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
Chemistry, Medicinal
Carlo Baggio, Anna Kulinich, Cassandra N. Dennys, Rochelle Rodrigo, Kathrin Meyer, Iryna Ethell, Maurizio Pellecchia
Summary: The study utilized an innovative NMR-guided screening and ligand design approach to derive low-molecular-weight ligands capable of mimicking interactions elicited by ephrin ligands. These agents demonstrated nanomolar affinity, activated receptors in cellular assays with motor neurons, and provided significant motor neuron protection from ALS patient-derived astrocytes. Structural studies on the complex between the ligand-binding domain and the most active agent offered insights into the agents' mechanism at a molecular level, forming a strong foundation for potential treatment of ALS and other human diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
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
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
Chemistry, Medicinal
Michael S. Malamas, Spiro Pavlopoulos, Shakiru O. Alapafuja, Shrouq Farah, Alexander Zvonok, Khadijah A. Mohammad, Jay West, Nicholas Thomas Perry, Dimitrios N. Pelekoudas, Girija Rajarshi, Christina Shields, Honrao Chandrashekhar, Jodi Wood, Alexandros Makriyannis
Summary: N-Acylethanolamines, particularly the palmitoylethanolamide hydrolyzed by NAAA, have been studied for their role in inflammation, pain, and drug addiction. Through synthesis and structure-activity relationship studies, potent inhibitors for hNAAA have been developed with high selectivity against other enzymes. These inhibitors have been identified as pharmacological tools for investigating the role of NAAA in various physiological processes.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
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
Chemistry, Medicinal
Csaba Weber, Melinda Sipos, Attila Paczal, Balazs Balint, Vilibald Kun, Nicolas Foloppe, Pawel Dokurno, Andrew J. Massey, David Lee Walmsley, Roderick E. Hubbard, James Murray, Karen Benwell, Thomas Edmonds, Didier Demarles, Alain Bruno, Mike Burbridge, Francisco Cruzalegui, Andras Kotschy
Summary: The kinase DYRK1A has been identified as a promising target for drug discovery, and a biaryl compound was developed through fragment screening to efficiently bind to its ATP site. Structural optimization cycles resulted in the transformation of this compound into potent and selective DYRK1A inhibitors, with a focus on fine-tuning selectivity by exploiting structural differences with DYRK2. These inhibitors demonstrated potent inhibition of DYRK1A in cell culture and in vivo, with drug-like properties and dose-dependent tumor growth inhibition in an ovarian carcinoma model.
JOURNAL OF MEDICINAL CHEMISTRY
(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
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.
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
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
Chemistry, Medicinal
Mladen Koravovic, Anand Mayasundari, Gordana Tasic, Fatemeh Keramatnia, Timothy R. Stachowski, Huarui Cui, Sergio C. Chai, Barbara Jonchere, Lei Yang, Yong Li, Xiang Fu, Ryan Hiltenbrand, Leena Paul, Vibhor Mishra, Jeffery M. Klco, Martine F. Roussel, William CK. Pomerantz, Marcus Fischer, Zoran Rankovic, Vladimir Savic
Summary: An X-ray structure of a CLICK chemistry-based BET PROTAC bound to BRD2(BD2) inspired the synthesis of JQ1 derived heterocyclic amides. These compounds displayed improved profiles compared to JQ1 and birabresib as potent BET inhibitors. A specific compound 1q (SJ1461) showed excellent affinity to both BRD4 and BRD2 and high potency in acute leukaemia and medulloblastoma cell lines. The co-crystal structure of 1q with BRD4-BD1 revealed polar interactions, explaining the observed affinity improvements. Furthermore, pharmacokinetic studies suggested that the heterocyclic amide moiety improved drug-like features. Our study led to the discovery of the potent and orally bioavailable BET inhibitor 1q (SJ1461) as a promising candidate for further development.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
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
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)
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
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)
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
Multidisciplinary Sciences
Thomas G. Laughlin, Amar Deep, Amy M. Prichard, Christian Seitz, Yajie Gu, Eray Enustun, Sergey Suslov, Kanika Khanna, Erica A. Birkholz, Emily Armbruster, J. Andrew McCammon, Rommie E. Amaro, Joe Pogliano, Kevin D. Corbett, Elizabeth Villa
Summary: This study identifies a protein called ChmA as the main component of the bacteriophage nuclear shell. The structure and dynamics of the ChmA shell provide insights into its formation and functions.
