Review
Pharmacology & Pharmacy
Daiki Hayashi, Edward A. Dennis
Summary: Glycerophospholipids are major components of cell membranes, with diverse molecular species. Phospholipase A2 (PLA2) is a superfamily of enzymes involved in lipid-mediated biological responses. Among them, GVIA iPLA2 is an enzyme with broad substrate specificity and is implicated in neurodegenerative diseases. The authors employed lipidomics and molecular dynamics techniques to elucidate its molecular basis and discussed therapeutic strategies for GVIA iPLA2-associated neurodegeneration (PLAN) diseases.
PHARMACOLOGY & THERAPEUTICS
(2023)
Article
Biochemistry & Molecular Biology
Shulin Hou, Junping Bai, Chunting Chen, Xiaozheng Zhang, Fangyuan Chang, Zhihua Cao, Tingting Xu, Jun Xie
Summary: sPLA2s are calcium-dependent enzymes involved in lipid metabolism and inflammation. Research shows that flexibly bound Ca2 is essential for the catalysis of hGIIE, contrasting with the stable binding of Ca2 in hGIIA.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Chutima Jansakun, Warangkana Chunglok, Sandro Altamura, Martina Muckenthaler, Simone Staffer, Sabine Tuma-Kellner, Uta Merle, Walee Chamulitrat
Summary: Polymorphisms of iPLA2 beta/PLA2G6 are associated with body weights and blood C-reactive protein. In this study, mice with myeloid-specific and hepatocyte-specific PLA2G6 deletion were generated and phenotyped after feeding with a specific diet. Myeloid-specific deletion led to aggravation of liver inflammation and fibrosis, while hepatocyte-specific deletion provided complete protection and attenuated expression of fatty-acid uptake and lipogenesis genes. These findings suggest that PLA2G6 inactivation in specific cells plays a role in the development of non-alcoholic steatohepatitis.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2023)
Article
Biochemistry & Molecular Biology
Masaya Koganesawa, Munehiro Yamaguchi, Sachin K. Samuchiwal, Barbara Balestrieri
Summary: Macrophages activated by IL-4 (M2) or LPS+IFN gamma (M1) have distinct lipid metabolism profiles, with Pla2g5 playing a key role in this process. Pla2g5 is involved in phospholipid metabolism and eicosanoid production in both types of activated macrophages.
Article
Biochemistry & Molecular Biology
Mona Alonazi, Aida Karray, Raida Jallouli, Abir Ben Bacha
Summary: This study reported the biochemical and enzymatic characteristics of PLA(2)-V from dromedary, as well as its antimicrobial and cytotoxic effects.
Article
Biochemistry & Molecular Biology
Yue Zhang, Jiankun Song, Yuanzhang Zhou, Huijun Jia, Tianyu Zhou, Yingbo Sun, Qiong Gao, Yue Zhao, Yujie Pan, Zhaolin Sun, Peng Chu
Summary: Ubiquitin-specific protease 22 (USP22) plays a prominent role in tumor development and immune reprogramming, and has been proposed as a potential therapeutic target for cancer. Rottlerin and Morusin were discovered as selective and potent USP22 inhibitors, which can increase histone ubiquitination levels and reduce the expression of Sirt1 and PD-L1 proteins. These findings suggest that Rottlerin and Morusin may have potential as drugs for anticancer therapy.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Petar P. S. Calic, Natalie B. Vinh, Chaille T. Webb, Tess R. Malcolm, Anna Ngo, Kym Lowes, Nyssa Drinkwater, Sheena McGowan, Peter J. Scammells
Summary: Malaria is still a global health threat, and resistance to artemisinin-based therapies requires the development of new drugs. The metalloaminopeptidases M1 and M17 of Plasmodium spp have been identified as potential drug targets, and inhibiting these enzymes shows antiplasmodial activity. This study aimed to improve the inhibitory properties of hydroxamic acid 2 by introducing polar moieties and revealed the importance of the S1' domain in the design of future inhibitors for PfA-M1 and PfA-M17.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Luyiyun Liang, Rina Takamiya, Yoshimi Miki, Kanako Heike, Yoshitaka Taketomi, Nao Sugimoto, Midori Yamaguchi, Hiroshi Shitara, Yasumasa Nishito, Tetsuyuki Kobayashi, Tetsuya Hirabayashi, Makoto Murakami
Summary: The study reveals that cPLA2epsilon plays a counterregulatory role in psoriatic inflammation by promoting the biosynthesis of anti-inflammatory lipid N-acylethanolamine (NAE). The findings provide important insights into the regulation of inflammation in psoriasis.
