Paradigms of convergent evolution in enzymes.

There are many occurrences of enzymes catalysing the same reaction but having significantly different structures. Leveraging the comprehensive information on enzymes stored in the Mechanism and Catalytic Site Atlas (M-CSA), we present a collection of 34 cases for which there is sufficient evidence of functional convergence without an evolutionary link. For each case, we compare enzymes which have identical Enzyme Commission numbers (i.

Large-scale annotation of biochemically relevant pockets and tunnels in cognate enzyme-ligand complexes.

Tunnels in enzymes with buried active sites are key structural features allowing the entry of substrates and the release of products, thus contributing to the catalytic efficiency. Targeting the bottlenecks of protein tunnels is also a powerful protein engineering strategy. However, the identification of functional tunnels in multiple protein structures is a non-trivial task that can only be addressed computationally.

Measuring the Interprofessional Health of the Pediatric Cardiovascular Operating Room Work Environment.

Introduction: Pediatric cardiac surgery is complex and has significant risk, requiring interprofessional teamwork for optimal outcomes. Unhealthy work environments have been linked to poor patient outcomes, staff dissatisfaction, and intention to leave. We describe the interprofessional health of pediatric cardiovascular operating room (CVOR) work environments in the United States and the establishment of a healthy work environment (HWE) benchmark score.

Multigenerational diabetes mellitus.

Gestational diabetes (GDM) changes the maternal metabolic and uterine environment, thus increasing the risk of short- and long-term adverse outcomes for both mother and child. Children of mothers who have GDM during their pregnancy are more likely to develop Type 2 Diabetes (T2D), early-onset cardiovascular disease and GDM when they themselves become pregnant, perpetuating a multigenerational increased risk of metabolic disease. The negative effect of GDM is exacerbated by maternal obesity, which induces a greater derangement of fetal adipogenesis and growth.

Enzyme function and evolution through the lens of bioinformatics.

Enzymes have been shaped by evolution over billions of years to catalyse the chemical reactions that support life on earth. Dispersed in the literature, or organised in online databases, knowledge about enzymes can be structured in distinct dimensions, either related to their quality as biological macromolecules, such as their sequence and structure, or related to their chemical functions, such as the catalytic site, kinetics, mechanism, and overall reaction. The evolution of enzymes can only be understood when each of these dimensions is considered.

EzMechanism: an automated tool to propose catalytic mechanisms of enzyme reactions.

Over the years, hundreds of enzyme reaction mechanisms have been studied using experimental and simulation methods. This rich literature on biological catalysis is now ripe for use as the foundation of new knowledge-based approaches to investigate enzyme mechanisms. Here, we present a tool able to automatically infer mechanistic paths for a given three-dimensional active site and enzyme reaction, based on a set of catalytic rules compiled from the Mechanism and Catalytic Site Atlas, a database of enzyme mechanisms.

The 3D Modules of Enzyme Catalysis: Deconstructing Active Sites into Distinct Functional Entities.

Enzyme catalysis is governed by a limited toolkit of residues and organic or inorganic co-factors. Therefore, it is expected that recurring residue arrangements will be found across the enzyme space, which perform a defined catalytic function, are structurally similar and occur in unrelated enzymes. Leveraging the integrated information in the Mechanism and Catalytic Site Atlas (M-CSA) (enzyme structure, sequence, catalytic residue annotations, catalysed reaction, detailed mechanism description), 3D templates were derived to represent compact groups of catalytic residues.

Lipoxin A promotes antibiotic and monocyte bacterial killing in established Pseudomonas aeruginosa biofilm formed under hydrodynamic conditions.

Pseudomonas aeruginosa is a gram-negative, opportunistic bacteria commonly found in wounds and in lungs of immunocompromised patients. These bacteria commonly form biofilms which encapsulate the bacteria, making it difficult for antibiotics or immune cells to reach the bacterial cells. We previously reported that Lipoxin A (LxA ), a Specialized Pro-resolving Mediator, has direct effects on P.

Computational analysis of drug resistance of taxanes bound to human β-tubulin mutant (D26E).

The single-point mutation D26E in human β-tubulin is associated with drug resistance seen with two anti-mitotic taxanes (paclitaxel and docetaxel) when used to treat cancers. The molecular mechanism of this resistance remains elusive. However, docetaxel and a third-generation taxane, cabazitaxel, are thought to overcome this resistance.

