan Sabuncu Maxime A. Siegler

Abstract A new nonheme iron(II) complex, Fe II (Me 3 TACN)((OSi Ph2 ) 2 O) ( 1 ), is reported. Reaction of 1 with NO (g) gives a stable mononitrosyl complex Fe(NO)(Me 3 TACN)((OSi Ph2 ) 2 O) ( 2 ), which was characterized by Mössbauer ( δ =0.52 mm s −1 , |Δ E Q |=0.80 mm s −1 ), EPR ( S =3/2), resonance Raman (RR) and Fe K‐edge X‐ray absorption spectroscopies. The data show that 2 is an {FeNO} 7 complex with an S =3/2 spin ground state. The RR spectrum ( λ exc =458 nm) of 2 combined with isotopic labeling ( 15 N, 18 O) reveals ν(N‐O)=1680 cm −1 , which is highly activated, and is a nearly identical match to that seen for the reactive mononitrosyl intermediate in the nonheme iron enzyme FDPnor (ν(NO)=1681 cm −1 ). Complex 2 reacts rapidly with H 2 O in THF to produce the N‐N coupled product N 2 O, providing the first example of a mononuclear nonheme iron complex that is capable of converting NO to N 2 O in the absence of an exogenous reductant.

10.1002/anie.202109062

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Protein‐Coated Biodegradable Gas‐Stabilizing Nanoparticles for Cancer Therapy and Diagnosis Using Focused Ultrasound

Advanced Materials Interfaces (2022)

Sinan Sabuncu Jose Montoya Mira Arnaud Quentel Michelle M. Gomes Fehmi Çivitçi

Abstract Surface‐engineered hydrophobic nanoparticles that can stabilize small gas pockets on their surfaces (i.e., gas‐stabilizing nanoparticles, GSNs) have been recently shown to be excellent contrast and cavitation agents for ultrasound theranostics. However, previously developed GSNs are not biodegradable, which limits their clinical translation potential. Here the development of biodegradable GSNs is shown by coating hydrophobically modified mesoporous silica nanoparticles with different protein solutions. It is found that these novel GSNs retain strong cavitation activity while rapidly degrading in simulated body fluid (SBF) or in vivo in days or a few weeks, respectively. Interestingly, GSNs coated with other stabilizing layers, Pluronic F127 polymer or phospholipids, demonstrated significantly slower degradation rates with only partial degradation even after a month of incubation in SBF. Next, it is shown that these biodegradable GSNs can be used to ablate tumor xenografts at lower ultrasound intensities, thus avoiding the side effects of high‐intensity ultrasound. Finally, it is shown that only tumors treated with GSNs and ultrasound can specifically enrich for circulating tumor DNA, which will improve liquid biopsies for understanding tumor heterogeneity and treatment response. Overall, this study details a simple yet effective method for preparing biodegradable GSNs with broad potential for applications in cancer diagnosis and therapy.

Biodegradable polymer

Simulated body fluid

Degradation

10.1002/admi.202201543

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A Reactive, Photogenerated High-Spin (S= 2) Fe^IV(O) Complex via O₂Activation

Journal of the American Chemical Society (2021)

Jesse B. Gordon Therese Albert Aniruddha Dey Sinan Sabuncu Maxime A. Siegler

Addition of dioxygen at low temperature to the non-heme ferrous complex FeII(Me3TACN)((OSiPh2)2O) (1) in 2-MeTHF produces a peroxo-bridged diferric complex Fe2III(μ-O2)(Me3TACN)2((OSiPh2)2O)2 (2), which was characterized by UV-vis, resonance Raman, and variable field Mössbauer spectroscopies. Illumination of a frozen solution of 2 in THF with white light leads to homolytic O-O bond cleavage and generation of a FeIV(O) complex 4 (ν(Fe=O) = 818 cm-1; δ = 0.22 mm s-1, ΔEQ = 0.23 mm s-1). Variable field Mössbauer spectroscopy measurements show that 4 is a rare example of a high-spin S = 2 FeIV(O) complex and the first synthetic example to be generated directly from O2. Complex 4 is highly reactive, as expected for a high-spin ferryl, and decays rapidly in fluid solution at cryogenic temperatures. This decay process in 2-MeTHF involves C-H cleavage of the solvent. However, the controlled photolysis of 2in situ with visible light and excess phenol substrate leads to competitive phenol oxidation, via the proposed transient generation of 4 as the active oxidant.

