Article
Microbiology
Gabriela de A. Burle-Caldas, Nailma S. A. dos Santos, Julia T. de Castro, Fernanda L. B. Mugge, Viviane Grazielle-Silva, Antonio Edson R. Oliveira, Milton C. A. Pereira, Joo Luis Reis-Cunha, Anderson Coqueiro dos Santos, Dawidson Assis Gomes, Daniella C. Bartholomeu, Nilmar S. Moretti, Sergio Schenkman, Ricardo T. Gazzinelli, Santuza M. R. Teixeira
Summary: Trans-sialidases (TS) are enzymes present on the surface of Trypanosoma cruzi, the causative agent of Chagas disease, and play a crucial role in the late stages of intracellular development and parasite egress. In this study, TS knockout parasites were generated using CRISPR-Cas9 technology, resulting in impaired parasite egress from infected cells. These TS mutants lost their ability to cause infection in vivo but provided full protection against a challenge infection with a virulent strain, indicating their potential as a live attenuated vaccine against Chagas disease.
Article
Biochemistry & Molecular Biology
Natalia Lins da Silva-Gomes, Leonardo Alexandre de Souza Ruivo, Claudia Moreira, Marcelo Meuser-Batista, Cristiane Franca da Silva, Denise da Gama Jaen Batista, Stenio Fragoso, Gabriel Melo de Oliveira, Maria de Nazare Correia Soeiro, Otacilio C. Moreira
Summary: In this study, genetically modified strains of Trypanosoma cruzi were used to evaluate the role of NTPDases in parasite infectivity. The results showed that parasites overexpressing TcNTPDase-1 had higher infectivity, while hemi-knockout parasites had lower infectivity and no significant electrocardiographic changes. These findings highlight the potential of NTPDases as a therapeutic target for Chagas disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Microbiology
Gabriela de A. Burle-Caldas, Nailma S. A. dos Santos, Julia T. de Castro, Fernanda L. B. Mugge, Viviane Grazielle-Silva, Antonio Edson R. Oliveira, Milton C. A. Pereira, Joao Luis Reis-Cunha, Anderson Coqueiro dos Santos, Dawidson Assis Gomes, Daniella C. Bartholomeu, Nilmar S. Moretti, Sergio Schenkman, Ricardo T. Gazzinelli, Santuza M. R. Teixeira
Summary: Trans-sialidases play a crucial role in the virulence of Trypanosoma cruzi, and using CRISPR-Cas9, aTS mutant parasites were generated which lost infectivity in vivo but provided full protection against a challenge infection with a virulent strain.
Article
Immunology
Gabriela Specker, Damian Estrada, Rafael Radi, Lucia Piacenza
Summary: This study demonstrates the protective effects of Trypanosoma cruzi mitochondrial peroxiredoxin (MPX) in macrophage infections and in response to nifurtimox (NFX) toxicity. MPX content increased after NFX treatment and overexpression of MPX enhanced resistance to the drug. MPX exhibits holdase activity and its overexpression was observed in temperature-challenged parasites. These findings suggest a protective role of MPX holdase activity against NFX toxicity.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Hanna Kwon, Jaswir Basran, Chinar Pathak, Mahdi Hussain, Samuel L. Freeman, Alistair J. Fielding, Anna J. Bailey, Natalia Stefanou, Hazel A. Sparkes, Takehiko Tosha, Keitaro Yamashita, Kunio Hirata, Hironori Murakami, Go Ueno, Hideo Ago, Kensuke Tono, Masaki Yamamoto, Hitomi Sawai, Yoshitsugu Shiro, Hiroshi Sugimoto, Emma L. Raven, Peter C. E. Moody
Summary: Oxygen activation in heme enzymes requires the formation of high oxidation states of iron, known as ferryl heme, with two intermediates known as Compound I and Compound II. Recent crystal structure studies of Compound II in cytochrome c peroxidase and ascorbate peroxidase reveal differences in iron-oxygen bond lengths, suggesting fine-tuning of the ferryl species across closely related peroxidase enzymes.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Immunology
Juan San Francisco, Constanza Astudillo, Jose Luis Vega, Alejandro Catalan, Bessy Gutierrez, Jorge E. Araya, Anibal Zailberger, Anabel Marina, Carlos Garcia, Nuria Sanchez, Antonio Osuna, Susana Vilchez, Marcel Ramirez, Janaina Macedo, Veronica Santiago Feijoli, Giuseppe Palmisano, Jorge Gonzalez
Summary: The study aimed to determine the mechanism underlying the pathogenicity of T. cruzi. The results showed that high-virulence C8C3 hvir was highly infectious in mice and demonstrated higher parasite loads compared to low-virulence C8C3 lvir. Comparative proteomics revealed differential regulation of proteins associated with bioenergetic and biosynthetic pathways in C8C3 hvir. Furthermore, C8C3 hvir expressed higher levels of virulence factors such as Cruzipain, complement regulatory protein, trans-sialidase, Tc-85, and sialylated epitopes.
