MDPI - Publisher of Open Access Journals

21 pages, 2397 KB

Open AccessArticle

Nido-Carborane Derivatives of (S)-Ornithine and (S)-Lysine as Potential Boron Delivery Agents: Synthesis and In Vitro Evaluation

by Dmitry A. Gruzdev, Galina L. Levit, Vera V. Musiyak, Angelina A. Telegina, Ilya N. Ganebnykh, Marina A. Ezhikova, Mikhail I. Kodess, Olga I. Solovieva, Tatiana Y. Gusel’nikova, Ivan A. Razumov and Victor P. Krasnov

Int. J. Mol. Sci. 2025, 26(17), 8560; https://doi.org/10.3390/ijms26178560 - 3 Sep 2025

Viewed by 1005

Abstract

Derivatives of natural amino acids are selectively absorbed by many types of tumour cells. This makes the use of amino acids, especially polyfunctional ones, attractive as a basis in the design of low-toxicity agents for targeted boron delivery for boron neutron capture therapy [...] Read more.

Derivatives of natural amino acids are selectively absorbed by many types of tumour cells. This makes the use of amino acids, especially polyfunctional ones, attractive as a basis in the design of low-toxicity agents for targeted boron delivery for boron neutron capture therapy (BNCT) of tumours. We synthesized a series of new (S)-ornithine and (S)-lysine derivatives containing a 7,8-dicarba-nido-undecaborane (nido-carborane) residue attached to the amino group in the side chain or alpha position. The MTT assay demonstrated moderate cytotoxicity of the lysine and ornithine derivatives containing a nido-carborane residue in the side chain. It has been found that sodium salt of N^ε-(nido-carboran-7-yl)acetyl-(S)-lysine is capable of accumulation by MDA-MB-231 (human breast carcinoma) and SK-Mel 28 (human melanoma) cell lines, providing a boron concentration of up to 0.67 µg/10⁶ cells in in vitro experiments. This (S)-lysine derivative containing a nido-carborane residue in the side chain can be considered as a promising compound for in-depth study in vivo experiments aimed at designing an efficient boron delivery agent for BNCT. Full article

(This article belongs to the Special Issue Innovative Strategies in the Design and Development of Anticancer Agents)

► Show Figures

Graphical abstract

13 pages, 1800 KB

Open AccessArticle

Influence of N^ε-Lysine Acetylation on the Formation of Protein Aggregates and Antibiotic Persistence in E. coli

by Karolina Stojowska-Swędrzyńska, Dorota Kuczyńska-Wiśnik and Ewa Laskowska

Molecules 2024, 29(2), 383; https://doi.org/10.3390/molecules29020383 - 12 Jan 2024

Cited by 2 | Viewed by 3058

Abstract

Numerous studies indicate that reversible N^ε-lysine acetylation in bacteria may play a key role in the regulation of metabolic processes, transcription and translation, biofilm formation, virulence, and drug resistance. Using appropriate mutant strains deficient in non-enzymatic acetylation and enzymatic acetylation or [...] Read more.

Numerous studies indicate that reversible N^ε-lysine acetylation in bacteria may play a key role in the regulation of metabolic processes, transcription and translation, biofilm formation, virulence, and drug resistance. Using appropriate mutant strains deficient in non-enzymatic acetylation and enzymatic acetylation or deacetylation pathways, we investigated the influence of protein acetylation on cell viability, protein aggregation, and persister formation in Escherichia coli. Lysine acetylation was found to increase protein aggregation and cell viability under the late stationary phase. Moreover, increased lysine acetylation stimulated the formation of persisters. These results suggest that acetylation-dependent aggregation may improve the survival of bacteria under adverse conditions (such as the late stationary phase) and during antibiotic treatment. Further experiments revealed that acetylation-favorable conditions may increase persister formation in Klebsiella pneumoniae clinical isolate. However, the exact mechanisms underlying the relationship between acetylation and persistence in this pathogen remain to be elucidated. Full article

(This article belongs to the Special Issue Protein Folding, towards the Comprehensive Understanding from Various Aspects)

► Show Figures

Graphical abstract

20 pages, 2717 KB

Open AccessReview

Deacetylation of Transcription Factors in Carcinogenesis

by Marta Halasa, Kamila Adamczuk, Grzegorz Adamczuk, Syeda Afshan, Andrzej Stepulak, Marek Cybulski and Anna Wawruszak

Int. J. Mol. Sci. 2021, 22(21), 11810; https://doi.org/10.3390/ijms222111810 - 30 Oct 2021

Cited by 17 | Viewed by 4485

Abstract

Reversible Nε-lysine acetylation/deacetylation is one of the most common post-translational modifications (PTM) of histones and non-histone proteins that is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). This epigenetic process is highly involved in carcinogenesis, affecting histone and non-histone proteins’ properties and [...] Read more.

