Diverse Class Research Articles

Iron-photocatalyzed Decarboxylative Oxygenation of Aliphatic Carboxylic Acids

Abstract Carboxylic acids, a bench-stable, readily available, and structurally diverse class of compounds, represent the ideal starting materials for organic synthesis. In this article, we highlight an iron-catalyzed decarboxylative C(sp3)−O bond-forming reaction that takes place under mild, photocatalytic, base-free conditions, using 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) derivatives as oxygenation reagents. The reaction is enabled by the ability of iron complexes to generate carbon-centered radicals directly from carboxylic acids through a sequence involving the photoinduced carboxylate-to-iron charge transfer, homolysis, and loss of carbon dioxide. The developed transformation displays exquisite substrate tolerance and was applied to various bio-active molecules. We performed an extensive mechanistic investigation via kinetic studies, electrochemistry, EPR, UV/Vis, HRMS, and DFT analysis. Those studies suggest that TEMPO plays three different roles in the reaction: it acts as an oxygenation reagent, serves as an oxidant to regenerate the Fe catalyst, and functions as an internal base for carboxylic acid deprotonation. The resulting TEMPO adducts are versatile synthons, which can be subsequently utilized in C−C and C−heteroatom bond-forming reactions employing commercially available organo-photocatalysts and nucleophilic reagents.

‘Caution will get us nowhere’: manifesto writing as collective practice with a diverse film-making class

This article puts forth a number of ideas on co-creation with film-making students, which can both enhance their own practice and critically situate it within the wider film, television and creative industries. In the case study presented here, students on a second-year module called Independent Filmmaking Practices at the University of Greenwich in 2021 wrote a collective manifesto, titled the ‘Dismantle-festo’. The case study presented here is partly for educators seeking in-class exercises which depart from mainstream thinking about the film and television industries. However, in presenting and analysing both the exercises which led to the manifesto, and the manifesto itself, this article is also partly a record of the concerns and hopes of this cohort, condensed within the radical format of the manifesto.

Lactonase activity of α-carbonic anhydrases allows identification of novel inhibitors.

Lactones, a diverse and abundant class of molecules found in nature, exhibit a wide range of bioactivities, including anti-inflammatory, anticancer, and antibacterial effects. Among them, acyl homoserine lactones (AHSLs) play a crucial role in quorum sensing, influencing bacterial pathogenicity and biofilm formation in Gram-negative bacteria. Paraoxonases (PONs), calcium-containing enzymes known for their lactonase activity, have been shown to hydrolyze AHSLs and reduce the biofilm formation of several pathogenic bacteria. In this study, we explored the potential lactonase activity of a class of zinc(II) enzymes, the carbonic anhydrases (CAs), aiming to uncover new insights into their catalytic versatility. Using LC-MS and MS/MS analyses, we investigated the lactonase activity of CAs and assessed several lactones through a stopped-flow kinetic assay as substrates/inhibitors. Our findings reveal that lactones are novel "prodrug" inhibitors of CAs, with lactones DHC and 6 showing the most promising inhibition constants (KIs) in the low micromolar range against both human and bacterial isozymes.

Asteroid Saponins: A Review of Their Bioactivity and Selective Cytotoxicity

Saponins are a diverse class of secondary metabolites that are often reported to exhibit a variety of pharmacological applications. While research into the elucidation and application of plant and class Holothuroidea-derived saponins (i.e., sea cucumbers) is extensive, the class Asteroidea-derived saponins (i.e., seastars) have been largely overlooked and primarily limited to elucidation. This review provides a comprehensive overview of the cytotoxic activities of asteroid-derived saponins against various cell cultures, for instance, mammalian erythrocytes, multiple microbial strains and cancer cell lines, including melanoma, breast, colon, and lung cancers. Highlighting the distinct structural variations in these saponins, this review examines their selective cytotoxicity and potency, with many demonstrating IC50 values in the low micromolar range. Specific compounds, such as asterosaponins and polyhydroxylated saponins, exhibit noteworthy effects, particularly against melanoma and lung carcinoma cells, while triterpenoid saponins were found to be highly cytotoxic to both erythrocytes and fungal cells. This review also addresses gaps in the research area, including the need for additional in vitro antimicrobial studies, in vivo studies, and further exploration of their mechanisms of action. By consolidating recent findings, we have shed light on the therapeutic potential of asteroid-derived steroidal saponins in developing novel antimicrobial and anticancer agents.