Article
Microbiology
Any Laura Flores-Villegas, Jesus Guillermo Jimenez-Cortes, James Gonzalez, Adriana Moreno-Rodriguez, Rebeca Perez-Cabeza de Vaca, Claudia Segal-Kischinevzky, Martha Bucio-Torres, Jose A. De Fuentes-Vicente, Elisabeth Nava-Lazaro, Paz Maria Salazar-Schettino, Margarita Cabrera Bravo
Summary: Trypanosoma cruzi, a parasite transmitted by triatomines, shows different virulence, tropism, and tssa gene expression in different isolates obtained from various triatomine species in Mexico.
Article
Biochemistry & Molecular Biology
Marilia L. Cirqueira, Leandro O. Bortot, Mayte Bolean, Mariana A. A. Aleixo, Pedro H. Luccas, Antonio J. Costa-Filho, Ana Paula Ramos, Pietro Ciancaglini, M. Cristina Nonato
Summary: Due to its severe burden and geographic distribution, Chagas disease has a significant social and economic impact on low-income countries. This study aims to understand the role of TcNTR in the basic parasite biology, investigate its potential as a drug target, and contribute to the fight against neglected tropical diseases. The results showed that TcNTR interacts with membranes, with a preference for those containing cardiolipin, and a 23-residue long insertion is involved in enzyme specificity and protein-membrane interaction.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Review
Biochemistry & Molecular Biology
Marcos Vinicius da Silva, Brenna Louise Cavalcanti Gondim, Tamires Marielem de Carvalho-Costa, Maria Tays Mendes, Marcela Rezende Lemes, Rafaela Miranda Barbosa, Talita Nunes Cardoso, Natalia Santos Nascimento, Daniela Bomfirm Barros, Marcia Vanusa da Silva, Juliana Reis Machado, Luico Roberto Cancado Castellano
Summary: Chagas Disease, a Neglected Tropical Disease affecting around seven million people, is currently treated with only two drugs, both with limitations. Therefore, the search for new therapeutic approaches is crucial for improving treatment outcomes.
CURRENT MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Roberto Docampo, Anibal Eugenio Vercesi
Summary: This review discusses the mechanisms of mitochondrial oxidant generation and removal, and the involvement of Ca2+ in trypanosome cell death, highlighting the need for further studies on ROS generation, defense mechanisms, and mitochondrial permeability transition pore in trypanosomatids.
ANTIOXIDANTS & REDOX SIGNALING
(2022)
Article
Biochemistry & Molecular Biology
Naiara Dutra Barroso Gomes, Emanuel Paula Magalhaes, Lyanna Rodrigues Ribeiro, John Washington Cavalcante, Marcelo Morais Gomes Maia, Felipe Ramon Cunha da Silva, Arif Ali, Marcia Machado Marinho, Emmanuel Silva Marinho, Helcio Silva dos Santos, Alice Maria Costa Martins, Ramon Roseo Paula Pessoa Bezerra de Menezes
Summary: This study evaluated the activity of synthetic p-aminochalcones against T. cruzi and found that they have a trypanocidal effect by causing membrane damage and oxidative stress. Their mechanism of action may be related to inhibition of cruzain and TR.
BIOORGANIC CHEMISTRY
(2023)
Article
Immunology
Carezza Botto-Mahan, Juana P. Correa, Raul Araya-Donoso, Francisca Farias, Esteban San Juan, Nicol Quiroga, Ricardo Campos-Soto, Claudio Reyes-Olivares, Daniel Gonzalez-Acuna
Summary: In this study, we assessed 4 lizard species in Chile for Trypanosoma cruzi and found that all species were infected. We also discovered that one species had the ability to transmit the protozoan, highlighting their role as reservoirs for T. cruzi.
EMERGING INFECTIOUS DISEASES
(2022)
Review
Microbiology
Abel Cruz Camacho, Daniel Alfandari, Ewa Kozela, Neta Regev-Rudzki
Summary: Extracellular vesicles (EVs) are essential for cell-cell communication. The roles of EVs in parasites, especially in terms of pathogenesis, are of great interest for medical insight and therapeutic intervention. However, the mechanisms of EV biogenesis in human parasitic protozoa, particularly in terms of the Endosomal Sorting Complex Required for Transport (ESCRT) machinery, remain elusive. This review focuses on the current knowledge of EV biogenesis pathways in the four main clades of human parasitic protozoa (apicomplexans, trypanosomatids, flagellates, and amoebae), highlighting the diversity in EV biogenesis and the involvement of the ESCRT system in these unique organisms.
