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Publications (39)
Iron–sulfur (Fe–S) clusters are ubiquitous metallocofactors involved in redox chemistry, radical generation and gene regulation. Common methods to monitor Fe–S clusters include spectroscopic analysis of purified proteins and autoradiographic visualization of radiolabeled iron distribution in proteomes. Here, we report a chemoproteomic strategy that...
Oxidative stress is a defining feature of most cancers, including those that stem from carcinogenic infections. Reactive oxygen species can drive tumor formation, yet the molecular oxidation events that contribute to tumorigenesis are largely unknown. Here we show that inactivation of a single, redox-sensitive cysteine in the host protease legumain...
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a cancer predisposition syndrome driven by mutation of the tumor suppressor fumarate hydratase ( FH ). Inactivation of FH causes accumulation of the electrophilic oncometabolite fumarate. In the absence of methods for reactivation, tumor suppressors can be targeted via identification of...
Selenoproteins comprise a small group of selenocysteine (Sec) containing proteins, often involved in redox homeostasis. While Sec is functionally similar to cysteine (Cys), with both acting as protein-centered nucleophiles, chemoproteomic strategies employing electrophilic probes have often failed to rigorously identify Sec residues, due to their r...
Oxidative stress is a defining feature of most cancers, including those that stem from carcinogenic infections. Reactive oxygen species (ROS) can drive tumor formation, yet the molecular oxidation events that contribute to tumorigenesis are largely unknown. Here we show that inactivation of a single, redox-sensitive cysteine in the host protease le...
Iron-sulfur (Fe-S) clusters are ubiquitous metallocofactors found across diverse protein families, where they perform myriad functions including redox chemistry, radical generation, and gene regulation. Monitoring Fe-S cluster occupancy in protein targets directly within native biological systems has been challenging. Commonly utilized spectroscopi...
Iron-sulfur clusters comprise one of the major classes of biological inorganic cofactors, that are often utilized in nature as redox active components in complex bioenergetic and biocatalytic pathways. This article presents an overview of the major classifications of biological iron-sulfur clusters, from the perspective of coordination chemistry, p...
An important context in which metabolism influences tumorigenesis is the genetic cancer syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a disease in which mutation of the TCA cycle enzyme fumarate hydratase (FH) causes hyperaccumulation of fumarate. This electrophilic oncometabolite can alter gene activity at the level of trans...
Metabolism and signaling intersect in the genetic cancer syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a disease in which mutation of the TCA cycle enzyme fumarate hydratase (FH) causes hyperaccumulation of fumarate. This electrophilic oncometabolite can alter gene activity at the level of transcription, via reversible inhibi...
Selenocysteine (Sec) is the 21st genetically encoded amino acid in organisms across all domains of life. Although structurally similar to cysteine (Cys), the Sec selenol group has unique properties that are attractive for protein engineering and biotechnology applications. Production of designer proteins with Sec (selenoproteins) at desired positio...
Dysregulated metabolism is a feature of many diseases, including cancer. In addition to providing energy and building blocks to growing cells, altered metabolism can assist in tumor growth by producing “oncometabolites”. For example, in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) inactivating mutations in fumarate hydratase (FH) lead...
Dysregulated metabolism is a feature of many diseases, including cancer. In addition to providing energy and building blocks to growing cells, altered metabolism can assist in tumor growth by producing “oncometabolites”. For example, in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) inactivating mutations in fumarate hydratase (FH) lead...
Unlike most other tissues, the colon epithelium is exposed to high levels of H2S derived from gut microbial metabolism. H2S is a signaling molecule that modulates various physiological effects. It is also a respiratory toxin that inhibits complex IV in the electron transfer chain (ETC). Colon epithelial cells are adapted to high environmental H2S e...
Mitochondria are cellular sites of diverse redox biology, including ROS production, iron-sulfur biogenesis, and secondary metabolism, which all rely on proteogenic reactive cysteine residues. Mass spectrometry-based proteomic methods to monitor the reactivity and functionality of cysteine residues across complex proteomes have greatly expanded over...
Hereditary cancer disorders often provide an important window into novel mechanisms supporting tumor growth. Understanding these mechanisms thus represents a vital goal. Toward this goal, here we report a chemoproteomic map of fumarate, a covalent oncometabolite whose accumulation marks the genetic cancer syndrome hereditary leiomyomatosis and rena...
Cysteine residues are concentrated at key functional sites within proteins, performing diverse roles in metal binding, catalysis, and redox chemistry. Chemoproteomic platforms to interrogate the reactive cysteinome have developed significantly over the past 10 years, resulting in a greater understanding of cysteine functionality, modification, and...