Article
Oncology
Upasana Ray, Debarshi Roy, Ling Jin, Prabhu Thirusangu, Julie Staub, Yinan Xiao, Eleftheria Kalogera, Andrea E. Wahner Hendrickson, Grace D. Cullen, Krista Goergen, Ann L. Oberg, Viji Shridhar
Summary: The study demonstrates that downregulation of PLA2G3 inhibits lipid droplet biogenesis, reduces cell growth, and increases sensitivity to platinum drugs in ovarian cancer cells.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2021)
Review
Biochemistry & Molecular Biology
Yoshitaka Taketomi, Yoshimi Miki, Makoto Murakami
Summary: The sPLA(2) family is a group of enzymes with unique tissue or cellular distributions and functions that exert their effects through hydrolysis of extracellular phospholipids. Recent studies have found that sPLA(2)-IIA can act as a modulator of the gut microbiota, affecting intestinal inflammation, allergy, and cancer. These studies reveal a connection between the gut microbiota and systemic homeostasis and diseases.
Article
Chemistry, Applied
Nantawat Tatiyaborworntham, Jie Yin, Mark P. Richards
Summary: The study found that the ability of PLA2 to inhibit lipid oxidation and suppress the oxidation of Hb to form methemoglobin and ferryl hemoglobin is pH-dependent and requires calcium ions for its hydrolyzing activity and antioxidant effect. Additionally, PLA2 was able to inhibit lipid oxidation without interfering with the interaction between hemin and the insoluble matrix of the washed muscle.
Article
Chemistry, Medicinal
Jian Yao, Yudong Yin, Hong Han, Shaoting Chen, Yuxiang Zheng, Benji Liang, Mengyue Wu, Kangqi Shu, Bikash Debnath, David B. Lombard, Quande Wang, Keguang Cheng, Nouri Neamati, Yanghan Liu
Summary: In this study, a novel SIRT5-selective inhibitor was identified and optimized, resulting in compound 47 with 100-fold improved potency. Compound 47 showed substantial selectivity for SIRT5 and acted as a substrate-competitive inhibitor. These findings provide possibilities for further research and development of therapeutic tools and drugs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Pharmacology & Pharmacy
Charikleia S. Batsika, Anna-Dimitra D. Gerogiannopoulou, Christiana Mantzourani, Sofia Vasilakaki, George Kokotos
Summary: This article summarizes the development of synthetic inhibitors targeting the four major types of human PLA(2), discussing their activities, applications, and therapeutic properties. It also examines the role of PLA(2) in the pathobiology of COVID-19.
EXPERT OPINION ON DRUG DISCOVERY
(2021)
Article
Cell Biology
Maria Mangini, Rosa D'Angelo, Caterina Vinciguerra, Christine Payre, Gerard Lambeau, Barbara Balestrieri, Julia F. F. Charles, Stefania Mariggio
Summary: This study investigates the role of group IIA secreted phospholipase A(2) (sPLA(2)-IIA) in osteoclast bone-resorption activity and syncytium formation. The results suggest that sPLA(2)-IIA is involved in the regulation of osteoclast maturation and fusion through both catalytic-dependent and independent mechanisms.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Aladahalli S. Giresha, Deepadarshan Urs, Sophiya Pundalik, Rajkumar S. Meti, Siddanakoppalu N. Pramod, Ballenahalli H. Supreetha, Madhusudana Somegowda, Kattepura K. Dharmappa, Ahmed M. El-Shehawi, Sarah Albogami, Mona M. Elseehy, Abdullah Alaklabi, Hosam O. Elansary, Alanoud Omur A. Mehder, Eman A. Mahmoud
Summary: The study evaluated the antioxidant molecule sinapic acid for its ability to inhibit sPLA(2)-IIA as an anti-inflammatory agent. Sinapic acid showed strong antioxidant potency and significantly reduced sPLA(2)-IIA activity, hemolytic activity, and mouse paw edema, demonstrating its anti-inflammatory and anti-hemorrhagic effects.