Article
Biochemistry & Molecular Biology
Evan R. Devallance, Heidi M. Schmidt, Madison Seman, Sara E. Lewis, Katherine C. Wood, Schuyler D. Vickers, Scott A. Hahn, Murugesan Velayutham, Emily A. Hileman, Dario A. Vitturi, Roberta Leonardi, Adam C. Straub, Eric E. Kelley
Summary: This study identified a previously unknown pathway in which XOR is upregulated via SP1/NF-kB and subsequently exported to the extracellular environment. This is the first study to demonstrate mechanistically that XOR can be specifically targeted for export as a compensatory response to heme/Fe overload.
Article
Biochemistry & Molecular Biology
Kanako Sugawara, Toru Yoshida, Rena Hirashima, Ryoko Toriumi, Hotaka Akiyama, Yurika Kakuta, Yuki Ishige, Yasushi Sugano
Summary: DyP-type peroxidases are a family of heme peroxidases known for their ability to degrade anthraquinone dyes, with subclassification into three classes based on genome sequences. SaDyP1 and SaDyP2, both members of class V, exhibit similar characteristics and substrate specificity, showing expression in mycelia of wild-type S. avermitilis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Lisa K. Folkes, Silvina Bartesaghi, Madia Trujillo, Peter Wardman, Rafael Radi
Summary: The use of free radicals in biology, particularly peroxynitrite-derived radicals, has attracted significant attention. This review discusses the principles and methods of selective radical generation by radiolysis, as well as the key reactions of peroxynitrite-derived radicals with potential biological targets. Additionally, studies involving the reactions of these radicals with lipoic acid/dihydrolipoic acid, hydrogen sulphide, and desferrioxamine are outlined.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Yunlong Shi, Ari Zeida, Caitlin E. Edwards, Michael L. Mallory, Santiago Sastre, Matias R. Machado, Raymond J. Pickles, Ling Fu, Keke Liu, Jing Yang, Ralph S. Baric, Richard C. Boucher, Rafael Radi, Kate S. Carroll
Summary: This study demonstrates the potential of thiol-based chemical probes in inhibiting coronavirus infections, providing a new strategy for drug development.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Physiology
Lucia Piacenza, Ari Zeida, Madia Trujillo, Rafael Radi
Summary: The free radical nitric oxide (NO) plays a key role in physiological processes, but its bioavailability is compromised in certain disease conditions due to increased production of superoxide radical. This leads to the inactivation of nitric oxide and the formation of peroxynitrite, which is implicated in various human diseases and the aging process. Understanding the complex biochemistry of peroxynitrite is crucial for developing therapeutic interventions.
PHYSIOLOGICAL REVIEWS
(2022)
Article
Biochemistry & Molecular Biology
Samuel L. Freeman, Vera Skafar, Hanna Kwon, Alistair J. Fielding, Peter C. E. Moody, Alejandra Martinez, Federico M. Issoglio, Lucas Inchausti, Pablo Smircich, Ari Zeida, Lucia Piacenza, Rafael Radi, Emma L. Raven
Summary: This study solved the structure and examined the reactivity of the Trypanosoma cruzi ascorbate peroxidase-cytochrome c peroxidase enzyme (TcAPx-CcP), a hybrid heme peroxidase in the protozoan parasite Trypanosoma cruzi. The results showed that TcAPx-CcP has overall structural similarity to other peroxidases, with differences in substrate-binding regions. Additionally, TcAPx-CcP preserves the electron transfer pathway from cytochrome c to heme, preferentially oxidizing cytochrome c but still capable of oxidizing ascorbate.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Brenna J. C. Walsh, Sofia Soares Costa, Katherine A. Edmonds, Jonathan C. Trinidad, Federico M. Issoglio, Jose A. Brito, David P. Giedroc
Summary: Hydrogen sulfide (H2S) is a cytoprotective agent used by bacteria in response to stress, and this study found that exogenous sulfide alters protein abundance and metabolic reactions in the gut microorganism Enterococcus faecalis, potentially affecting fatty acid pathways.
