Digital Commons Network^™

Fhf2 Gene Deletion Causes Temperature-Sensitive Cardiac Conduction Failure, David S. Park, Akshay Shekhar, Christopher Marra, Xianming Lin, Carolina Vasquez, Sergio Solinas, Kevin Kelley, Gregory Morley, Mitchell Goldfarb, Glenn I. Fishman

Publications and Research

Fever is a highly conserved systemic response to infection dating back over 600 million years. Although conferring a survival benefit, fever can negatively impact the function of excitable tissues, such as the heart, producing cardiac arrhythmias. Here we show that mice lacking fibroblast growth factor homologous factor 2 (FHF2) have normal cardiac rhythm at baseline, but increasing core body temperature by as little as 3 C causes coved-type STelevations and progressive conduction failure that is fully reversible upon return to normothermia. FHF2-deficient cardiomyocytes generate action potentials upon current injection at 25 C but are unexcitable at 40 C. The absence …

Hiv-1 Integrates Widely Throughout The Genome Of The Human Blood Fluke Schistosoma Mansoni., Sutas Suttiprapa, Gabriel Rinaldi, Isheng J Tsai, Victoria H. Mann, Larisa Dubrovsky, Hong-Bin Yan, Nancy Holroyd, Thomas Huckvale, Caroline Durrant, Anna V Protasio, Tatiana Pushkarsky, Sergey Iordanskiy, Matthew Berriman, Michael I. Bukrinsky, Paul J. Brindley

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Schistosomiasis is the most important helminthic disease of humanity in terms of morbidity and mortality. Facile manipulation of schistosomes using lentiviruses would enable advances in functional genomics in these and related neglected tropical diseases pathogens including tapeworms, and including their non-dividing cells. Such approaches have hitherto been unavailable. Blood stream forms of the human blood fluke, Schistosoma mansoni, the causative agent of the hepatointestinal schistosomiasis, were infected with the human HIV-1 isolate NL4-3 pseudotyped with vesicular stomatitis virus glycoprotein. The appearance of strong stop and positive strand cDNAs indicated that virions fused to schistosome cells, the nucleocapsid internalized and the …

Replication-Transciption Switch In Human Mitochondria, Karen Agaronyan

Graduate School of Biomedical Sciences Theses and Dissertations

Coordinated replication and expression of mitochondrial genome is critical for metabolically active cells during various stages of development. However, it is not known whether replication and transcription can occur simultaneously without interfering with each other and whether mtDNA copy number can be regulated by the transcription machinery. Human mitochondrial RNA polymerase (mtRNAP) is a central enzyme involved in gene expression in mitochondria. It generates genome-size polycistronic transcripts and also makes replication primers at two origins of replication. MtRNAP is distantly related to phage T7 RNAP. While T7 RNAP is optimized to produce large amounts of transcripts to overcompete the bacterial …

Dorsal Scapular Artery Variations And Relationship To The Brachial Plexus, And A Related Thoracic Outlet Syndrome Case, Anne-Marie A. Verenna, Daniela Alexandru, Afshin Karimi, Justin M. Brown, Geoffrey M. Bove, Frank J. Daly, Anthony M. Pastore, Helen E. Pearson, Mary F. Barbe

Biomedical Sciences Faculty Publications

Knowledge of the relationship of the dorsal scapular artery (DSA) with the brachial plexus is limited. We report a case of a variant DSA path, and revisit DSA origins and underinvestigated relationship with the plexus in cadavers. The DSA was examined in a male patient and 106 cadavers. In the case, we observed an unusual DSA compressing the lower plexus trunk, that resulted in intermittent radiating pain and paresthesia. In the cadavers, the DSA originated most commonly from the subclavian artery (71%), with 35% from the thyrocervical trunk. Nine sides of eight cadavers (seven females) had two DSA branches per …

Global Access To Radiation Therapy For Cervical Cancer: The Cost Of Inaction, Jacob Van Dyk, D Rodin, Timothy Paul Hanna, E Burger, Eduardo Zubizarreta, Mei Ling Yap, Michael Barton, Rifat Atun, Felicia Marie Knaul, Y Lievens, Mary K. Gospodarowicz, D A. Jaffray, M Milosevic

Oncology Publications

No abstract provided.

