Identification of Cysteine Metabolism Regulator (CymR)-Derived Pentapeptides as Nanomolar Inhibitors of -Acetyl-l-serine Sulfhydrylase (CysK).

The pathway of bacterial cysteine biosynthesis is gaining traction for the development of antibiotic adjuvants. Bacterial cysteine biosynthesis is generally facilitated by two enzymes possessing -acetyl-l-serine sulfhydrylases (OASS), CysK and CysM. In , there exists a single OASS homologue, CysK.

Identification of cysteine metabolism regulator (CymR)-derived pentapeptides as nanomolar inhibitors of O-acetyl-ʟ-serine sulfhydrylase (CysK).

Unlabelled: The conditionally essential pathway of bacterial cysteine biosynthesis is gaining traction for the development of antibiotic adjuvants. Bacterial cysteine biosynthesis is generally facilitated by two enzymes possessing O-acetyl-ʟ-serine sulfhydrylase (OASS) activity, CysK and CysM. CysK enzymes can also form functional complexes with other proteins that regulate cysteine metabolism.

Towards a High-Affinity Peptidomimetic Targeting Proliferating Cell Nuclear Antigen from .

Invasive fungal infections (IFIs) are prevalent in immunocompromised patients. Due to alarming levels of increasing resistance in clinical settings, new drugs targeting the major fungal pathogen are required. Attractive drug targets are those involved in essential processes like DNA replication, such as proliferating cell nuclear antigens (PCNAs).

Structure-guided design and synthesis of ATP-competitive N-acyl-substituted sulfamide d-alanine-d-alanine ligase inhibitors.

d-Alanine-d-alanine ligase (Ddl) catalyses the ATP-dependent formation of d-Ala-d-Ala, a critical component in bacterial cell wall biosynthesis and is a validated target for new antimicrobial agents. Here, we describe the structure-guided design, synthesis, and evaluation of ATP-competitive N-acyl-substituted sulfamides 27-36, 42, 46, 47 as inhibitors of Staphylococcus aureus Ddl (SaDdl). A crystal structure of SaDdl complexed with ATP and d-Ala-d-Ala (PDB: 7U9K) identified ATP-mimetic 8 as an initial scaffold for further inhibitor design.

warpDOCK: Large-Scale Virtual Drug Discovery Using Cloud Infrastructure.

warpDOCK is an open-source pipeline for virtual small-molecule drug discovery using cloud infrastructure. warpDOCK is designed from the ground up for the Oracle Cloud Infrastructure (OCI), enabling harmonious parallelism of docking calculations over thousands to hundreds of thousands of cores. This enables cost-effective sampling of ultra-large chemical libraries, potentially reducing the time to identify lead drug candidates by orders of magnitude.

Comparative functional and structural analysis of Pseudomonas aeruginosa d-alanine-d-alanine ligase isoforms as prospective antibiotic targets.

Pseudomonas aeruginosa is a major human pathogen in the healthcare setting. The emergence of multi-drug-resistant and extensive drug-resistant P. aeruginosa is of great concern, and clearly indicates that new alternatives to current first-line antibiotics are required in the future.

Designing Fluorescent Nuclear Permeable Peptidomimetics to Target Proliferating Cell Nuclear Antigen.

Human proliferating cell nuclear antigen (PCNA) is a critical mediator of DNA replication and repair, acting as a docking platform for replication proteins. Disrupting these interactions with a peptidomimetic agent presents as a promising avenue to limit proliferation of cancerous cells. Here, a p21-derived peptide was employed as a starting scaffold to design a modular peptidomimetic that interacts with PCNA and is cellular and nuclear permeable.

Biochemical and structural characterization of meningococcal methylenetetrahydrofolate reductase.

Methylenetetrahydrofolate reductase (MTHFR) is a key metabolic enzyme in colonization and virulence of Neisseria meningitidis, a causative agent of meningococcal diseases. Here, the biochemical and structural properties of MTHFR from a virulent strain of N. meningitidis serogroup B (NmMTHFR) were characterized.

PPARγ Corepression Involves Alternate Ligand Conformation and Inflation of H12 Ensembles.

Inverse agonists of peroxisome proliferator activated receptor γ (PPARγ) have emerged as safer alternatives to full agonists for their reduced side effects while still maintaining impressive insulin-sensitizing properties. To shed light on their molecular mechanism, we characterized the interaction of the PPARγ ligand binding domain with SR10221. X-ray crystallography revealed a novel binding mode of SR10221 in the presence of a transcriptionally repressing corepressor peptide, resulting in much greater destabilization of the activation helix, H12, than without corepressor peptide.

YgiC and YjfC Possess Peptide─Spermidine Ligase Activity.

Polyamines and polyamine-containing metabolites are involved in many cellular processes related to bacterial cell growth and survival. In , the bifunctional enzyme glutathionylspermidine synthetase/amidase (GspSA) controls the production of glutathionylspermidine, which has a protective role against oxidative stress. also encodes two enzymes with homology to the synthetase domain of GspSA, YgiC, and YjfC; however, these do not catalyze the formation of glutathionylspermidine, and their catalytic function remained unknown.

Discovery of an ʟ-amino acid ligase implicated in Staphylococcal sulfur amino acid metabolism.

Enzymes involved in Staphylococcus aureus amino acid metabolism have recently gained traction as promising targets for the development of new antibiotics, however, not all aspects of this process are understood. The ATP-grasp superfamily includes enzymes that predominantly catalyze the ATP-dependent ligation of various carboxylate and amine substrates. One subset, ʟ-amino acid ligases (LALs), primarily catalyze the formation of dipeptide products in Gram-positive bacteria, however, their involvement in S.

Inhibition of Dethiobiotin Synthase (DTBS): Toward Next-Generation Antituberculosis Agents.

dethiobiotin synthase (DTBS) is a crucial enzyme involved in the biosynthesis of biotin in the causative agent of tuberculosis, . Here, we report a binder of DTBS, cyclopentylacetic acid ( = 3.4 ± 0.

Immunogenicity study of engineered ferritins with C- and N-terminus insertion of Epstein-Barr nuclear antigen 1 epitope.

Human ferritin heavy chain, an example of a protein nanoparticle, has recently been used as a vaccine delivery platform. Human ferritin has advantages of uniform architecture, robust thermal and chemical stabilities, and good biocompatibility and biodegradation. There is however a lack of understanding about the relationship between insertion sites in ferritin (N-terminus and C-terminus) and the corresponding humoral and cell-mediated immune responses.

An antimony-phosphomolybdate microassay of ATPase activity through the detection of inorganic phosphate.

Colorimetric methods are convenient for the determination of inorganic phosphate. However, the acidic conditions required can complicate measurement of ATPase through non-enzymatic ATP hydrolysis. Here we present an optimized antimony-phosphomolybdate microassay for the simple and rapid detection of ATPase activity, with micromolar sensitivity.

d-Alanine-d-alanine ligase as a model for the activation of ATP-grasp enzymes by monovalent cations.

The ATP-grasp superfamily of enzymes shares an atypical nucleotide-binding site known as the ATP-grasp fold. These enzymes are involved in many biological pathways in all domains of life. One ATP-grasp enzyme, d-alanine-d-alanine ligase (Ddl), catalyzes ATP-dependent formation of the d-alanyl-d-alanine dipeptide essential for bacterial cell wall biosynthesis and is therefore an important antibiotic drug target.