Article
Biochemistry & Molecular Biology
Surl-Hee Ahn, Gary A. Huber, J. Andrew McCammon
Summary: Intrinsically disordered proteins (IDPs) have attracted significant attention due to their involvement in biological processes and diseases. Computational studies using Brownian dynamics (BD) simulations with a coarse-grained force field for proteins (COFFDROP) have been conducted to complement experimental work. The researchers found that IDPs' properties, such as hydrodynamic radii and entanglement indices, are influenced by salt concentration.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Joshua C. Corpuz, Ashay Patel, Tony D. Davis, Larissa M. Podust, J. Andrew McCammon, Michael D. Burkart
Summary: This study reveals the binding specificities between peptidyl carrier proteins (PCPs) and adenylation (A) domains in non-ribosomal peptide synthetases (NRPSs) using chemical biology approaches. The research also demonstrates the possibility of controlling PCP binding specificity through modifying interfacial interactions.
ACS CHEMICAL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Yohei Takahashi, Krystal C. Bosmans, Po -Kai Hsu, Karnelia Paul, Christian Seitz, Chung-Yueh Yeh, Yuh-Shuh Wang, Dmitry Yarmolinsky, Maija Sierla, Triin Vahisalu, J. Andrew McCammon, Jaakko Kangasjaervi, Li Zhang, Hannes Kollist, Thien Trac, Julian I. Schroeder
Summary: The rise in atmospheric CO2 concentration affects stomatal closing in plants, impacting transpirational water loss, photosynthesis, and growth. This study identifies MPK4/12 and HT1 as the primary CO2 sensors in plants, located upstream of the CBC1 kinase. These findings are significant for understanding the plant response to CO2.
Article
Biochemistry & Molecular Biology
Jui-Hung Weng, Wen Ma, Jian Wu, Pallavi Kaila Sharma, Steve Silletti, J. Andrew McCammon, Susan Taylor
Summary: Mutations in LRRK2 increase the risk of Parkinson's disease, and its pathological functions are often associated with abnormal kinase activity. This study combines enhanced sampling simulations with HDX-MS to investigate the dynamic changes and allosteric communications within the C-terminal domains of LRRK2. It is found that different types of kinase inhibitors stabilize distinct kinase conformations and modulate the interdomain interactions between the kinase and GTPase domains.
ACS CHEMICAL BIOLOGY
(2023)
Review
Chemistry, Medicinal
Scott Hollingsworth, Scott Johnson, Pouyan Khakbaz, Yilin Meng, Varnavas Mouchlis, Olivia Pierce, Vera Prytkova, Erik Vik, Dahlia Weiss, Veerabahu Shanmugasundaram
Summary: Traditional targets and modalities are no longer the main focus of future drug discovery. There is a shift towards novel modalities such as protein degradation. The review article highlights the emerging targeting chimeras (TACs) and their potential for medicine design and scientific research.
MEDICINAL CHEMISTRY RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Terra Sztain, Joshua C. Corpuz, Thomas G. Bartholow, Javier O. Sanlley Hernandez, Ziran Jiang, Desirae A. Mellor, Graham W. Heberlig, James J. La Clair, J. Andrew Mccammon, Michael D. Burkart
Summary: Carrier-protein-dependent metabolic pathways rely on protein-protein interactions to control enzyme reactivity and timing. Computational methods, such as the improved Rosetta score function, can be used to design customized pathways by optimizing protein-protein interactions. This method provides a promising platform for engineering carrier-protein-dependent pathways.
ACS CHEMICAL BIOLOGY
(2023)
Article
Physics, Applied
Marcus T. Hock, Abigail E. Teitgen, Kimberly J. McCabe, Sophia P. Hirakis, Gary A. Huber, Michael Regnier, Rommie E. Amaro, J. Andrew McCammon, Andrew D. McCulloch
Summary: dATP, a natural analog of ATP, has been shown to enhance cardiac function. In this study, computational modeling was used to investigate the mechanism by which dATP accelerates calcium re-uptake into the sarcoplasmic reticulum during cardiac relaxation. The results showed that dATP interacts with SERCA and increases calcium association rate constants, ultimately leading to accelerated calcium transient decay observed experimentally.
JOURNAL OF APPLIED PHYSICS
(2023)
Article
Chemistry, Physical
Christian Seitz, Ilker Deveci, J. Andrew McCammon
Summary: This study investigates how protein glycosylation and lateral crowding effects modulate the stability and dynamics of influenza neuraminidase. The results show that glycans stabilize the protein structure, while a crowded membrane environment encourages large-scale conformational changes.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2023)
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)