Article
Biochemistry & Molecular Biology
Daiki Hayashi, Varnavas D. Mouchlis, Edward A. Dennis
Summary: Glycerophospholipids are major components of cell membranes with diverse fatty acyl chain compositions and polar head groups. Phospholipase A(2) enzymes play a critical role in metabolism by hydrolyzing glycerophospholipids, and different human PLA(2) enzymes show distinct preferences for sn-1 acyl chain linkages.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
(2022)
Article
Chemistry, Multidisciplinary
Nikoleta Spiliopoulou, Petros L. Gkizis, Ierasia Triandafillidi, Nikolaos F. Nikitas, Charikleia S. Batsika, Aikaterini Bisticha, Christoforos G. Kokotos
Summary: In this paper, we restudied the mechanism of action of phenylglyoxylic acid (PhCOCOOH) in photochemical reactions and proposed a unified mechanism. Additionally, we compared its action as a photoinitiator with known and commercially available photoinitiators.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Multidisciplinary Sciences
Varnavas D. Mouchlis, Daiki Hayashi, Alexis M. Vasquez, Jian Cao, J. Andrew McCammon, Edward A. Dennis
Summary: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) associates with lipoproteins in human plasma and hydrolyzes oxidized phospholipids. The mechanism of enzyme-membrane association and substrate specificity were studied using lipidomics and mass spectrometry techniques.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Editorial Material
Oncology
Bart Vanhaesebroeck, John E. Burke, Ralitsa R. Madsen
Summary: PIK3CA is a frequently activated kinase gene in solid tumors. This study shows that the PI3Kα inhibitors taselisib and inavolisib can induce degradation of mutant p110α protein in breast cancer cells that are positive for HER2 RTK, thereby limiting feedback-mediated drug resistance and potentially widening the therapeutic range of PI3Kα inhibition.
Article
Biochemistry & Molecular Biology
Maria A. Theodoropoulou, Anastasia Psarra, Martin Erhardt, Aikaterini Nikolaou, Anna-Dimitra D. Gerogiannopoulou, Dimitra Hadjipavlou-Litina, Daiki Hayashi, Edward A. Dennis, Andrea Huwiler, George Kokotos
Summary: The search for new drugs that can regulate the production of prostaglandin E-2 (PGE(2)) is crucial in the treatment of inflammatory diseases. In this study, we synthesized and evaluated a series of compounds, and identified N-acylated and N-alkylated 2-aminobenzothiazoles as potential leads. These compounds showed significant inhibition of PGE(2) generation in rat mesangial cells and demonstrated better anti-inflammatory activity than indomethacin. The findings suggest that N-acylated or N-alkylated 2-aminobenzothiazoles could be promising candidates for regulating PGE(2) formation.
Article
Chemistry, Multidisciplinary
Chiara Borsari, Erhan Keles, Jacob A. McPhail, Alexander Schaefer, Rohitha Sriramaratnam, Wojciech Goch, Thorsten Schaefer, Martina De Pascale, Wojciech Bal, Matthias Gstaiger, John E. Burke, Matthias P. Wymann
Summary: This study demonstrates a design strategy for covalent protein kinase inhibitors targeting PI3Kα by introducing reactive warheads. Compounds with high inhibitory activity and long-lasting efficacy have been identified.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Review
Cell Biology
Jacob A. McPhail, John E. Burke
Summary: Lipid phosphoinositides play important roles as signaling molecules and markers of organelle identity in eukaryotic cells. Viruses can manipulate the kinases and phosphatases involved in phosphoinositide generation for their replication. This review focuses on PI4KA and PI4KB, discussing their roles in signaling, membrane trafficking, and virus manipulation. The molecular mechanisms by which PI4KA and PI4KB are activated and usurped by viruses are also explored.
Review
Biotechnology & Applied Microbiology
John E. Burke, Joanna Triscott, Brooke M. Emerling, Gerald R. Hammond
Summary: This Review describes the structure, function, regulation, and disease roles of clinically relevant PIKs outside of class I PI3Ks, as well as the development of potent and specific small-molecule inhibitors. Phosphoinositide kinases are master regulators of cellular processes and their dysregulation has been implicated in various human diseases. Recent years have seen increased interest in targeting phosphoinositide kinases beyond class I PI3Ks, leading to the clinical development of selective inhibitors. This comprehensive analysis provides an overview of the current understanding and progress in the development of phosphoinositide kinase inhibitors.