Reversible Nε-lysine acetylation/deacetylation is one of the most common post-translational modifications (PTM) of histones and non-histone proteins that is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). This epigenetic process is highly involved in carcinogenesis, affecting histone and non-histone proteins’ properties and their biological functions. Some of the transcription factors, including tumor suppressors and oncoproteins, undergo this modification altering different cell signaling pathways. HDACs deacetylate their targets, which leads to either the upregulation or downregulation of proteins involved in the regulation of cell cycle and apoptosis, ultimately influencing tumor growth, invasion, and drug resistance. Therefore, epigenetic modifications are of great clinical importance and may constitute a new therapeutic target in cancer treatment. This review is aimed to present the significance of HDACs in carcinogenesis through their influence on functions of transcription factors, and therefore regulation of different signaling pathways, cancer progression, and metastasis. Full article

(This article belongs to the Special Issue Gene Expression and Chromatin Biology 2.0)

► Show Figures

Figure 1

16 pages, 1627 KB

Open AccessArticle

Changes of the Proteome and Acetylome during Transition into the Stationary Phase in the Organohalide-Respiring Dehalococcoides mccartyi Strain CBDB1

by Franziska Greiner-Haas, Martin von Bergen, Gary Sawers, Ute Lechner and Dominique Türkowsky

Microorganisms 2021, 9(2), 365; https://doi.org/10.3390/microorganisms9020365 - 12 Feb 2021

Cited by 7 | Viewed by 2838

Abstract

The strictly anaerobic bactGIerium Dehalococcoides mccartyi obligatorily depends on organohalide respiration for energy conservation and growth. The bacterium also plays an important role in bioremediation. Since there is no guarantee of a continuous supply of halogenated substrates in its natural environment, the question [...] Read more.

The strictly anaerobic bactGIerium Dehalococcoides mccartyi obligatorily depends on organohalide respiration for energy conservation and growth. The bacterium also plays an important role in bioremediation. Since there is no guarantee of a continuous supply of halogenated substrates in its natural environment, the question arises of how D. mccartyi maintains the synthesis and activity of dehalogenating enzymes under these conditions. Acetylation is a means by which energy-restricted microorganisms can modulate and maintain protein levels and their functionality. Here, we analyzed the proteome and Nε-lysine acetylome of D. mccartyi strain CBDB1 during growth with 1,2,3-trichlorobenzene as an electron acceptor. The high abundance of the membrane-localized organohalide respiration complex, consisting of the reductive dehalogenases CbrA and CbdbA80, the uptake hydrogenase HupLS, and the organohalide respiration-associated molybdoenzyme OmeA, was shown throughout growth. In addition, the number of acetylated proteins increased from 5% to 11% during the transition from the exponential to the stationary phase. Acetylation of the key proteins of central acetate metabolism and of CbrA, CbdbA80, and TatA, a component of the twin-arginine translocation machinery, suggests that acetylation might contribute to maintenance of the organohalide-respiring capacity of the bacterium during the stationary phase, thus providing a means of ensuring membrane protein integrity and a proton gradient. Full article

(This article belongs to the Section Environmental Microbiology)

► Show Figures

Figure 1

21 pages, 4310 KB

Open AccessArticle

Lysine Acetylation Reshapes the Downstream Signaling Landscape of Vav1 in Lymphocytes

by Sonia Rodríguez-Fdez, Lucía Fernández-Nevado, L. Francisco Lorenzo-Martín and Xosé R. Bustelo

Cells 2020, 9(3), 609; https://doi.org/10.3390/cells9030609 - 4 Mar 2020

Cited by 6 | Viewed by 3752

Abstract

Vav1 works both as a catalytic Rho GTPase activator and an adaptor molecule. These functions, which are critical for T cell development and antigenic responses, are tyrosine phosphorylation-dependent. However, it is not known whether other posttranslational modifications can contribute to the regulation of [...] Read more.

Vav1 works both as a catalytic Rho GTPase activator and an adaptor molecule. These functions, which are critical for T cell development and antigenic responses, are tyrosine phosphorylation-dependent. However, it is not known whether other posttranslational modifications can contribute to the regulation of the biological activity of this protein. Here, we show that Vav1 becomes acetylated on lysine residues in a stimulation- and SH2 domain-dependent manner. Using a collection of both acetylation- and deacetylation-mimicking mutants, we show that the acetylation of four lysine residues (Lys²²², Lys²⁵², Lys⁵⁸⁷, and Lys⁷¹⁶) leads to the downmodulation of the adaptor function of Vav1 that triggers the stimulation of the nuclear factor of activated T cells (NFAT). These sites belong to two functional subclasses according to mechanistic criteria. We have also unveiled additional acetylation sites potentially involved in either the stimulation (Lys⁷⁸²) or the downmodulation (Lys³³⁵, Lys³⁷⁴) of specific Vav1-dependent downstream responses. Collectively, these results indicate that Nε-lysine acetylation can play variegated roles in the regulation of Vav1 signaling. Unlike the case of the tyrosine phosphorylation step, this new regulatory layer is not conserved in other Vav family paralogs. Full article

