The pikromycin (Pik)/methymycin biosynthetic pathway of Streptomyces venezuelae represents a valuable system for dissecting the fundamental mechanisms of modular polyketide biosynthesis, aminodeoxysugar assembly, glycosyltransfer, and hydroxylation leading to the production of a series of macrolide antibiotics, including the natural ketolides narbomycin and pikromycin. In this study, we describe four x-ray crystal structures and allied functional studies for PikC, the remarkable P450 monooxygenase responsible for production of a number of related macrolide products from the Pik pathway. The results provide important new insights into the structural basis for the C10/C12 and C12/C14 hydroxylation patterns for the 12-(YC-17) and 14-membered ring (narbomycin) macrolides, respectively. This includes two different ligand-free structures in an asymmetric unit (resolution 2.1 A) and two co-crystal structures with bound endogenous substrates YC-17 (resolution 2.35 A)or narbomycin (resolution 1.7 A). A central feature of the enzyme-substrate interaction involves anchoring of the desosamine residue in two alternative binding pockets based on a series of distinct amino acid residues that form a salt bridge and a hydrogen-bonding network with the deoxysugar C3' dimethylamino group. Functional significance of the salt bridge was corroborated by site-directed mutagenesis that revealed a key role for Glu-94 in YC-17 binding and Glu-85 for narbomycin binding. Taken together, the x-ray structure analysis, site-directed mutagenesis, and corresponding product distribution studies reveal that PikC substrate tolerance and product diversity result from a combination of alternative anchoring modes rather than an induced fit mechanism.
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http://dx.doi.org/10.1074/jbc.M605478200 | DOI Listing |
Int J Biol Macromol
January 2025
College of Pharmacy, Shaanxi University of Chinese Medicine, Shiji Ave., Xi'an-xianyang New Economic Zone, Shaanxi Province 712046, People's Republic of China. Electronic address:
Ophiopogonis japonicus is a famous medicinal plant in China with a long history of medicinal and food origin. It contains various chemical components, such as polysaccharides, steroidal saponins, alkaloids, flavonoids, etc. According to traditional Chinese medicine (TCM) theory, it has the efficacy of moistening the lungs and nourishing the yin, benefiting the stomach by generating fluids, and clearing the heart to get rid of vexation.
View Article and Find Full Text PDFPediatr Neurol
January 2025
Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; Pediatrics Research Group, Institut de Recerca Sant Pau (IR-Sant Pau), Barcelona, Spain; Pediatric Neurology Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Background: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy associated with loss-of-function variants in the SCN1A gene. Although predominantly expressed in the central nervous system, SCN1A is also expressed in the heart, suggesting a potential link between neuronal and cardiac channelopathies. Additionally, DS carries a high risk of sudden unexpected death in epilepsy (SUDEP).
View Article and Find Full Text PDFInt J Med Inform
January 2025
ISCTE-Instituto Universitário de Lisboa, Lisbon, Portugal; Universidade da Beira Interior Faculdade de Ciências da Saúde, Covilha, Portugal.
Introduction: In the WHO European Region, 44 of 53 reporting Member States (MS) have a national digital health strategy (NDHS) or policy. Their formulation is heterogenous and evolving and should best reflect public common interest. This research aims to explore how a public value approach improves the relevance of digital health policies and services, increasing their capacity to better serve the diverse range of societal interests.
View Article and Find Full Text PDFMol Divers
January 2025
Key Laboratory for Macromolecular Science of Shaanxi Province, School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi'an, 710119, People's Republic of China.
Molecular Property Prediction (MPP) is a fundamental task in important research fields such as chemistry, materials, biology, and medicine, where traditional computational chemistry methods based on quantum mechanics often consume substantial time and computing power. In recent years, machine learning has been increasingly used in computational chemistry, in which graph neural networks have shown good performance in molecular property prediction tasks, but they have some limitations in terms of generalizability, interpretability, and certainty. In order to address the above challenges, a Multiscale Molecular Structural Neural Network (MMSNet) is proposed in this paper, which obtains rich multiscale molecular representations through the information fusion between bonded and non-bonded "message passing" structures at the atomic scale and spatial feature information "encoder-decoder" structures at the molecular scale; a multi-level attention mechanism is introduced on the basis of theoretical analysis of molecular mechanics in order to enhance the model's interpretability; the prediction results of MMSNet are used as label values and clustered in the molecular library by the K-NN (K-Nearest Neighbors) algorithm to reverse match the spatial structure of the molecules, and the certainty of the model is quantified by comparing virtual screening results across different K-values.
View Article and Find Full Text PDFClin Oral Investig
January 2025
State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
Objectives: To develop a platform including a deep convolutional neural network (DCNN) for automatic segmentation of the maxillary sinus (MS) and adjacent structures, and automatic algorithms for measuring 3-dimensional (3D) clinical parameters.
Materials And Methods: 175 CBCTs containing 242 MS were used as the training, validating and testing datasets at the ratio of 7:1:2. The datasets contained healthy MS and MS with mild (2-4 mm), moderate (4-10 mm) and severe (10- mm) mucosal thickening.
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