Regulation Of Ifn-Γ Expression, John Fenimore, Howard A. Young

United States Public Health Resources

Interferon gamma, referred to here as IFN- γ, is a major component in immunological cell signaling and is a critical regulatory protein for overall immune system function. First discovered in 1965 (Wheelock Science 149: (3681)310–311, 1965), IFN- γ is the only Type II interferon identified. Its expression is both positively and negatively controlled by different factors. In this chapter, we will review the transcriptional and post-transcriptional control of IFN-γ expression. In the transcriptional control part, the regular activators and suppressors are summarized, we will also focus on the epigenetic control, such as chromosome access, DNA methylation, and histone acetylation. The …

Chronic Expression Of Interferon-Gamma Leads To Murine Autoimmune Cholangitis With A Female Predominance, Heekyong R. Bae, Patrick S.C. Leung, Koichi Tsuneyama, Julio C. Valencia, Deborah L. Hodge, Seohyun Kim, Tim Back, Megan Karwan, Anand S. Merchant, Nobuyuki Baba, Dechun Feng, Ogyi Park, Bin Gao, Guo Xiang Yang, M. Eric Gershwin, Howard A. Young

United States Public Health Resources

In most autoimmune diseases the serologic hallmarks of disease precede clinical pathology by years. Therefore, the use of animal models in defining early disease events becomes critical. We took advantage of a “designer” mouse with dysregulation of interferon gamma (IFNγ) characterized by prolonged and chronic expression of IFNγ through deletion of the IFNγ 3′-untranslated region adenylate uridylate-rich element (ARE). The ARE-Del-/- mice develop primary biliary cholangitis (PBC) with a female predominance that mimics human PBC that is characterized by up-regulation of total bile acids, spontaneous production of anti-mitochondrial antibodies, and portal duct inflammation. Transfer of CD4 T cells from ARE-Del-/- …

Alteration Of The Ping And Pong Orf1 Proteins Allows For Hyperactive Transposition Of Mping, Lisette Payero, Giselle Outten, Courtney Burckhalter, C. Nathan Hancock

Journal of the South Carolina Academy of Science

No abstract provided.

Bioactivation Of Trimethoprim To Protein-Reactive Metabolites In Human Liver Microsomes., Jennifer Goldman, Yakov M. Koen, Steven A. Rogers, Kelin Li, J Steven Leeder, Robert P. Hanzlik

Manuscripts, Articles, Book Chapters and Other Papers

The formation of drug-protein adducts via metabolic activation and covalent binding may stimulate an immune response or may result in direct cell toxicity. Protein covalent binding is a potentially pivotal step in the development of idiosyncratic adverse drug reactions (IADRs). Trimethoprim (TMP)-sulfamethoxazole (SMX) is a combination antibiotic that commonly causes IADRs. Recent data suggest that the contribution of the TMP component of TMP-SMX to IADRs may be underappreciated. We previously demonstrated that TMP is bioactivated to chemically reactive intermediates that can be trapped in vitro by N-acetyl cysteine (NAC), and we have detected TMP-NAC adducts (i.e., mercapturic acids) in the …

Effects Of Auditory Vection Speed And Directional Congruence On Perceptions Of Visual Vection, Isabella Alexis Gagliano

Psychology Theses & Dissertations

Spatial disorientation is a major contributor to aircraft mishaps. One potential contributing factor is vection, an illusion of self-motion. Although vection is commonly thought of as a visual illusion, it can also be produced through audition. The purpose of the current experiment was to explore interactions between conflicting visual and auditory vection cues, specifically with regard to the speed and direction of rotation. The ultimate goal was to explore the extent to which aural vection could diminish or enhance the perception of visual vection. The study used a 3 × 2 within-groups factorial design. Participants were exposed to three levels …

Ontogeny Of Hepatic Drug Transporters As Quantified By Lc-Ms/Ms Proteomics., B Prasad, Andrea Gaedigk, M Vrana, R Gaedigk, J Steven Leeder, L Salphati, X Chu, G Xiao, Ceca Hop, R Evers, L Gan, J D Unadkat