Computational and Experimental Insights into Pharmacological Potential: Synthesis, In Vitro Evaluation, and Molecular Docking Analysis of Bioactive Urea and Thiourea Derivatives.

This study delves into the synthesis, in vitro assessment, and molecular docking analysis of bioactive urea and thiourea derivatives, which have gained attention in pharma chemistry due to their versatile chemical reactivity and potential therapeutic applications. One pot synthetic methodology was employed to create a diverse class of compounds. Subsequent in vitro assessments, including antimicrobial assays, unveiled the pharmacological potential of these derivatives, offering insights into their ability to inhibit pathogenic microorganisms. Molecular docking analysis provided computational insights into the interactions between these compounds and specific biomolecules, shedding light on their potential mechanisms of action. In sum, this comprehensive exploration contributes to the discovery of innovative therapeutic agents, as this bioactive urea and thiourea derivatives hold promise for addressing pressing healthcare challenges.

Recent Advances in the Hydroxylation of Boronic Acids

Hydroxylated compounds represent a significant and diverse class of substances in the field of chemistry. These compounds play critical roles in various chemical reactions and are essential components in numerous industrial applications. Recent years have witnessed remarkable advancements in the synthesis of hydroxylated compounds, especially those derived from boronic acids. The synthesis of hydroxylated compounds from boronic acids typically involves the utilization of various types of catalysts, which are essential for enhancing reaction rates and selectivity, including metal catalysts such as CuFe₂O₄, Cu@C₃N₄, AgNPs, and Ti0.97Ni0.3O1.97, as well as non‐metal catalysts like polycaprolactone (PCL), TFB‐BMTH COF materials, C70, and graphene oxide (GO). These catalytic reactions often require the addition of oxidants such as hydrogen peroxide (H₂O₂) or molecular oxygen, which serve as critical reagents in the hydroxylation process. In certain cases, organic bases act as electron donors to propel the reaction. Furthermore, some studies have reported oxidative hydroxylation reactions that are catalyst‐free.This review aims to summarize the recent advancements and breakthroughs in the synthesis of hydroxylated compounds from boronic acids, with a particular focus on research conducted from 2014 to 2024.

Navigating English for Specific Purposes (ESP) in Morocco: Challenges, Opportunities, and Technological Integration

This study examines the perceptions and experiences of law and humanities students at the multidisciplinary faculty of Taza, Sidi Mohamed Ben Abdellah University, regarding English for Specific Purposes (ESP) education in Morocco. Using a mixed-methods approach, quantitative data from a survey of 130 students is complemented by qualitative insights from interviews and classroom observations. Findings reveal that 79% of respondents stress the need for ESP curricula tailored to their academic disciplines, with over 70% advocating for increased class frequency and interactive instructional methods. Challenges include technological limitations, such as compatibility issues with the Rosetta Stone application, and significant disparities in student proficiency levels, which complicate instruction in large, diverse classes. A gap in lesson adequacy is also noted between law and humanities students, underscoring the need for discipline-specific approaches. Recommendations include enhancing collaboration between language instructors and subject-matter experts, addressing logistical barriers, and improving technology integration. These measures aim to strengthen ESP programs in Morocco, equipping students with the skills needed for academic and professional success.

Developmental Toxicity of Alkylated PAHs and Substituted Phenanthrenes: Structural Nuances Drive Diverse Toxicity and AHR activation

Polycyclic aromatic hydrocarbons (PAHs) are a diverse class of chemicals that occur in complex mixtures including parent and substituted PAHs. To understand the hazard posed by complex environmental PAH mixtures, we must first understand the structural drivers of activity and mode of action of individual PAHs. Understanding the toxicity of alkylated PAHs is important as they often occur in higher abundance in environmental matrices and can be more biologically active than their parent compounds. 104 alkylated PAHs were screened from 11 different parent compounds with emphasis on substituted phenanthrenes and their structurally dependent toxicity differences. Using a high-throughput early life stage zebrafish assay, embryos were exposed to concentrations between 0.1 to 100 μM and assessed for morphological and behavioral outcomes. The aryl hydrocarbon receptor (AHR) is often implicated in the toxicity of PAHs and the induction of cytochrome P4501A (cyp1a) is an excellent biomarker of Ahr activation. Embryos were evaluated for cyp1a induction using a fluorescence reporter line. Alkyl and polar phenanthrene derivatives were further assessed for spatial cyp1a expression and Ahr dependence of morphological effects. In the alkyl PAH screen 35 (33.7%) elicited a morphological or behavioral response and of those 23 (65%) also induced cyp1a. 31 (29.8%) of the chemicals only induced cyp1a. Toxicity varied substantially in response to substitution location, the amount of ring substitutions and alkyl chain length. Cyp1a induction varied by parent compound group and was a poor indicator of morphological or behavioral outcomes. Polar phenanthrenes were more biologically active than alkylated phenanthrene derivatives and their toxicity was not dependent upon the Ahr2, Ahr1a or Ahr1b when tested individually, despite cyp1a induction by 50% of polar phenanthrenes. Our results demonstrated that induction of cyp1a did not always correlate with PAH toxicity or Ahr dependence and that the type and location of phenanthrene substitution determined potency.

