Article
Biochemistry & Molecular Biology
Annika Klimpel, Katharina Stillger, Janica L. Wiederstein, Marcus Krueger, Ines Neundorf
Summary: Cysteine prenylation is a post-translational modification that controls important biological functions of proteins. This modification mainly occurs at the C-terminal CaaX box of eukaryotic proteins. New tools, such as cell-permeable peptides with a CaaX motif, have been developed to study and regulate this modification.
Article
Biochemistry & Molecular Biology
Lauren M. Adams, Caroline J. DeHart, Bryon S. Drown, Lissa C. Anderson, William Bocik, Emily S. Boja, Tara M. Hiltke, Christopher L. Hendrickson, Henry Rodriguez, Michael Caldwell, Reza Vafabakhsh, Neil L. Kelleher
Summary: This study evaluates the protein modifications of two isoforms of the KRAS gene in human cancer. It finds differential modifications between KRAS4A and KRAS4B, and identifies a truncated proteoform of KRAS4B lacking the C185 residue which affects its membrane association and downstream signaling.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Microbiology
Rajani Ravishankar, Emily R. Hildebrandt, Grace Greenway, Nadeem Asad, Sangram Gore, Timothy M. Dore, Walter K. Schmidt
Summary: CAAX proteins undergo various posttranslational modifications, and this study used a proteolysis-resistant CAAX sequence to investigate Saccharomyces cerevisiae Ras2 GTPase. The results showed that the type of CAAX motif affected Ras2 protein levels, localization, and function.
MICROBIOLOGY SPECTRUM
(2023)
Article
Chemistry, Multidisciplinary
Xiaolin Zou, Zhen Hui, Robert A. Shepherd, Shuaiqiang Zhao, Yanfei Wu, Zhuanglin Shen, Cuiping Pang, Shipeng Zhou, Zehai Yu, Jiahai Zhou, Bradly S. Moore, Laura M. Sanchez, Xiaoyu Tang
Summary: This study provides a comprehensive exploration of the genetic and biochemical aspects of the enzymes responsible for the assembly and cleavage of the acylated peptide prodrug scaffolds in the assembly line biosynthesis of didemnin cyclic peptides. The findings shed light on the complex prodrug release mechanism underlying the synthesis and secretion of didemnin compounds and offer novel insights into the expanded role of CAAX hydrolases in microbes. This knowledge can be used for the strategic design of genome mining approaches to discover new bioactive natural products that employ similar prodrug biochemical strategies.
Article
Multidisciplinary Sciences
Allen K. Kim, Helen D. Wu, Takanari Inoue
Summary: The study successfully designed a molecular switch that can rapidly translocate to different cellular locations based on the activity of PKA. By arranging peptide sequences and testing different valence numbers, an efficient peptide switch was identified that exhibited dynamic translocation dependent on PKA activity.
SCIENTIFIC REPORTS
(2021)
Article
Multidisciplinary Sciences
Brittany M. Berger, Wayland Yeung, Arnav Goyal, Zhongliang Zhou, Emily R. Hildebrandt, Natarajan Kannan, Walter K. Schmidt
Summary: Using a machine learning approach, this study aims to improve prenylation predictions by expanding the repertoire of predicted FTase targets and providing a framework for functional classification.
Article
Medicine, General & Internal
Marta Sagastagoitia-Fornie, Eduardo Barge-Caballero, Gonzalo Barge-Caballero, David Couto-Mallon, Maria J. Paniagua-Martin, Daniel Enriquez-Vazquez, Paula Blanco-Canosa, Zulaika Grille-Cancela, Manuel Jimenez-Navarro, Javier Muniz, Jose M. Vazquez-Rodriguez, Maria G. Crespo-Leiro
Summary: This study assessed the incidence of cancer diagnosis and cancer-related mortality in patients with heart failure (HF). The results showed that patients with HF had higher incidence rates of cancer diagnosis and cancer-related mortality than the general population.