Manuscripts, Articles, Book Chapters and Other Papers

Protein expression of major hepatic uptake and efflux drug transporters in human pediatric (n = 69) and adult (n = 41) livers was quantified by liquid chromatography / tandem mass spectroscopy (LC-MS/MS). Transporter protein expression of OCT1, OATP1B3, P-gp, and MRP3 was age-dependent. Particularly, significant differences were observed in transporter expression (P < 0.05) between the following age groups: neonates vs. adults (OCT1, OATP1B3, P-gp), neonates or infants vs. adolescents and/or adults (OCT1, OATP1B3, and P-gp), infants vs. children (OATP1B3 and P-gp), and adolescents vs. adults (MRP3). OCT1 showed the largest increase, of almost 5-fold, in protein expression with age. Ontogenic expression of OATP1B1 was confounded by genotype and was revealed only in livers harboring SLCO1B1*1A/*1A. In livers >1 year, tissues harboring SLCO1B1*14/*1A showed 2.5-fold higher (P < 0.05) protein expression than SLCO1B1*15/*1A. Integration of these ontogeny data in physiologically based pharmacokinetic (PBPK) models will be a crucial step in predicting hepatic drug disposition in children.

Insight Into The Molecular Pathophysiology Of Myelodysplastic Syndromes: Targets For Novel Therapy, Mohammad Faizan Zahid, Mrinal M. Patnaik, Naseema Gangat, Shahrukh K. Hashmi, David A. Rizzieri

Medical College Documents

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by abnormal cellular differentiation and maturation with variable progression to acute leukemia. Over the last decade, scientific discoveries have unraveled specific pathways involved in the complex pathophysiology of MDS. Prominent examples include aberrations in cytokines and their signaling pathways (such as tumor necrosis factor-alpha, interferon-gamma, SMAD proteins), mutations in genes encoding the RNA splicing machinery (SF3B1, SRSF2, ZRSR2, and U2AF1 genes), mutations in genes disrupting the epigenetic machinery (TET2, DNMT3A, DNMT3B, EZH2, ASXL1). In addition, abnormalities in regulatory T-cell dynamics and atypical interactions between the bone marrow microenvironment, stroma and …

Synthesis, Self-Assembly, And Immunological Activity Of Α-Galactose-Functionalized Dendron–Lipid Amphiphiles, John Trant, Namrata Jain, D. M. Mazzuca, J Trevor Mcintosh, Bo Fan, S M Mansour Haeryfar, Sebastien Lecommandoux, Elizabeth Gillies

Chemistry Publications

Nanoassemblies presenting multivalent displays of biologically active carbohydrates are of significant interest for a wide array of biomedical applications ranging from drug delivery to immunotherapy. In this study, glycodendron–lipid hybrids were developed as a new and tunable class of dendritic amphiphiles. A modular synthesis was used to prepare dendron–lipid hybrids comprising distearylglycerol and 0 through 4th generation polyester dendrons with peripheral protected amines. Following deprotection of the amines, an isothiocyanate derivative of C-linked α-galactose (α-Gal) was conjugated to the dendron peripheries, affording amphiphiles with 1 to 16 α-Gal moieties. Self-assembly in …

Mirna-145 Increases Therapeutic Sensibility To Gemcitabine Treatment Of Pancreatic Adenocarcinoma Cells., Yong Lin, Xin Ge, Yiyang Wen, Zhu-Mei Shi, Qiu-Dan Chen, Min Wang, Ling-Zhi Liu, Bing-Hua Jiang, Yuan Lu

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Pancreatic adenocarcinoma is one of the most leading causes of cancer-related deaths worldwide. Although recent advances provide various treatment options, pancreatic adenocarcinoma has poor prognosis due to its late diagnosis and ineffective therapeutic multimodality. Gemcitabine is the effective first-line drug in pancreatic adenocarcinoma treatment. However, gemcitabine chemoresistance of pancreatic adenocarcinoma cells has been a major obstacle for limiting its treatment effect. Our study found that p70S6K1 plays an important role in gemcitabine chemoresistence. MiR-145 is a tumor suppressor which directly targets p70S6K1 for inhibiting its expression in pancreatic adenocarcinoma, providing new therapeutic scheme. Our findings revealed a new mechanism underlying …

Week Of September 26, 2016, New York Medical College

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• 2015 NYMC Faculty Authors Lauded
• NYMC Lights It Up Gold
• NYMC Student Clubs Reach Record High
• SHSP Student Lands Competitive Summer Internship

Vulvodynia; An Under-Recognized Disease, Simona Roxana Georgescu, Cristina I. Mitran, Mădălina I. Mitran, Maria I. Sârbu, Mircea Tampa

Journal of Mind and Medical Sciences

Vulvodynia is a chronic condition which affects an increasing number of women; it presents currently an incidence that is higher than had previously been estimated. Regarding pathogenesis, several (hormonal, infectious, inflammatory and psychological) factors have been proposed, but vulvodynia etiology remains still unclear. This disorder is a multifactorial condition with a significant impact on the patient’s quality of life, yet is difficult to diagnose (an under-estimated/ under-recognized affection). Certain medical investigations are required in order to exclude other diseases (the diagnosis of vulvodynia being one of exclusion), but anamnesis and physical examination are essential steps in the diagnosis.