Homolysis

Bond cleavage

10.1021/jacs.1c10051

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Citations (21)

Ultrafast Background-Free Ultrasound Imaging Using Blinking Nanoparticles

Nano Letters (2023)

Sinan Sabuncu Ruth Javier Ramirez Jared M. Fischer Fehmi Çivitçi Adem Yıldırım

Localization-based ultrasound imaging methods that use microbubbles or nanodroplets offer high-resolution imaging with improved sensitivity and reduced background signal. However, these methods require long acquisition times (typically seconds to minutes), preventing their use for real-time imaging and, thus, limiting their clinical translational potential. Here, we present a new ultrafast localization method using blinking ultrasound-responsive nanoparticles (BNPs). When activated with high frame rate (1 kHz) plane wave ultrasound pulses with a mechanical index of 1.5, the BNPs incept growth of micrometer-sized bubbles, which in turn collapse and generate a blinking ultrasound signal. We showed that background-free ultrasound images could be obtained by localizing these blinking events using acquisition times as low as 11 ms. In addition, we demonstrated that BNPs enable in vivo background-free ultrasound imaging in mice. We envision that BNPs will facilitate the clinical translation of localization-based ultrasound imaging for more sensitive detection of cancer and other diseases.

Ultrasound imaging

Mechanical index

Frame rate

SIGNAL (programming language)

10.1021/acs.nanolett.2c04504

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Artificial Metalloproteins with Dinuclear Iron–Hydroxido Centers

Journal of the American Chemical Society (2021)

Kelsey R. Miller Saborni Biswas Andrew J. Jasniewski Alec H. Follmer Ankita Biswas

Dinuclear iron centers with a bridging hydroxido or oxido ligand form active sites within a variety of metalloproteins. A key feature of these sites is the ability of the protein to control the structures around the Fe centers, which leads to entatic states that are essential for function. To simulate this controlled environment, artificial proteins have been engineered using biotin–streptavidin (Sav) technology in which Fe complexes from adjacent subunits can assemble to form [FeIII–(μ-OH)–FeIII] cores. The assembly process is promoted by the site-specific localization of the Fe complexes within a subunit through the designed mutation of a tyrosinate side chain to coordinate the Fe centers. An important outcome is that the Sav host can regulate the Fe···Fe separation, which is known to be important for function in natural metalloproteins. Spectroscopic and structural studies from X-ray diffraction methods revealed uncommonly long Fe···Fe separations that change by less than 0.3 Å upon the binding of additional bridging ligands. The structural constraints imposed by the protein host on the di-Fe cores are unique and create examples of active sites having entatic states within engineered artificial metalloproteins.

Metalloprotein

10.1021/jacs.0c12564

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Citations (14)

Temperature-dependent breakdown of hydrogen peroxide-treated ZnO and TiO₂ nanoparticle agglomerates

Beilstein Journal of Nanotechnology (2015)

Sinan Sabuncu Mustafa Çulha

Metal oxide nanoparticles (MONPs) are used in a variety of applications including drug formulations, paint, sensors and biomedical devices due to their unique physicochemical properties. One of the major problems with their widespread implementation is their uncontrolled agglomeration. One approach to reduce agglomeration is to alter their surface chemistry with a proper functionality in an environmentally friendly way. In this study, the influence of hydrogen peroxide (H2O2) treatment on the dispersion of ZnO and TiO2 nanoparticle (NP) agglomerates as a function of temperature is studied. The H2O2 treatment of the MONPs increases the density of hydroxyl (-OH) groups on the NP surface, as verified with FTIR spectroscopy. The influence of heating on the dispersion of H2O2-treated ZnO and TiO2 NPs is investigated using dynamic light scattering. The untreated and H2O2-treated ZnO and TiO2 NP suspensions were heated from 30 °C to 90 °C at 5 °C intervals to monitor the breakdown of large aggregates into smaller aggregates and individual nanoparticles. It was shown that the combined effect of hydroxylation and heating enhances the dispersion of ZnO and TiO2 NPs in water.