Physicochemistry and comparative metagenomics of a tropical estuary persistently inundated with anthropogenic pollutants.

The physicochemistry, metabolic properties, and microbial community structure of a tropical estuary persistently inundated with anthropogenic pollutants were elucidated using diverse analytical tools and a shotgun metagenomics approach. The physicochemistry of the Awoye estuary surface water (AEW) and sediment (AES) revealed higher values in the sediment for most of the parameters analyzed, while aside from copper and zinc, the concentrations of the detected heavy metals (Cd, Cr, Pb, Fe, As, Ni, Hg, Mn, Se) in the water and sediment were higher than the acceptable thresholds. Hydrocarbon content analysis revealed increasingly high concentrations of high molecular weight polycyclic aromatic hydrocarbons (HMW PAHs) in the sediment. Structurally, the predominant taxa in the AEW metagenome are Proteobacteria (50.35%), Alphaproteobacteria (43.31%), Brevundimonas (49.96%), and Leptolyngbya boryana (14.93%), while in the sediment (AES) metagenome, Proteobacteria (53.03%), Gammaproteobacteria (28.66%), Azospirillum (6.51%), and Acidihalobacter prosperus (7.56%) were preponderant. Statistical analysis of the two microbiomes (AEW, AES) revealed significant statistical differences (P < 0.05) at all the hierarchical levels. Functional characterization of the two metagenomes revealed extensive adaptations of the sediment microbiome to various environmental stressors as evident in the high numbers of putative genes involved in the degradation of diverse classes of aromatic hydrocarbons, efflux, detoxification, and transport of heavy metals, and metabolism of organic/inorganic nutrients. Findings from this study revealed that the estuary sediment is the sink for most of the anthropogenic pollutants and harbors the more adapted microbiome that could serve as a potential bioresource for the bioremediation of the perturbed estuary.

Mechanism of action of the toxic proline mimic azetidine 2-carboxylic acid in plants.

Plants have an amazing capacity to outcompete neighboring organisms for space and resources. Toxic metabolites are major players in these interactions, which can have a broad range of effectiveness by targeting conserved molecular mechanisms, such as protein biosynthesis. However, lack of knowledge about defensive metabolite pathways, their mechanisms of action, and resistance mechanisms limits our ability to manipulate these pathways for enhanced crop resilience. Nonproteogenic amino acids (NPAAs) are a structurally diverse class of metabolites with a variety of functions but are typically not incorporated during protein biosynthesis. Here, we investigate the mechanism of action of the NPAA azetidine-2-carboxylic acid (Aze), an analog of the amino acid proline (Pro). Using a combination of plate-based assays, metabolite feeding, metabolomics, and proteomics, we show that Aze inhibits the root growth of Arabidopsis and other plants. Aze-induced growth reduction was restored by supplementing L-, but not D-Pro, and nontargeted proteomics confirm that Aze is misincorporated for Pro during protein biosynthesis, specifically on cytosolically translated proteins. Gene expression analysis, free amino acid profiling, and proteomics show that the unfolded protein response is upregulated during Aze treatment implicating that Aze misincorporation results in accumulation of misfolded proteins triggering a global stress response. This study demonstrates the mechanism of action of Aze in plants and provides a foundation for understanding the biological functions of proteotoxic metabolites.

Laser weld spot detection based on YOLO-weld.