SelectBCM tool: a batch evaluation framework to select the most appropriate batch-correction methods for bulk transcriptome analysis.

Bulk transcriptomes are an essential data resource for understanding basic and disease biology. However, integrating information from different experiments remains challenging because of the batch effect generated by various technological and biological variations in the transcriptome. Numerous batch-correction methods to deal with this batch effect have been developed in the past.

Using mechanism similarity to understand enzyme evolution.

Unlabelled: Enzyme reactions take place in the active site through a series of catalytic steps, which are collectively termed the enzyme mechanism. The catalytic step is thereby the individual unit to consider for the purposes of building new enzyme mechanisms - i.e.

AlphaFold2 protein structure prediction: Implications for drug discovery.

The drug discovery process involves designing compounds to selectively interact with their targets. The majority of therapeutic targets for low molecular weight (small molecule) drugs are proteins. The outstanding accuracy with which recent artificial intelligence methods compile the three-dimensional structure of proteins has made protein targets more accessible to the drug design process.

Mapping the Constrained Coding Regions in the Human Genome to Their Corresponding Proteins.

Constrained Coding Regions (CCRs) in the human genome have been derived from DNA sequencing data of large cohorts of healthy control populations, available in the Genome Aggregation Database (gnomAD) [1]. They identify regions depleted of protein-changing variants and thus identify segments of the genome that have been constrained during human evolution. By mapping these DNA-defined regions from genomic coordinates onto the corresponding protein positions and combining this information with protein annotations, we have explored the distribution of CCRs and compared their co-occurrence with different protein functional features, previously annotated at the amino acid level in public databases.

Human populations in the world's mountains: Spatio-temporal patterns and potential controls.

Changing climate and human demographics in the world's mountains will have increasingly profound environmental and societal consequences across all elevations. Quantifying current human populations in and near mountains is crucial to ensure that any interventions in these complex social-ecological systems are appropriately resourced, and that valuable ecosystems are effectively protected. However, comprehensive and reproducible analyses on this subject are lacking.

Capturing the geometry, function, and evolution of enzymes with 3D templates.

Structural templates are 3D signatures representing protein functional sites, such as ligand binding cavities, metal coordination motifs, or catalytic sites. Here we explore methods to generate template libraries and algorithms to query structures for conserved 3D motifs. Applications of templates are discussed, as well as some exemplar cases for examining evolutionary links in enzymes.

GRaSP-web: a machine learning strategy to predict binding sites based on residue neighborhood graphs.

Proteins are essential macromolecules for the maintenance of living systems. Many of them perform their function by interacting with other molecules in regions called binding sites. The identification and characterization of these regions are of fundamental importance to determine protein function, being a fundamental step in processes such as drug design and discovery.

Conformational Variation in Enzyme Catalysis: A Structural Study on Catalytic Residues.

Conformational variation in catalytic residues can be captured as alternative snapshots in enzyme crystal structures. Addressing the question of whether active site flexibility is an intrinsic and essential property of enzymes for catalysis, we present a comprehensive study on the 3D variation of active sites of 925 enzyme families, using explicit catalytic residue annotations from the Mechanism and Catalytic Site Atlas and structural data from the Protein Data Bank. Through weighted pairwise superposition of the functional atoms of active sites, we captured structural variability at single-residue level and examined the geometrical changes as ligands bind or as mutations occur.

Resolvin D2 promotes host defense in a 2 - hit model of sepsis with secondary lung infection.

In the development of sepsis, there is early, massive inflammation which can lead to multiple organ failure. Later there is an immunosuppressed phase where the host is susceptible to secondary infections or is unable to clear existing infection. Specialized Pro-resolving Mediators (SPMs) are endogenously produced lipids which resolve infection by decreasing bacteria load and reducing systemic inflammatory response.

Role of Specialized Pro-Resolving Mediators in Modifying Host Defense and Decreasing Bacterial Virulence.

Bacterial infection activates the innate immune system as part of the host's defense against invading pathogens. Host response to bacterial pathogens includes leukocyte activation, inflammatory mediator release, phagocytosis, and killing of bacteria. An appropriate host response requires resolution.

PDBsum extras: SARS-CoV-2 and AlphaFold models.

The PDBsum web server provides structural analyses of the entries in the Protein Data Bank (PDB). Two recent additions are described here. The first is the detailed analysis of the SARS-CoV-2 virus protein structures in the PDB.