(This article belongs to the Special Issue GTPase Pathways in Health and Diseases)

► Show Figures

Figure 1

12 pages, 2732 KB

Open AccessCommunication

Cyclic Peptide-Based Sirtuin Substrates

by Di Chen, Lingling Yan and Weiping Zheng

Molecules 2019, 24(3), 424; https://doi.org/10.3390/molecules24030424 - 24 Jan 2019

Viewed by 3542

Abstract

In the current study, four side chain-to-side chain cyclic peptides (three 5-mers and one 4-mer) harboring N^ε-acetyl-lysine or N^ε-myristoyl-lysine were found to be in vitro substrates of the human SIRT1/2/3-catalyzed deacylation with good substrate activities, as judged by the k_cat/K_M ratios. Full article

(This article belongs to the Special Issue Peptides in Chemical Biology and Drug Discovery)

► Show Figures

Graphical abstract

16 pages, 2831 KB

Open AccessArticle

Lysine Acetylation Regulates Alanyl-tRNA Synthetase Activity in Escherichia coli

by Takuya Umehara, Saori Kosono, Dieter Söll and Koji Tamura

Genes 2018, 9(10), 473; https://doi.org/10.3390/genes9100473 - 28 Sep 2018

Cited by 12 | Viewed by 5271

Abstract

Protein lysine acetylation is a widely conserved posttranslational modification in all three domains of life. Lysine acetylation frequently occurs in aminoacyl-tRNA synthetases (aaRSs) from many organisms. In this study, we determined the impact of the naturally occurring acetylation at lysine-73 (K73) in Escherichia [...] Read more.

Protein lysine acetylation is a widely conserved posttranslational modification in all three domains of life. Lysine acetylation frequently occurs in aminoacyl-tRNA synthetases (aaRSs) from many organisms. In this study, we determined the impact of the naturally occurring acetylation at lysine-73 (K73) in Escherichia coli class II alanyl-tRNA synthetase (AlaRS) on its alanylation activity. We prepared an AlaRS K73Ac variant in which N^ε-acetyl-l-lysine was incorporated at position 73 using an expanded genetic code system in E. coli. The AlaRS K73Ac variant showed low activity compared to the AlaRS wild type (WT). Nicotinamide treatment or CobB-deletion in an E. coli led to elevated acetylation levels of AlaRS K73Ac and strongly reduced alanylation activities. We assumed that alanylation by AlaRS is affected by K73 acetylation, and the modification is sensitive to CobB deacetylase in vivo. We also showed that E. coli expresses two CobB isoforms (CobB-L and CobB-S) in vivo. CobB-S displayed the deacetylase activity of the AlaRS K73Ac variant in vitro. Our results imply a potential regulatory role for lysine acetylation in controlling the activity of aaRSs and protein synthesis. Full article

(This article belongs to the Special Issue Synthetic DNA and RNA Programming)

► Show Figures

Figure 1

11 pages, 226 KB

Open AccessArticle

Substituting N^ε-thioacetyl-lysine for N^ε-acetyl-lysine in Peptide Substrates as a General Approach to Inhibiting Human NAD⁺-dependent Protein Deacetylases

by David G. Fatkins and Weiping Zheng

Int. J. Mol. Sci. 2008, 9(1), 1-11; https://doi.org/10.3390/ijms9010001 - 7 Jan 2008

Cited by 41 | Viewed by 11168

Abstract

Inhibitors of human NAD⁺-dependent protein deacetylases possess great value for deciphering the biology of these enzymes and as potential therapeutics for metabolic and agerelated diseases and cancer. In the current study, we have experimentally demonstrated that, the potent inhibition we obtained [...] Read more.

Inhibitors of human NAD⁺-dependent protein deacetylases possess great value for deciphering the biology of these enzymes and as potential therapeutics for metabolic and agerelated diseases and cancer. In the current study, we have experimentally demonstrated that, the potent inhibition we obtained previously for one of these enzymes (i.e. sirtuin type 1 (SIRT1)) by simply replacing N^ε-thioacetyl-lysine for N^ε-acetyl-lysine in its peptide substrate, represented a general and efficient strategy to develop potent and selective inhibitors of human NAD⁺-dependent protein deacetylase enzymes. Indeed, by using this simple inhibition strategy, potent (low-micromolar) and selective (≤40-fold) SIRT2 and SIRT3 inhibitors, which were either comparable or superior to currently existing inhibitors, have also been quickly identified in the current study. These inhibitors could be used as chemical biological tools or as lead compounds for further focused structure-activity optimization. Full article

(This article belongs to the Special Issue Interaction of Biological Molecules)

► Show Figures

Search Results (8)

Further Information

Guidelines

MDPI Initiatives

Follow MDPI

Saved Queries

Search Filter Reset All

Years

Feature Papers

Subjects

Journals

Article Types

Countries / Regions

Search Results (8)

Further Information

Guidelines

MDPI Initiatives

Follow MDPI