NATURE REVIEWS DRUG DISCOVERY
(2023)
Article
Multidisciplinary Sciences
Ronja Reinhardt, Kai Hirzel, Gisela Link, Stephan A. Eisler, Tanja Hagele, Matthew A. H. Parson, John E. Burke, Angelika Hausser, Thomas A. Leonard
Summary: Phosphorylation is a common mechanism in cell signaling, and protein kinases are often regulated by phosphorylation. However, PKD regulates itself through dimerization-mediated trans-autoinhibition, followed by autophosphorylation, to control its activity.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Meredith L. Jenkins, Harish Ranga-Prasad, Matthew A. H. Parson, Noah J. Harris, Manoj K. Rathinaswamy, John E. Burke
Summary: The PIK3CA gene is frequently mutated in human cancer, and this study reveals the molecular mechanisms underlying the increased activity mediated by different oncogenic mutations in PIK3CA. Through a combination of biochemical assays and HDX-MS, the authors uncover unique regulatory mechanisms and explain how these mutations activate PI3K. This work has important implications for the development of mutant selective inhibitors.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Alexandria L. Shaw, Matthew A. H. Parson, Linda Truebestein, Meredith L. Jenkins, Thomas A. Leonard, John E. Burke
Summary: Akt is a key regulator of cell growth signaling and its hyperactivation is oncogenic. This study used hydrogen deuterium exchange mass spectrometry to investigate the conformational changes induced by Akt inhibitors. The findings provide valuable insights for designing targeted therapeutics against Akt.
Article
Cell Biology
Manoj K. Rathinaswamy, Meredith L. Jenkins, Benjamin R. Duewell, Xuxiao Zhang, Noah J. Harris, John T. Evans, Jordan T. B. Stariha, Udit Dalwadi, Kaelin D. Fleming, Harish Ranga-Prasad, Calvin K. Yip, Roger L. Williams, Scott D. Hansen, John E. Burke
Summary: This study investigates the activation mechanisms of phosphoinositide 3-kinase (PI3Ky) in immune cells. Using various experimental methods, the researchers identified molecular differences between the p110y-p84 and p110y-p101 complexes, which explain their differential membrane recruitment and activation by Ras and GPCRs. The findings provide key insights into the molecular basis of PI3Ky complex activation.
Article
Biochemistry & Molecular Biology
Matthew J. Conroy, Robert M. Andrews, Simon Andrews, Lauren Cockayne, Edward A. Dennis, Eoin Fahy, Caroline Gaud, William J. Griffiths, Geoff Jukes, Maksim Kolchin, Karla Mendivelso, Andrea F. Lopez-Clavijo, Caroline Ready, Shankar Subramaniam, Valerie B. O'Donnell
Summary: LIPID MAPS is a systematic and standardized approach for organizing lipid structural and biochemical data, and it has become the accepted community standard. It provides databases, software tools, and educational resources. The recent expansion of LIPID MAPS includes richer metadata, improved interoperability, and programmatic access. In addition, LIPID MAPS collaborates with WikiPathways to curate pathway data and annotate lipids.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Pathology
Christina M. Mckenzie, Matt Marinkovich, Anibal G. Armien, Judy St. Leger, Aaron M. Armando, Edward A. Dennis, Oswald Quehenberger, Alison Righton
Summary: This study presents the pedigree analysis, clinical manifestations, gross, microscopic, ultrastructural, and lipidomic findings of four female superb bird-of-paradise (SBOP) siblings, revealing a primary inherited glycerolipid storage disease. These birds, offspring of closely related parents, displayed characteristic lesions including tissue distortion due to the accumulation of lipid vacuoles in various organs. Lipidomic profiling confirmed the presence of triacylglycerols in the cytoplasmic lipid deposits. Further investigations, such as genome sequencing and genotyping, are necessary to determine the underlying genetic mechanism of this disease.
VETERINARY PATHOLOGY
(2023)
Review
Chemistry, Multidisciplinary
Varnavas D. Mouchlis, Edward A. Dennis
Summary: Water-soluble proteins and membrane-bound proteins bind specific lipid molecules on membrane surfaces. Phospholipases, especially PLA2, play an important role in hydrolyzing phospholipids. The interaction between PLA2 and membranes can induce conformational changes in PLA2 and activate it for catalysis. These studies provide insights into membrane-protein interactions and related biological functions.
ACCOUNTS OF CHEMICAL RESEARCH
(2022)