Although many …

Structural Dichotomy Of The Mind; The Role Of Sexual Neuromodulators, Ion G. Motofei, David L. Rowland

Journal of Mind and Medical Sciences

The mind (mental function) and sexuality represent two distinct environmental functions, but which are supported within the brain by a common (somatic-autonomic) neurobiological substrate. As a consequence, mental function takes on autonomic characteristics from the sexual-autonomic system (like autonomy, duality), while sexual function takes on features from mental functioning (such as lateralization). In this paper we discuss the lateralized action of two classes of sexual neuromodulators: hormones and pheromones. This process of lateralization is assimilated with the structural dichotomy of the mind.

A relatively similar process but related to informational dichotomy of the mind will be presented in a forthcoming …

Immunomodulators As Therapeutic Agents In Mitigating The Progression Of Parkinson's Disease, Bethany Grimmig, Josh Morganti, Kevin Nash, Paula C. Bickford

Sanders-Brown Center on Aging Faculty Publications

Parkinson’s disease (PD) is a common neurodegenerative disorder that primarily afflicts the elderly. It is characterized by motor dysfunction due to extensive neuron loss in the substantia nigra pars compacta. There are multiple biological processes that are negatively impacted during the pathogenesis of PD, and are implicated in the cell death in this region. Neuroinflammation is evidently involved in PD pathology and mitigating the inflammatory cascade has been a therapeutic strategy. Age is the number one risk factor for PD and thus needs to be considered in the context of disease pathology. Here, we discuss the role of neuroinflammation within …

Neprilysin Is A Mediator Of Alternative Renin-Angiotensin-System Activation In The Murine And Human Kidney, Oliver Domenig, Arndt Manzel, Nadja Grobe, Eva Königshausen, Christopher C. Kaltenecker, Johannes J. Kovarik, Susan B. Gurley, Dunja Van Oyen, Marlies Antlanger, Michael Bader, Daisy Motta-Santos, Jose Carlos Santos, Robson A. Santos, Khalid M. Elased, Marcus D. Säemann, Ralf A. Linker, Marko Poglitsch

Pharmacology and Toxicology Faculty Publications

Cardiovascular and renal pathologies are frequently associated with an activated renin-angiotensin-system (RAS) and increased levels of its main effector and vasoconstrictor hormone angiotensin II (Ang II). Angiotensin-converting-enzyme-2 (ACE2) has been described as a crucial enzymatic player in shifting the RAS towards its so-called alternative vasodilative and reno-protective axis by enzymatically converting Ang II to angiotensin-(1-7) (Ang-(1-7)). Yet, the relative contribution of ACE2 to Ang-(1-7) formation in vivo has not been elucidated. Mass spectrometry based quantification of angiotensin metabolites in the kidney and plasma of ACE2 KO mice surprisingly revealed an increase in Ang-(1-7), suggesting additional pathways to be responsible for …

Heterogeneity Among Isolates Reveals That Fitness In Low Oxygen Correlates With Aspergillus Fumigatus Virulence, Caitlin H. Kowalski, Sarah R. Beattie, Kevin K. Fuller, Elizabeth A. Mcgurk, Yi-Wei Tang, Tobias Hohl, Joshua Obar, Robert Cramer Jr.

Dartmouth Scholarship

Previous work has shown that environmental and clinical isolates of Aspergillus fumigatus represent a diverse population that occupies a variety of niches, has extensive genetic diversity, and exhibits virulence heterogeneity in a number of animal models of invasive pulmonary aspergillosis (IPA). However, mechanisms explaining differences in virulence among A. fumigatus isolates remain enigmatic. Here, we report a significant difference in virulence of two common lab strains, CEA10 and AF293, in the murine triamcinolone immunosuppression model of IPA, in which we previously identified severe low oxygen microenvironments surrounding fungal lesions. Therefore, we hypothesize that the ability to thrive within these lesions …