Meeting Abstract
Biochemistry & Molecular Biology
Giuliana Cardozo, Mauricio Mastrogiovanni, Rafael Radi, Madia Trujillo, Anibal M. Reyes
FREE RADICAL BIOLOGY AND MEDICINE
(2022)
Meeting Abstract
Biochemistry & Molecular Biology
Rogerio Aleixo Silva, Renato Domingos, Madia Trujillo, Arnaldo Filho, Cristiano Oliveira, Regina Baldini, Jesmond Dalli, Luis Netto
FREE RADICAL BIOLOGY AND MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Nicolas Campolo, Mauricio Mastrogiovanni, Michele Mariotti, Federico M. Issoglio, Dario Estrin, Per Hagglund, Tilman Grune, Michael J. Davies, Silvina Bartesaghi, Rafael Radi
Summary: Glutamine synthetase (GS) is an important enzyme that plays a crucial role in nitrogen metabolism. This study investigated the oxidative inactivation of human GS by peroxynitrite (ONOO-) in vitro. The results showed that ONOO- exposure led to a dose-dependent loss of GS activity and various oxidative modifications of the enzyme. Multiple tyrosine nitration sites and dityrosine cross-links were identified, but nitration of specific tyrosine residues alone was not responsible for enzyme inactivation. In addition, ONOO- induced GS aggregation and activity loss, with thiol oxidation being a key modification to elicit aggregation.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Federico N. Pedron, Andresa Messias, Ari Zeida, Adrian E. Roitberg, Dario A. Estrin
Summary: This study presents a methodology to obtain Lennard-Jones parameters for cysteine and selenocysteine in different oxidation and protonation states, and validates their impact on protein structure and dynamics through classical molecular dynamics simulations.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Multidisciplinary Sciences
Florencia Tomasina, Jennyfer Martinez, Ari Zeida, Maria Laura Chiribao, Veronica Demicheli, Agustin Correa, Celia Quijano, Laura Castro, Robert H. Carnahan, Paige Vinson, Matt Goff, Tracy Cooper, W. Hayes McDonald, Natalie Castellana, Luciana Hannibal, Paul T. Morse, Junmei Wan, Maik Huttemann, Ronald Jemmerson, Lucia Piacenza, Rafael Radi
Summary: Cytochrome c (cyt c) undergoes reversible conformational changes under biologically relevant conditions, but revealing these alternative conformations at the cell and tissue level is challenging. This study successfully resurrected a monoclonal antibody (mAb) that recognizes a key conformational change in cyt c and showed similar performance to the original mAb. Using this antibody, alternative conformations of cyt c were identified in cells under oxidative or senescence-induced challenge, and these conformations translocated to the nucleus without causing apoptosis.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Alejandra Martinez-D'Alto, Xia Yan, Tyler C. Detomasi, Richard I. Sayler, William C. Thomas, Nicholas J. Talbot, Michael A. Marletta
Summary: Blast disease caused by the fungus Magnaporthe oryzae leads to significant crop loss in cereal plants. The study shows that the expression of the putative polysaccharide monooxygenase MoPMO9A is increased during infection. MoPMO9A exhibits activity on cereal-derived mixed β-D-glucans and its domain architecture is different from other characterized AA9 PMOs. The results suggest that MoPMO9A plays a role in MBG degradation during plant infection.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Giuliana Cardozo, Mauricio Mastrogiovanni, Ari Zeida, Nicolas Viera, Rafael Radi, Anibal M. Reyes, Madia Trujillo
Summary: Human peroxiredoxin 3 (HsPrx3) is oxidized and hyperoxidized by (f)FA-OOHs, including arachidonic acid and eicosapentaenoic acid peroxidation products. Biophysical methods and molecular dynamic simulations suggest that HsPrx3 can bind hydrophobic structures and interact with the hydroperoxide group of (f)FA-OOHs. Kinetic simulation analysis supports that mitochondrial (f)FA-OOHs can lead to HsPrx3 hyperoxidation.
Article
Chemistry, Physical
Jonathan A. Semelak, Ari Zeida, Nicolas O. Foglia, Dario A. Estrin
Summary: In this work, we propose an approach to model reactive processes in complex environments that does not require a priori selection of a reaction coordinate. By combining QM/MM simulations with the FENEB method, we successfully optimize MFEP in different reactive processes and study the robustness of the method and the influence of sampling on the optimized results.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Biochemistry & Molecular Biology
Sebastian F. Villar, Laura Corrales-Gonzalez, Belen Marquez de los Santos, Joaquin Dalla Rizza, Ari Zeida, Ana Denicola, Gerardo Ferrer-Sueta
Summary: The reduction reactions of cytosolic human peroxiredoxins (Prx) in their disulfide form by thioredoxins (Trx) were studied. The reactivity of the nucleophilic cysteine in Trx was found to be greatly affected by the formation of the Prx-Trx complex. This activation mechanism helps understand the reduction of Prx by alternative reductants involved in redox signaling.