Laser weld point detection is crucial in modern industrial manufacturing, yet it faces challenges such as a limited number of samples, uneven distribution, and diverse, irregular shapes. To address these issues, this paper proposes an innovative model, YOLO-Weld, which achieves lightweight design while enhancing detection accuracy. Firstly, a targeted data augmentation strategy is employed to increase both the quantity and diversity of samples from minority classes. Following this, a Diverse Class Normalization Loss (DCNLoss)function is designed to emphasize the importance of tail data in the model's training. Secondly, the Adaptive Hierarchical Intersection over Union Loss (AHIoU Loss)function is introduced, which assigns varying levels of attention to different Intersections over Union (IoU) samples, with a particular focus on moderate IoU samples, thereby accelerating the bounding box regression process. Finally, a lightweight multi-scale feature processing module, MSBCSPELAN, is proposed to enhance multi-scale feature handling while reducing the number of model parameters. Experimental results indicate that YOLO-Weld significantly improves the accuracy and efficiency of laser weld point detection, with mean Average Precision at 50 ([Formula: see text]) and mean Average Precision at 50:95 ([Formula: see text]) increasing by 15.6% and 15.8%, respectively. Additionally, the model's parameter count is reduced by 0.4M, GFLOPS decreases by 1.1, precision improves by 4.3%, recall rises by 22.2%, and the F1 score increases by 15.1%.

ROLE OF H3K27me3 AND Ki67 LABELLING INDEX IN ASSESSING THE BIOLOGICAL BEHAVIOUR OF MENINGIOMAS

Meningiomas are non-malignant neoplasms primarily originating from arachnoid cells and are classified into three grades [1, 2, and 3] based on histological features according to the WHO classification. However, this classification system is imperfect especially for grade 1 and 2 meningiomas as many grade 1 tumors recur. Meningiomas are hence a histologically diverse class of tumors exhibiting more unpredictable behaviour. Therefore, more improved classification is required, possibly using novel and more dependable biomarkers. In this study, we aim to investigate the role of the H3K27me3 and Ki67 labelling index in assessing the biological behaviour of meningiomas. The study was conceived, with the primary objective of examining the expression of H3k27me3 and Ki67 labelling index in grade 1/2 meningiomas with atypical features to ascertain if this potentially impacts patient prognosis. Upon obtaining clearance from the Institutional Ethical Committee (IEC), the authors studied 81 cases of meningiomas including 11 recurrent cases. The study used immunohistochemistry to evaluate the Ki67 index and H3K27me3 immunohistochemistry. The Ki67 labelling Index was determined by counting the positively stained MIB-1 cells and categorizing them into <5%, 5-10% and > 10%. The H3k27me3 staining was evaluated by finding the product of the tumor cells showing positive staining and the intensity of staining. Based on the product of the two, the cases were subdivided into Negative [0], Low [1-4] and high expression [5-9] of H3K27me3. The results showed that presence of atypical morphological features including necrosis and prominent nucleoli in grade 1 meningioma and low expression of H3K27me3 was significantly associated with higher grade, recurrence, and shorter progression-free survival (Kaplan Meier curves showed higher negative slope). The study also found that a higher Ki67 labelling Index was associated with recurrence and poor prognosis. This suggest that the H3K27me3 and Ki67 labelling Index can be useful prognostic markers in meningiomas, particularly in challenging grade 1 and 2 cases and recurrent meningiomas. The study highlights the importance of the H3K27me3 and Ki67 Labelling Index in assessing the biological behaviour of meningiomas. The findings provide valuable insights into the prognosis and treatment of meningiomas, emphasizing the need for further research to validate these markers and develop targeted therapeutic strategies.

A study on solutions of fractional order equal-width equation using novel approach

The time-fractional equal-width equation plays a vital role in plasma physics, serving as an essential tool for elucidating the dynamics of hydromagnetic waves in cold plasma, a critical component for the comprehensive understanding of plasma-related phenomena. Furthermore, this equation finds application in fluid mechanics, which models the transmission of nonlinear waves across shallow waters. In this study, we employ an innovative technique to solve time-fractional equal-width equation, demonstrating the q-homotopy analysis transform technique. This considered technique was implemented to find the effective approximated solution of the considered equations. The obtained results are discussed through the 3D plots and graphs that express the physical representation. The results derived from the q-homotopy analysis transform method are presented in a series form, exhibiting swift convergence and capturing the behavior of the equal-width equation’s solution with minimal error, and the convergence analysis and uniqueness of the solution using the projected method have been secured using the fixed-point theory. The projected method we used does not require linearization, perturbations, or discretization, which significantly reduces computations. The results disclose that the proposed technique is highly effective, methodical, and easy to apply for complex and nonlinear systems, helping us to capture the associated behavior of diverse classes of phenomena. The numerical simulations presented ensure higher accuracy and are compared with other techniques to evaluate approximate errors. In comparison with other techniques, the considered method is a competent tool to get an analytical solution of an considered equation and the methodology employed herein for the considered equation is demonstrated to be both efficient and dependable, marking a significant advancement in the field.