Week Of September 19, 2016, New York Medical College

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• NYMC Lights It Up Gold
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Tau Phosphorylation At Alzheimer's Disease-Related Ser356 Contributes To Tau Stabilization When Par-1/Mark Activity Is Elevated., Kanae Ando, Mikiko Oka, Yosuke Ohtake, Motoki Hayashishita, Sawako Shimizu, Shin-Ichi Hisanaga, Koichi M. Iijima

Department of Neuroscience Faculty Papers

Abnormal phosphorylation of the microtubule-associated protein tau is observed in many neurodegenerative diseases, including Alzheimer's disease (AD). AD-related phosphorylation of two tau residues, Ser262 and Ser356, by PAR-1/MARK stabilizes tau in the initial phase of mismetabolism, leading to subsequent phosphorylation events, accumulation, and toxicity. However, the relative contribution of phosphorylation at each of these sites to tau stabilization has not yet been elucidated. In a Drosophila model of human tau toxicity, we found that tau was phosphorylated at Ser262, but not at Ser356, and that blocking Ser262 phosphorylation decreased total tau levels. By contrast, when PAR-1 was co-overexpressed with tau, …

Structural Diversity In The Type Iv Pili Of Multidrug-Resistant Acinetobacter, Kurt H. Piepenbrink, Erik Lillehoj, Christian M. Harding, Jason W. Labonte, Xiaotong Zuo, Chelsea A. Rapp, Robert S. Munson Jr, Simeon E. Goldblum, Mario F. Feldman, Jeffrey J. Gray, Eric J. Sundberg

Food for Health: Publications

Acinetobacter baumannii is a Gram-negative coccobacillus found primarily in hospital settings that has recently emerged as a source of hospital-acquired infections. A. baumannii expresses a variety of virulence factors, including type IV pili, bacterial extracellular appendages often essential for attachment to host cells. Here, we report the high resolution structures of the major pilin subunit, PilA, from three Acinetobacter strains, demonstrating thatA. baumannii subsets produce morphologically distinct type IV pilin glycoproteins. We examine the consequences of this heterogeneity for protein folding and assembly as well as host-cell adhesion by Acinetobacter. Comparisons of genomic and structural data with pilin proteins from …

Week Of September 6, 2016, New York Medical College

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• NYMC and Westchester DOH Collaborate to Combat Opioid Overdoses
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The Role Of Na/K-Atpase Signaling In Oxidative Stress Related To Obesity And Cardiovascular Disease, Krithika Srikanthan, Joseph I. Shapiro Md, Komal Sodhi

Biochemistry and Microbiology

Na/K-ATPase has been extensively studied for its ion pumping function, but, in the past several decades, has been identified as a scaffolding and signaling protein. Initially it was found that cardiotonic steroids (CTS) mediate signal transduction through the Na/K-ATPase and result in the generation of reactive oxygen species (ROS), which are also capable of initiating the signal cascade. However, in recent years, this Na/K-ATPase/ROS amplification loop has demonstrated significance in oxidative stress related disease states, including obesity, atherosclerosis, heart failure, uremic cardiomyopathy, and hypertension. The discovery of this novel oxidative stress signaling pathway, holds significant therapeutic

The Neu1-Selective Sialidase Inhibitor, C9- Butyl-Amide-Dana, Blocks Sialidase Activity And Neu1-Mediated Bioactivities In Human Lung In Vitro And Murine Lung In Vivo, Sang W. Hyun, Anguo Liu, Zhenguo Liu, Alan S. Cross, Avelino C. Verceles, Sadagopan Magesh, Yadagiri Kommagalla, Chandrababunaidu Kona, Hiromune Ando, Irina G. Luzina, Sergei P. Atamas, Kurt H. Piepenbrink, Eric J. Sundberg, Wei Guang, Hideharu Ishida, Erik P. Lillehoj, Simeon E. Goldblum

Food for Health: Publications

Neuraminidase-1 (NEU1) is the predominant sialidase expressed in human airway epithelia and lung microvascular endothelia where it mediates multiple biological processes. We tested whether the NEU1-selective sialidase inhibitor, C9-butyl-amide-2-deoxy-2,3-dehydro-Nacetylneuraminic acid (C9-BA-DANA), inhibits one or more established NEU1-mediated bioactivities in human lung cells. We established the IC50 values of C9-BA-DANA for total sialidase activity in human airway epithelia, lung microvascular endothelia and lung fibroblasts to be 3.74 µM, 13.0 µM and 4.82 µM, respectively. In human airway epithelia, C9-BA-DANA dose-dependently inhibited flagellin-induced, NEU1-mediated mucin-1 ectodomain desialylation, adhesiveness for Pseudomonas aeruginosa and shedding. In lung microvascular endothelia, C9-BA-DANA reversed NEU1-driven restraint of …