EUROPEAN JOURNAL OF INTERNAL MEDICINE
(2022)
Article
Medical Laboratory Technology
Sadra Mohaghegh, Parisa Motie, Saeed Reza Motamedian
Summary: Studies have found that ACE2 has a protective effect against COVID-19, but the virus can use ACE2 for entry into host cells. The expression of ACE2 can be influenced by factors such as hypertension, diabetes, obesity, and androgens, which may increase the severity of infection. Research on the impact of ACE gene polymorphism is ongoing, with contradictory results reported.
CLINICAL CHEMISTRY AND LABORATORY MEDICINE
(2021)
Article
Pharmacology & Pharmacy
Taikang Yao, Zhenchao Wu, Zilu Wang, Liting Chen, Beibei Liu, Ming Lu, Ning Shen
Summary: Observational studies and meta-analyses have shown a positive correlation between the use of angiotensin-converting enzyme inhibitors (ACEIs) and lung cancer. The study used Mendelian randomization to verify the associations between ACE inhibition, ACEI-induced cough, and the risk of lung cancer. The results indicate a significant relationship between ACE inhibition and the development of lung cancer, as well as a higher risk of lung cancer for Europeans with ACEI-induced cough.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Biology
Ian M. Ahearn, Helen R. Court, Farid Siddiqui, Daniel Abankwa, Mark R. Philips
Summary: ICMT is crucial for the efficient delivery of NRAS to the plasma membrane, as well as for its carboxyl methylation, binding with PDE6d, and flux through the Golgi.
LIFE SCIENCE ALLIANCE
(2021)
Article
Medicine, Research & Experimental
Shilong Li, Rangaprasad Sarangarajan, Tomi Jun, Yu-Han Kao, Zichen Wang, Ke Hao, Emilio Schadt, Michael A. Kiebish, Elder Granger, Niven R. Narain, Rong Chen, Eric E. Schadt, Li Li
Summary: The study found that the use of ACE-I/ARB during hospitalization was significantly associated with a reduced in-hospital mortality rate in COVID-19 positive African American patients. Specifically, ARB hospital use was significantly associated with reduced in-hospital mortality in the African American population.
JOURNAL OF CLINICAL INVESTIGATION
(2021)
Review
Cardiac & Cardiovascular Systems
Carmen Spaccarotella, Maria Mazzitelli, Serena Migliarino, Antonio Curcio, Salvatore De Rosa, Carlo Torti, Ciro Indolfi
Summary: COVID-19, caused by the novel coronavirus, has led to a global pandemic with a high mortality rate. Patients infected with SARS-CoV-2 may experience cardiac issues, and the use of antiviral drugs can worsen heart function. The virus targets ACE2, impacting lung and heart function, and there is uncertainty regarding the use of ACE inhibitors and ARBs.
JOURNAL OF CARDIOVASCULAR MEDICINE
(2021)
Article
Chemistry, Medicinal
Matthias Franz, Britta Moerchen, Carsten Degenhart, Daniel Guelden, Oleksandr Shkura, Dirk Wolters, Uwe Koch, Bert Klebl, Raphael Stoll, Iris Helfrich, Juergen Scherkenbeck
Summary: This study presents an alternative strategy to prevent Ras protein activation by modifying its farnesylation through the use of supramolecular receptors. Research on Ras proteins in the past has been hindered by the difficulty in addressing protein-protein interactions, limiting the progress towards small molecule inhibitors.
Article
Multidisciplinary Sciences
Atila Duque Rossi, Joao Locke Ferreira de Araujo, Tailah Bernardo de Almeida, Marcelo Ribeiro-Alves, Camila de Almeida Velozo, Jessica Maciel de Almeida, Isabela de Carvalho Leitao, Samila Natiane Ferreira, Jessica da Silva Oliveira, Hugo Jose Alves, Helena Toledo Scheid, Debora Souza Faffe, Rafael Mello Galliez, Renata Eliane de Avila, Gustavo Gomes Resende, Mauro Martins Teixeira, Orlando da Costa Ferreira Junior, Terezinha Marta P. P. Castineiras, Renan Pedra Souza, Amilcar Tanuri, Renato Santana de Aguiar, Shana Priscila Coutinho Barroso, Cynthia Chester Cardoso
Summary: ACE2 and TMPRSS2 levels are positively correlated with age, which is strongly associated with respiratory distress. Increased ACE2 levels have a protective effect against this outcome, while the TMPRSS2/ACE2 ratio is associated with risk. In modeling COVID-19 severity, the TMPRSS2/ACE2 ratio outperforms ACE2.