An Ecological Perspective on the Challenges in Language Education: Focus on Agency and Affordances

The article presents an overview of recent research trends from an ecological perspective, arguing that the ecological perspective can be most aptly used to describe current language education, characterized by dynamic and unpredictable changes. It delineates such topics as the spread of technology and out-of-school language learning, linguistically diverse classes, and teacher wellbeing. The notion of teacher agency is addressed, which can be critical in the perception of the challenges in education, i.e. whether they will be used as affordances to modify teaching or as a threat undermining the teacher’s professional identity. In conclusion, guidelines for current teacher education are provided.

N6-methyladenosine RNA modification in head and neck squamous cell carcinoma (HNSCC): current status and future insights.

N6-methyladenosine (m6A) plays a pivotal role in regulating epitranscriptomic mechanisms and is closely linked to the normal functioning of diverse classes of RNAs, both coding as well as noncoding. Recent research highlights the role of m6A RNA methylation in the onset and progression of several cancers, including head and neck squamous cell carcinoma (HNSCC). HNSCC ranks as the seventh most common cancer globally, with a five-year patient survival rate of just 50%. Elevated m6A RNA methylation levels and deregulated expression of various m6A modifiers, i.e. writers, readers, and erasers, have been reported across nearly all HNSCC subtypes. Numerous studies have demonstrated that m6A modifications significantly impact key hallmarks of HNSCC, such as proliferation, apoptosis, migration, and invasion. Furthermore, m6A impacts epithelial-mesenchymal transition (EMT), drug resistance, and aerobic glycolysis, and disrupts the tumor microenvironment. Additionally, transcripts regulated by m6A in HNSCC present themselves as potential diagnostic and prognostic biomarkers. This review attempts to comprehensively summarize the role of m6A RNA methylation and its modifiers in regulating various facets of HNSCC pathogenesis.

Single-cell transcriptomics unveils molecular signatures of neuronal vulnerability in a mouse model of prion disease that overlap with Alzheimer’s disease

Understanding why certain neurons are more sensitive to dysfunction and death caused by misfolded proteins could provide therapeutically relevant insights into neurodegenerative disorders. Here, we harnessed single-cell transcriptomics to examine live neurons isolated from prion-infected female mice, aiming to identify and characterize prion-vulnerable neuronal subsets. Our analysis revealed distinct transcriptional responses across neuronal subsets, with a consistent pathway-level depletion of synaptic gene expression in damage-vulnerable neurons. By scoring neuronal damage based on the magnitude of depleted synaptic gene expression, we identified a diverse spectrum of prion-vulnerable glutamatergic, GABAergic, and medium spiny neurons. Comparison between prion-vulnerable and resistant neurons highlighted baseline gene expression differences that could influence neuronal vulnerability. For instance, the neuroprotective cold-shock protein Rbm3 exhibited higher baseline gene expression in prion-resistant neurons and was robustly upregulated across diverse neuronal classes upon prion infection. We also identified vulnerability-correlated transcripts that overlapped between prion and Alzheimer’s disease. Our findings not only demonstrate the potential of single-cell transcriptomics to identify damage-vulnerable neurons, but also provide molecular insights into neuronal vulnerability and highlight commonalties across neurodegenerative disorders.

Pattern-Based Genome Mining Guides Discovery of the Antibiotic Indanopyrrole A from a Marine Streptomycete.

Terrestrial actinomycetes in the genus Streptomyces have long been recognized as prolific producers of small-molecule natural products, including many clinically important antibiotics and cytotoxic agents. Although Streptomyces can also be isolated from marine environments, their potential for natural product biosynthesis remains underexplored. The MAR4 clade of largely marine-derived Streptomyces has been a rich source of novel halogenated natural products of diverse structural classes. To further explore the biosynthetic potential of this group, we applied pattern-based genome mining, leading to the discovery of the first halogenated pyrroloketoindane natural products, indanopyrrole A (1) and B (2), and the bioinformatic linkage of these compounds to an orphan biosynthetic gene cluster (BCG) in 20 MAR4 genomes. Indanopyrrole A displays potent broad-spectrum antibiotic activity against clinically relevant pathogens. A comparison of the putative indanopyrrole BGC with that of the related compound indanomycin provides new insights into the terminal cyclization and offloading mechanisms in pyrroloketoindane biosynthesis. Broader searches of public databases reveal the rarity of this BGC while also highlighting opportunities for discovering additional compounds in this uncommon class.