The Global Economic And Health Burden Of Human Hookworm Infection., Sarah M Bartsch, Peter J. Hotez, Lindsey Asti, Kristina M Zapf, Maria Elena Bottazzi, David J. Diemert, Bruce Y Lee

Microbiology, Immunology, and Tropical Medicine Faculty Publications

BACKGROUND: Even though human hookworm infection is highly endemic in many countries throughout the world, its global economic and health impact is not well known. Without a better understanding of hookworm's economic burden worldwide, it is difficult for decision makers such as funders, policy makers, disease control officials, and intervention manufacturers to determine how much time, energy, and resources to invest in hookworm control.

METHODOLOGY/PRINCIPLE FINDINGS: We developed a computational simulation model to estimate the economic and health burden of hookworm infection in every country, WHO region, and globally, in 2016 from the societal perspective. Globally, hookworm infection resulted in …

Cyp2c44 Gene Disruption Exacerbated Pulmonary Hypertension And Heart Failure In Female But Not Male Mice, Sachindra R. Joshi, Anand Lakhkar, Vidhi Dhagia, Ariadne Zias, Vasiliki Soldatos, Kaori Oshima, Houli Jiang, Katherine Gotlinger, Jorge H Capdevila, Michal L. Schwartzman, Ivan F. Mcmurtry, Sachin A. Gupte

NYMC Faculty Publications

Epoxyeicosatrienoicacids (EETs), synthesized from arachidonic acid by epoxygenases of the CYP2C and CYP2J gene subfamilies, contribute to hypoxic pulmonary vasoconstriction (HPV) in mice. Despite their roles in HPV, it is controversial whether EETs mediate or ameliorate pulmonary hypertension (PH). A recent study showed that deficiency of Cyp2j did not protect male and female mice from hypoxia-induced PH. Since CYP2C44 is a functionally important epoxygenase, we hypothesized that knockout of the Cyp2c44 gene would protect both sexes of mice from hypoxia-induced PH. We tested this hypothesis in wild-type (WT) and Cyp2c44 knockout (Cyp2c44 (-/-)) mice exposed to normoxia (room air) and …

Mice With A Heterozygous Lrp6 Deletion Have Impaired Fracture Healing, Travis A. Burgers, Juan F. Vivanco, Juraj Zahatnansky, Andrew J. Vander Moren, James J. Mason, Bart O. Williams

Mechanical Engineering Faculty Publications

Bone fracture non-unions, the failure of a fracture to heal, occur in 10%–20% of fractures and are a costly and debilitating clinical problem. The Wnt/β-catenin pathway is critical in bone development and fracture healing. Polymorphisms of linking low-density lipoprotein receptor-related protein 6 (LRP6), a Wnt-binding receptor, have been associated with decreased bone mineral density and fragility fractures, although this remains controversial. Mice with a homozygous deletion of Lrp6 have severe skeletal abnormalities and are not viable, whereas mice with a heterozygous deletion have a combinatory effect with Lrp5 to decrease bone mineral density. As fracture healing closely models embryonic skeletal …

Peroxiredoxin Catalysis At Atomic Resolution, Arden Perkins, Derek Parsonage, Kimberly J. Nelson, O. Maduka Ogba, Paul Ha-Yeon Cheong, Leslie B. Poole, P. Andrew Karplus

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Peroxiredoxins (Prxs) are ubiquitous cysteine-based peroxidases that guard cells against oxidative damage, are virulence factors for pathogens, and are involved in eukaryotic redox regulatory pathways. We have analyzed catalytically active crystals to capture atomic resolution snapshots of a PrxQ-subfamily enzyme (from Xanthomonas campestris) proceeding through thiolate, sulfenate, and sulfinate species. These analyses provide structures of unprecedented accuracy for seeding theoretical studies, and show novel conformational intermediates giving insight into the reaction pathway. Based on a highly non-standard geometry seen for the sulfenate intermediate, we infer that the sulfenate formation itself can strongly promote local unfolding of the active site to …