Agglomerate

10.3762/bjnano.6.193

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Insight into the Spatial Arrangement of the Lysine Tyrosylquinone and Cu2+ in the Active Site of Lysyl Oxidase-like 2

International Journal of Molecular Sciences (2022)

Alex Meier Hee-Jung Moon Sinan Sabuncu Priya Singh Trey Ronnebaum

Lysyl oxidase-2 (LOXL2) is a Cu2+ and lysine tyrosylquinone (LTQ)-dependent amine oxidase that catalyzes the oxidative deamination of peptidyl lysine and hydroxylysine residues to promote crosslinking of extracellular matrix proteins. LTQ is post-translationally derived from Lys653 and Tyr689, but its biogenesis mechanism remains still elusive. A 2.4 Å Zn2+-bound precursor structure lacking LTQ (PDB:5ZE3) has become available, where Lys653 and Tyr689 are 16.6 Å apart, thus a substantial conformational rearrangement is expected to take place for LTQ biogenesis. However, we have recently shown that the overall structures of the precursor (no LTQ) and the mature (LTQ-containing) LOXL2s are very similar and disulfide bonds are conserved. In this study, we aim to gain insights into the spatial arrangement of LTQ and the active site Cu2+ in the mature LOXL2 using a recombinant LOXL2 that is inhibited by 2-hydrazinopyridine (2HP). Comparative UV-vis and resonance Raman spectroscopic studies of the 2HP-inhibited LOXL2 and the corresponding model compounds and an EPR study of the latter support that 2HP-modified LTQ serves as a tridentate ligand to the active site Cu2. We propose that LTQ resides within 2.9 Å of the active site of Cu2+ in the mature LOXL2, and both LTQ and Cu2+ are solvent-exposed.

Lysyl Oxidase

Hydroxylysine

Deamination

Oxidative deamination

10.3390/ijms232213966

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Citations (8)

Nitric Oxide Reductase Activity in Heme–Nonheme Binuclear Engineered Myoglobins through a One-Electron Reduction Cycle

Journal of the American Chemical Society (2018)

Sinan Sabuncu Julian H. Reed Yi Lu Pierre Moënne‐Loccoz

FeBMbs are structural and functional models of native bacterial nitric oxide reductases (NORs) generated through engineering of myoglobin. These biosynthetic models replicate the heme–nonheme diiron site of NORs and allow substitutions of metal centers and heme cofactors. Here, we provide evidence for multiple NOR turnover in monoformyl-heme-containing FeBMb1 proteins loaded with FeII, CoII, or ZnII metal ions at the FeB site (FeII/CoII/ZnII–FeBMb1(MF-heme)). FTIR detection of the ν(NNO) band of N2O at 2231 cm–1 provides a direct quantitative measurement of the product in solution. A maximum number of turnover is observed with FeII–FeBMb1(MF-heme), but the NOR activity is retained when the FeB site is loaded with ZnII. These data support the viability of a one-electron semireduced pathway for the reduction of NO at binuclear centers in reducing conditions.

Hemeprotein

10.1021/jacs.8b11037

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Citations (16)

Temperature-dependent breakdown of hydrogen peroxide-treated ZnO and TiO2 nanoparticle agglomerates

nano Online (2016)

Sinan Sabuncu Mustafa Çulha

Agglomerate

10.1515/nano.bjneah.6.193

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Citations (1)

Structural and Spectroscopic Characterization of a Product Schiff Base Intermediate in the Reaction of the Quinoprotein Glycine Oxidase, GoxA

Biochemistry (2019)

Dante Avalos Sinan Sabuncu Kyle J. Mamounis Victor L. Davidson Pierre Moënne‐Loccoz

The LodA-like proteins make up a recently identified family of enzymes that rely on a cysteine tryptophylquinone cofactor for catalysis. They differ from other tryptophylquinone enzymes in that they are oxidases rather than dehydrogenases. GoxA is a member of this family that catalyzes the oxidative deamination of glycine. Our previous work with GoxA from Pseudoalteromonas luteoviolacea demonstrated that this protein forms a stable intermediate upon anaerobic incubation with glycine. The spectroscopic properties of this species were unique among those identified for tryptophylquinone enzymes characterized to date. Here we use X-ray crystallography and resonance Raman spectroscopy to identify the GoxA catalytic intermediate as a product Schiff base. Structural work additionally highlights features of the active site pocket that confer substrate specificity, intermediate stabilization, and catalytic activity. The unusual properties of GoxA are discussed within the context of the other tryptophylquinone enzymes.

Oxidative deamination

Resonance Raman spectroscopy

10.1021/acs.biochem.8b01145

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Citations (4)