SCIENTIFIC REPORTS
(2021)
Article
Multidisciplinary Sciences
Ah Ran Oh, Jungchan Park, Jong-Hwan Lee, Jeong Jin Min, Joonhee Gook, Jae Ni Jang, Seung-Hwa Lee, Kyunga Kim, Joonghyun Ahn
Summary: A study on patients undergoing cancer surgery found that RAAS inhibitors had a positive effect in reducing the 5-year mortality and recurrence rates of the patients.
SCIENTIFIC REPORTS
(2022)
Article
Biochemistry & Molecular Biology
Dayana Rodriguez-Contreras, Alec F. Condon, David C. Buck, Naeem Asad, Timothy M. Dore, Dineke S. Verbeek, Marina A. J. Tijssen, Ujwal Shinde, John T. Williams, Kim A. Neve
Summary: A novel dopamine D2 receptor mutation was found to be constitutively active and signaling-biased, with enhanced basal activation and reduced arrestin recruitment compared to the wild type receptor. The impact of this variant in a specific brain region may vary depending on the expression levels of G proteins and GRK.
ACS CHEMICAL NEUROSCIENCE
(2021)
Article
Cell Biology
Alec F. Condon, Brooks G. Robinson, Naeem Asad, Timothy M. Dore, Lin Tian, John T. Williams
Summary: This study investigates the temporal dynamics of functional interaction between dopamine and D2 dopamine receptors during neuromodulation, highlighting the impact of highly localized dopamine release on downstream signaling.
Article
Biochemistry & Molecular Biology
Garrett L. Schey, Peter H. Buttery, Emily R. Hildebrandt, Sadie X. Novak, Walter K. Schmidt, James L. Hougland, Mark D. Distefano
Summary: A new systematic approach combining solid-phase peptide synthesis and mass spectrometric analysis has been developed to discover novel peptide substrates for FTase. Experimental results show that this method successfully identifies multiple substrates for FTase, with some even surpassing the benchmark sequence CMIIM in efficiency.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Runhui Liang, Xin Lan, Naeem Asad, Timothy M. Dore, Qidi Zhang, Lili Du, David Lee Phillips
Summary: The study investigated the photolysis reactions of CyHQ-caged amines using time-resolved spectroscopy, revealing an unexpected Hofmann-Martius rearrangement reaction. By characterizing reaction intermediates, a photodynamic mechanism of this reaction was deduced, providing insights for designing novel photoactivatable aniline molecules.
PHOTOCHEMISTRY AND PHOTOBIOLOGY
(2022)
Article
Chemistry, Medicinal
Alasdair Smith, Richard J. Wall, Stephen Patterson, Tim Rowan, Eva Rico Vidal, Laste Stojanovski, Margaret Huggett, Shahienaz E. Hampton, Michael G. Thomas, Victoriano Corpas Lopez, Kirsten Gillingwater, Jeff Duke, Grant Napier, Rose Peter, Herve S. Vitouley, Justin R. Harrison, Rachel Milne, Laura Jeacock, Nicola Baker, Susan H. Davis, Frederick Simeons, Jennifer Riley, David Horn, Reto Brun, Fabio Zuccotto, Michael J. Witty, Susan Wyllie, Kevin D. Read, Ian H. Gilbert
Summary: African animal trypanosomiasis is a major problem in cattle and other livestocks in sub-Saharan Africa and current treatments are facing drug resistance. A medicinal chemistry program has developed a lead compound capable of curing cattle infected with two types of trypanosomes via intravenous dosing, with potential for further optimization to provide a single-dose intramuscular treatment for this disease.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Brittany M. Berger, Wayland Yeung, Arnav Goyal, Zhongliang Zhou, Emily R. Hildebrandt, Natarajan Kannan, Walter K. Schmidt
Summary: Using a machine learning approach, this study aims to improve prenylation predictions by expanding the repertoire of predicted FTase targets and providing a framework for functional classification.