Selenium (Se), as an essential trace element, plays crucial roles in many organisms including humans. The biological functions of selenium are mainly mediated by selenoproteins, a unique class of selenium-containing proteins in which selenium is inserted in the form of selenocysteine. Due to their low abundance and uneven tissue distribution, detec...
Mammalian selenocysteine (Sec)-containing proteins, selenoproteins, are important to (patho)physiological processes, including redox homeostasis. Sec residues have been recalcitrant to mass spectrometry-based chemoproteomic methods that enrich for reactive cysteine (Cys) residues with electrophilic chemical probes, despite confirmed reactivity of S...
Hereditary cancer disorders often provide an important window into novel mechanisms supporting tumor growth and survival. Understanding these mechanisms and developing biomarkers to identify their presence thus represents a vital goal. Towards this goal, here we report a chemoproteomic map of the covalent targets of fumarate, an oncometabolite whos...
Cruciferous vegetables such as broccoli and kale have well documented chemopreventative and anticancer effects that are attributed to the presence of isothiocyanates (ITCs). ITCs modulate the levels of many oncogenic proteins, but the molecular mechanisms of ITC action are not understood. We previously reported that phenethyl isothiocyanate (PEITC)...
The mitochondria are dynamic organelles that regulate oxidative metabolism and mediate cellular redox homeostasis. Proteins within the mitochondria are exposed to large fluxes in the surrounding redox environment. In particular, cysteine residues within mitochondrial proteins sense and respond to these redox changes through oxidative modifications...
Cysteine residues serve critical roles in protein function and are susceptible to numerous posttranslational modifications (PTMs) that serve to modulate the activity and localization of diverse proteins. Many of these PTMs are highly transient and labile, necessitating methods to study these modifications directly within the context of living cells...
In the nematode Caenorhabditis elegans, inactivating mutations in the insulin/IGF-1 receptor, DAF-2, result in a 2-fold increase in lifespan mediated by DAF-16, a FOXO-family transcription factor. Downstream protein activities that directly regulate longevity during impaired insulin/IGF-1 signaling (IIS) are poorly characterized. Here, we use globa...
The mitochondria are critical mediators of cellular redox homeostasis due to their role in the generation and dissipation of reactive oxygen/nitrogen species (ROS/RNS). Modulations in ROS/RNS levels in the mitochondria are often reflected through oxidation/nitrosation of highly redox-sensitive cysteine residues within this organelle. Oxidation/nitr...
Ergothioneine is a histidine thiol derivative. Its mycobacterial biosynthetic pathway has five steps (EgtA-E catalysis) with two novel reactions: a mononuclear nonheme iron enzyme (EgtB) catalyzed oxidative C-S bond formation and a PLP-mediated C-S lyase (EgtE) reaction. Our bioinformatic and biochemical analyses indicate that the fungus Neurospora...
Protein-reactive electrophiles are critical to chemical proteomic applications including activity-based protein profiling, site-selective protein modification and covalent inhibitor development. Here, we explore the protein reactivity of a panel of aryl halides that function through a nucleophilic aromatic substitution (SNAr) mechanism. We show tha...
A subset of biological Fe-S clusters contain protein-based ligands other than cysteine (Cys). The most common alternative ligand is histidine, while aspartate, arginine, and threonine ligation have also been identified. With the exception of the 2-Cys, 2-His ligated Rieske clusters, the functions of these uniquely ligated clusters are, in general,...
While its biological function remains unclear, the 3-Cys, 1-His ligated human [2Fe-2S] cluster containing protein mitoNEET is of interest due to its interaction with the anti-diabetes drug pioglitazone. The mitoNEET [2Fe-2S] cluster demonstrates proton coupled-electron transfer (PCET) and marked cluster instability which have both been linked to th...
MitoNEET, a novel 3-Cys, 1-His ligated redox active [2Fe-2S] cluster binding protein, is found at the cytosolic face of the outer mitochondrial membrane in humans. While its biological function remains unclear, mitoNEET is of interest due to its interaction with the anti-diabetes drug pioglitazone, a member of the TZD drug family. Here, a character...
MitoNEET is a small mitochondrial protein that has been identified recently as a target for the thiazolidinedione (TZD) class of diabetes drugs. MitoNEET also binds a unique three-Cys- and one-His-ligated [corrected] [2Fe-2S] cluster. Here we use protein film voltammetry (PFV) as a means to probe the redox properties of mitoNEET and demonstrate the...