Case Report: Dust Remover Inhalant Use Disorder in an Individual in Early Remission from Alcohol Use Disorder Treated with Naltrexone.

Inhalants are a very diverse class of substances with a highly prevalent recreational use. Difluroethane (DFE) is a psychoactive ingredient present in several propellants and dust remover products. Past reports have described the toxicological effects of this compound, but its addictive potential is poorly described in the literature. We present a case report (N = 1) of an adult man who very rapidly developed a severe inhalant use disorder (IUD), in the context of an early remission of an alcohol use disorder (AUD). He received treatment with naltrexone in a residential treatment program. He provided verbal and written consent for the publication of this case report. This is the first follow-up case of dust remover-IUD treated with naltrexone described in the literature. This case is clinically important for several reasons, including its atypical age of presentation, rapid progression, medical consequences, and positive response to multimodal treatment. The easy availability and lack of regulation of many inhalants, such as DFE, combined with the inability to be detected in regular screening tests, make this phenomenon a potential public health threat. We hypothesize that, consistent with previous reports, there might be a common neurobiological signature between AUD and IUD.

C. elegans PPEF-type phosphatase (Retinal degeneration C ortholog) functions in diverse classes of cilia to regulate nematode behaviors

Primary (non-motile) cilia represent structurally and functionally diverse organelles whose roles as specialized cellular antenna are central to animal cell signaling pathways, sensory physiology and development. An ever-growing number of ciliary proteins, including those found in vertebrate photoreceptors, have been uncovered and linked to human disorders termed ciliopathies. Here, we demonstrate that an evolutionarily-conserved PPEF-family serine-threonine phosphatase, not functionally linked to cilia in any organism but associated with rhabdomeric (non-ciliary) photoreceptor degeneration in the Drosophila rdgC (retinal degeneration C) mutant, is a bona fide ciliary protein in C. elegans. The nematode protein, PEF-1, depends on transition zone proteins, which make up a ‘ciliary gate’ in the proximal-most region of the cilium, for its compartmentalization within cilia. Animals lacking PEF-1 protein function display structural defects to several types of cilia, including potential degeneration of microtubules. They also exhibit anomalies to cilium-dependent behaviors, including impaired responses to chemical, temperature, light, and noxious CO2 stimuli. Lastly, we demonstrate that PEF-1 function depends on conserved myristoylation and palmitoylation signals. Collectively, our findings broaden the role of PPEF proteins to include cilia, and suggest that the poorly-characterized mammalian PPEF1 and PPEF2 orthologs may also have ciliary functions and thus represent ciliopathy candidates.

Biocatalytic Tetrapeptide Macrocyclization by Cryptic Penicillin-binding Protein-type Thioesterases.

Cyclic tetrapeptides (CTPs) are a diverse class of natural products with a broad range of biological activities. However, they are extremely challenging to synthesize due to the ring strain associated with their small ring size. While chemical methods have been developed to access CTPs, they generally require the presence of certain amino acids, limiting their substrate scopes. Herein, we report the first bioinformatics guided discovery of a thioesterase from a cryptic biosynthetic gene cluster for peptide cyclization. Specifically, we hypothesized that predicted Penicillin-binding type thioesterases (PBP-TEs) from cryptic nonribosomal peptide synthetase gene clusters containing four adenylation domains would catalyze tetrapeptide cyclization. We found that one of the predicted PBP-TEs, WP516, efficiently cyclizes a wide variety of tetrapeptide substrates. To date, it is only the second stand-alone enzyme capable of cyclizing tetrapeptides, and its substrate scope greatly surpasses that of the only other reported tetrapeptide cyclase Ulm16. AlphaFold modeling and covalent docking were used to rationalize the broad substrate scope of WP516 in comparison to other PBP-TEs. Overall, the bioinformatics guided workflow outlined in this paper, and the discovery of WP516, represent promising tools for the biocatalytic production of head-to-tail CTPs, as well as a more general strategy for discovery of enzymes for peptide cyclization.