Small-Molecule Acetylation by GCN5-Related N-Acetyltransferases in Bacteria

SUMMARY Acetylation is a conserved modification used to regulate a variety of cellular pathways, such as gene expression, protein synthesis, detoxification, and virulence. Acetyltransferase enzymes transfer an acetyl moiety, usually from acetyl coenzyme A (AcCoA), onto a target substrate, thereby modulating activity or stability. Members of the GCN5-N-acetyltransferase (GNAT) protein superfamily are found in all domains of life and are characterized by a core structural domain architecture. These enzymes can modify primary amines of small molecules or of lysyl residues of proteins. From the initial discovery of antibiotic acetylation, GNATs have been shown to modify a myriad of small-molecule substrates, including tRNAs, polyamines, cell wall components, and other toxins. This review focuses on the literature on small-molecule substrates of GNATs in bacteria, including structural examples, to understand ligand binding and catalysis. Understanding the plethora and versatility of substrates helps frame the role of acetylation within the larger context of bacterial cellular physiology.

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Structure vs. Function of TRIB1—Myeloid Neoplasms and Beyond

Cancers ◽

10.3390/cancers13123060 ◽

2021 ◽

Vol 13 (12) ◽

pp. 3060

Author(s):

Hamish D McMillan ◽

Karen Keeshan ◽

Anita K Dunbier ◽

Peter D Mace

Keyword(s):

Small Molecules ◽

Small Molecule ◽

Tumour Progression ◽

Conformational Switching ◽

Myeloid Neoplasms ◽

Exciting Potential ◽

Cancer Types ◽

Prostate Cancers ◽

Predict Treatment Response

The Tribbles family of proteins—comprising TRIB1, TRIB2, TRIB3 and more distantly related STK40—play important, but distinct, roles in differentiation, development and oncogenesis. Of the four Tribbles proteins, TRIB1 has been most well characterised structurally and plays roles in diverse cancer types. The most well-understood role of TRIB1 is in acute myeloid leukaemia, where it can regulate C/EBP transcription factors and kinase pathways. Structure–function studies have uncovered conformational switching of TRIB1 from an inactive to an active state when it binds to C/EBPα. This conformational switching is centred on the active site of TRIB1, which appears to be accessible to small-molecule inhibitors in spite of its inability to bind ATP. Beyond myeloid neoplasms, TRIB1 plays diverse roles in signalling pathways with well-established roles in tumour progression. Thus, TRIB1 can affect both development and chemoresistance in leukaemia; glioma; and breast, lung and prostate cancers. The pervasive roles of TRIB1 and other Tribbles proteins across breast, prostate, lung and other cancer types, combined with small-molecule susceptibility shown by mechanistic studies, suggests an exciting potential for Tribbles as direct targets of small molecules or biomarkers to predict treatment response.

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Small molecule inhibitors of the mitochondrial ClpXP protease possess cytostatic potential and re-sensitize chemo-resistant cancers

Scientific Reports ◽

10.1038/s41598-021-90801-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Martina Meßner ◽

Melanie M. Mandl ◽

Mathias W. Hackl ◽

Till Reinhardt ◽

Maximilian A. Ardelt ◽

...

Keyword(s):

Small Molecules ◽

Small Molecule ◽

Small Molecule Inhibitors ◽

Breast Cancer Cell Lines ◽

Cancer Therapies ◽

Oxygen Species ◽

Transport Chain ◽

Anti Cancer ◽

Major Attention

AbstractThe human mitochondrial ClpXP protease complex (HsClpXP) has recently attracted major attention as a target for novel anti-cancer therapies. Despite its important role in disease progression, the cellular role of HsClpXP is poorly characterized and only few small molecule inhibitors have been reported. Herein, we screened previously established S. aureus ClpXP inhibitors against the related human protease complex and identified potent small molecules against human ClpXP. The hit compounds showed anti-cancer activity in a panoply of leukemia, liver and breast cancer cell lines. We found that the bacterial ClpXP inhibitor 334 impairs the electron transport chain (ETC), enhances the production of mitochondrial reactive oxygen species (mtROS) and thereby promotes protein carbonylation, aberrant proteostasis and apoptosis. In addition, 334 induces cell death in re-isolated patient-derived xenograft (PDX) leukemia cells, potentiates the effect of DNA-damaging cytostatics and re-sensitizes resistant cancers to chemotherapy in non-apoptotic doses.