Article
Chemistry, Medicinal
Davide Deodato, Nadeem Asad, Timothy M. Dore
Summary: The discovery of an effective M-pro inhibitor provides potential for the development of novel coronavirus antivirals, bringing us closer to ending the COVID-19 pandemic and preparing for future outbreaks. Through computational tools and virtual screening, a hit compound with promising inhibitory activity against M-pro was identified, demonstrating the significance of structure-based drug discovery in combating viral infections.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Neurosciences
Alec F. Condon, Naeem Asad, Timothy M. Dore, John T. Williams
Summary: The activity of dopamine neurons is influenced by both intrinsic properties and afferent projections. This study found that the interaction between D2 and GABA(B) receptors can affect the amplitude and kinetics of GIRK current. Additionally, the cooperative interaction between G protein beta gamma subunits and GIRK channels plays an important regulatory role.
JOURNAL OF PHYSIOLOGY-LONDON
(2022)
Article
Chemistry, Physical
Naeem Asad, Davide Deodato, Sangram Gore, Timothy M. Dore
Summary: By functionalizing four derivatives, the release of tertiary amines via two-photon excitation (2PE) was studied. These derivatives exhibited good properties in biological settings and an optimized photoremovable protecting group (PPG) mediated the efficient photoactivation of various biological effectors.
Article
Biochemistry & Molecular Biology
Manohar Puppala, Jasmine E. Carrothers, Nadeem Asad, Mark A. Bernard, Daniel S. Kim, Magnus B. Widegren, Timothy M. Dore
Summary: Utilizing antenna-based light harvesting strategies can enhance sensitivity to two-photon excitation (2PE), allowing precise control over the timing and location of glutamate activation, which is highly useful for studying the physiological aspects of the brain.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Microbiology
Rajani Ravishankar, Emily R. Hildebrandt, Grace Greenway, Nadeem Asad, Sangram Gore, Timothy M. Dore, Walter K. Schmidt
Summary: CAAX proteins undergo various posttranslational modifications, and this study used a proteolysis-resistant CAAX sequence to investigate Saccharomyces cerevisiae Ras2 GTPase. The results showed that the type of CAAX motif affected Ras2 protein levels, localization, and function.
MICROBIOLOGY SPECTRUM
(2023)
Article
Genetics & Heredity
June H. Kim, Emily R. Hildebrandt, Anushka Sarkar, Wayland Yeung, La Ryel A. Waldon, Natarajan Kannan, Walter K. Schmidt
Summary: This study comprehensively evaluated all possible CXXX sequences as targets of farnesyltransferase (FTase) using the reporter Ydj1. It found that yeast FTase can farnesylate sequences outside the CaaX motif and that these sequences do not undergo the canonical 3-step pathway. The study also revealed that yeast FTase specificity is mainly influenced by restrictive amino acids at a(2) and X positions, rather than the resemblance of the CaaX motif.
G3-GENES GENOMES GENETICS
(2023)
Article
Biochemistry & Molecular Biology
Naeem Asad, Davide Deodato, Nadeem Asad, Sangram Gore, Timothy M. Dore
Summary: Phenols confer bioactivity to a plethora of organic compounds. Protecting the phenolic functionality with photoremovable protecting groups (PPGs) sensitive to two-photon excitation (2PE) can block the bioactivity and provide controlled release of these compounds. A study found that a two-photon sensitive PPG can efficiently release phenols and has attributes useful for biological use. The findings are important for understanding neurological signaling and the roles of neurotransmitters.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Chemistry, Organic
Davide Deodato, Naeem Asad, Timothy M. Dore
Summary: TMP-CyHQ-AMPA is a photoactivatable agonist of AMPA receptors that can release AMPA with high quantum yield upon visible light or 2-photon excitation, allowing for the study of excitatory transmission between neurons. The compound is soluble in physiological buffer and does not hydrolyze in the absence of light, providing exceptional spatial-temporal resolution for studying glutamatergic neuronal transmission in complex tissue preparations.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2021)