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Mimicking growth factors: role of small molecule scaffold additives in promoting tissue regeneration and repair

RSC Advances ◽

10.1039/c9ra02765c ◽

2019 ◽

Vol 9 (32) ◽

pp. 18124-18146 ◽

Cited By ~ 9

Author(s):

Nowsheen Goonoo ◽

Archana Bhaw-Luximon

Keyword(s):

Growth Factors ◽

Small Molecules ◽

Small Molecule ◽

Tissue Regeneration ◽

Tissue Repair

Scaffold loaded with small molecules mimicking the action of growth factors for tissue repair.

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Non-Peptidic Small Molecule Components from Cone Snail Venoms

Frontiers in Pharmacology ◽

10.3389/fphar.2021.655981 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhenjian Lin ◽

Joshua P. Torres ◽

Maren Watkins ◽

Noemi Paguigan ◽

Changshan Niu ◽

...

Keyword(s):

Small Molecules ◽

Small Molecule ◽

Prey Capture ◽

Marine Biodiversity ◽

Cone Snail ◽

Pharmacological Agents ◽

Basal Clade ◽

Initial Discovery ◽

Cone Snails ◽

Pharmaceutical Agents

Venomous molluscs (Superfamily Conoidea) comprise a substantial fraction of tropical marine biodiversity (>15,000 species). Prior characterization of cone snail venoms established that bioactive venom components used to capture prey, defend against predators and for competitive interactions were relatively small, structured peptides (10–35 amino acids), most with multiple disulfide crosslinks. These venom components (“conotoxins, conopeptides”) have been widely studied in many laboratories, leading to pharmaceutical agents and probes. In this review, we describe how it has recently become clear that to varying degrees, cone snail venoms also contain bioactive non-peptidic small molecule components. Since the initial discovery of genuanine as the first bioactive venom small molecule with an unprecedented structure, a broad set of cone snail venoms have been examined for non-peptidic bioactive components. In particular, a basal clade of cone snails (Stephanoconus) that prey on polychaetes produce genuanine and many other small molecules in their venoms, suggesting that this lineage may be a rich source of non-peptidic cone snail venom natural products. In contrast to standing dogma in the field that peptide and proteins are predominantly used for prey capture in cone snails, these small molecules also contribute to prey capture and push the molecular diversity of cone snails beyond peptides. The compounds so far characterized are active on neurons and thus may potentially serve as leads for neuronal diseases. Thus, in analogy to the incredible pharmacopeia resulting from studying venom peptides, these small molecules may provide a new resource of pharmacological agents.

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A Global Review on Short Peptides: Frontiers and Perspectives

Molecules ◽

10.3390/molecules26020430 ◽

2021 ◽

Vol 26 (2) ◽

pp. 430

Author(s):

Vasso Apostolopoulos ◽

Joanna Bojarska ◽

Tsun-Thai Chai ◽

Sherif Elnagdy ◽

Krzysztof Kaczmarek ◽

...

Keyword(s):

Protein Interactions ◽

Targeted Delivery ◽

Swot Analysis ◽

Functional Materials ◽

Great Promise ◽

Short Peptides ◽

Altered Peptide Ligands ◽

Short Peptide ◽

Domains Of Life

Peptides are fragments of proteins that carry out biological functions. They act as signaling entities via all domains of life and interfere with protein-protein interactions, which are indispensable in bio-processes. Short peptides include fundamental molecular information for a prelude to the symphony of life. They have aroused considerable interest due to their unique features and great promise in innovative bio-therapies. This work focusing on the current state-of-the-art short peptide-based therapeutical developments is the first global review written by researchers from all continents, as a celebration of 100 years of peptide therapeutics since the commencement of insulin therapy in the 1920s. Peptide “drugs” initially played only the role of hormone analogs to balance disorders. Nowadays, they achieve numerous biomedical tasks, can cross membranes, or reach intracellular targets. The role of peptides in bio-processes can hardly be mimicked by other chemical substances. The article is divided into independent sections, which are related to either the progress in short peptide-based theranostics or the problems posing challenge to bio-medicine. In particular, the SWOT analysis of short peptides, their relevance in therapies of diverse diseases, improvements in (bio)synthesis platforms, advanced nano-supramolecular technologies, aptamers, altered peptide ligands and in silico methodologies to overcome peptide limitations, modern smart bio-functional materials, vaccines, and drug/gene-targeted delivery systems are discussed.

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Small-Molecule Targeted Aβ42 Aggregate Degradation: Negatively Charged Small Molecules Are More Promising than the Neutral Ones

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.1c00047 ◽

2021 ◽

Author(s):

Jinfei Mei ◽

Huijuan Yang ◽

Bo Sun ◽

Chengqiang Liu ◽

Hongqi Ai

Keyword(s):

Small Molecules ◽

Small Molecule

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Role of Perfluorophenyl Group in the Side Chain of Small-Molecule n-Type Organic Semiconductors in Stress Stability of Single-Crystal Transistors

The Journal of Physical Chemistry Letters ◽

10.1021/acs.jpclett.0c03012 ◽

2021 ◽

pp. 2095-2101

Author(s):

Shohei Kumagai ◽

Craig P. Yu ◽

Shunsuke Nakano ◽

Tatsuro Annaka ◽

Masato Mitani ◽

...

Keyword(s):

Single Crystal ◽

Organic Semiconductors ◽

Small Molecule ◽

Side Chain

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STEM-20. A CANCER STEM CELL-SELECTIVE APOPTOSIS-INDUCING SMALL MOLECULE FOR THE TREATMENT OF GBM

Neuro-Oncology ◽

10.1093/neuonc/noaa215.837 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii200-ii200

Author(s):

Stephen Skirboll ◽

Natasha Lucki ◽

Genaro Villa ◽

Naja Vergani ◽

Michael Bollong ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Small Molecules ◽

Small Molecule ◽

Large Scale ◽

Critical Role ◽

Tumor Formation ◽

Cell Type ◽

Caspase 1 ◽

Activation Assay

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is the most aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation and maintenance, drug resistance, and recurrence following surgery. New therapeutic strategies for the treatment of GBM have recently focused on targeting CSCs. Here we have used an unbiased large-scale screening approach to identify drug-like small molecules that induce apoptosis in GBM CSCs in a cell type-selective manner. METHODS A luciferase-based survival assay of patient-derived GBM CSC lines was established to perform a large-scale screen of ∼one million drug-like small molecules with the goal of identifying novel compounds that are selectively toxic to chemoresistant GBM CSCs. Compounds found to kill GBM CSC lines as compared to control cell types were further characterized. A caspase activation assay was used to evaluate the mechanism of induced cell death. A xenograft animal model using patient-derived GBM CSCs was employed to test the leading candidate for suppression of in vivo tumor formation. RESULTS We identified a small molecule, termed RIPGBM, from the cell-based chemical screen that induces apoptosis in primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of RIPGBM appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an intracranial GBM xenograft mouse model, RIPGBM was found to significantly suppress tumor formation. CONCLUSIONS Our chemical genetics-based approach has identified a small molecule drug candidate and a potential drug target that selectively targets cancer stem cells and provides an approach for the treatment of GBMs.

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Role of SpoVA Proteins in Release of Dipicolinic Acid during Germination of Bacillus subtilis Spores Triggered by Dodecylamine or Lysozyme

Journal of Bacteriology ◽

10.1128/jb.01613-06 ◽

2006 ◽

Vol 189 (5) ◽

pp. 1565-1572 ◽

Cited By ~ 82

Author(s):

Venkata Ramana Vepachedu ◽

Peter Setlow

Keyword(s):

Bacillus Subtilis ◽

Small Molecules ◽

Spore Germination ◽

Dipicolinic Acid ◽

Temperature Sensitive ◽

Wild Type ◽

Ph Optimum ◽

Inner Membrane ◽

Temperature Sensitive Mutants

ABSTRACT The release of dipicolinic acid (DPA) during the germination of Bacillus subtilis spores by the cationic surfactant dodecylamine exhibited a pH optimum of ∼9 and a temperature optimum of 60°C. DPA release during dodecylamine germination of B. subtilis spores with fourfold-elevated levels of the SpoVA proteins that have been suggested to be involved in the release of DPA during nutrient germination was about fourfold faster than DPA release during dodecylamine germination of wild-type spores and was inhibited by HgCl2. Spores carrying temperature-sensitive mutants in the spoVA operon were also temperature sensitive in DPA release during dodecylamine germination as well as in lysozyme germination of decoated spores. In addition to DPA, dodecylamine triggered the release of amounts of Ca2+ almost equivalent to those of DPA, and at least one other abundant spore small molecule, glutamic acid, was released in parallel with Ca2+ and DPA. These data indicate that (i) dodecylamine triggers spore germination by opening a channel in the inner membrane for Ca2+-DPA and other small molecules, (ii) this channel is composed at least in part of proteins, and (iii) SpoVA proteins are involved in the release of Ca2+-DPA and other small molecules during spore germination, perhaps by being a part of a channel in the spore's inner membrane.

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