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1.
J Am Chem Soc ; 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38848464

RESUMO

Histone monoaminylation (i.e., serotonylation and dopaminylation) is an emerging category of epigenetic mark occurring on the fifth glutamine (Q5) residue of H3 N-terminal tail, which plays significant roles in gene transcription. Current analysis of histone monoaminylation is mainly based on site-specific antibodies and mass spectrometry, which either lacks high resolution or is time-consuming. In this study, we report the development of chemical probes for bioorthogonal labeling and enrichment of histone serotonylation and dopaminylation. These probes were successfully applied for the monoaminylation analysis of in vitro biochemical assays, cells, and tissue samples. The enrichment of monoaminylated histones by the probes further confirmed the crosstalk between H3Q5 monoaminylation and H3K4 methylation. Finally, combining the ex vivo and in vitro analyses based on the developed probes, we have shown that both histone serotonylation and dopaminylation are highly enriched in tumor tissues that overexpress transglutaminase 2 (TGM2) and regulate the three-dimensional architecture of cellular chromatin.

2.
J Proteome Res ; 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38838187

RESUMO

Histone dopaminylation is a newly identified epigenetic mark that plays a role in the regulation of gene transcription, where an isopeptide bond is formed between the fifth amino acid of H3 (i.e., glutamine) and dopamine. Recently, we developed a chemical probe to specifically label and enrich histone dopaminylation via bioorthogonal chemistry. Given this powerful tool, we found that histone H3 glutamine 5 dopaminylation (H3Q5dop) was highly enriched in colorectal tumors, which could be attributed to the high expression level of its regulator, transglutaminase 2 (TGM2), in colon cancer cells. Due to the enzyme promiscuity of TGM2, nonhistone proteins have also been identified as dopaminylation targets; however, the dopaminylated proteome in cancer cells still remains elusive. Here, we utilized our chemical probe to enrich dopaminylated proteins from colorectal cancer cells in a bioorthogonal manner and performed the chemical proteomics analysis. Therefore, 425 dopaminylated proteins were identified, many of which are involved in nucleic acid metabolism and transcription pathways. More importantly, a number of dopaminylation sites were identified and attributed to the successful application of our chemical probe. Overall, these findings shed light on the significant association between cellular protein dopaminylation and cancer development, further suggesting that targeting these pathways may become a promising anticancer strategy.

3.
bioRxiv ; 2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38712070

RESUMO

Histone dopaminylation is a newly identified epigenetic mark that plays a role in the regulation of gene transcription, where an isopeptide bond is formed between the fifth amino acid residue of H3 ( i.e. , glutamine) and dopamine. In our previous studies, we discovered that the dynamics of this post-translational modification (including installation, removal, and replacement) were regulated by a single enzyme, transglutaminase 2 (TGM2), through reversible transamination. Recently, we developed a chemical probe to specifically label and enrich histone dopaminylation via bioorthogonal chemistry. Given this powerful tool, we found that histone H3 glutamine 5 dopaminylation (H3Q5dop) was highly enriched in colorectal tumors, which could be attributed to the high expression level of TGM2 in colon cancer cells. Due to the enzyme promiscuity of TGM2, non-histone proteins have also been identified as targets of dopaminylation on glutamine residues, however, the dopaminylated proteome in cancer cells still remains elusive. Here, we utilized our chemical probe to enrich dopaminylated proteins from colorectal cancer cells in a bioorthogonal manner and performed the chemical proteomics analysis. Therefore, 425 dopaminylated proteins were identified, many of which are involved in nucleic acid metabolism and transcription pathways. More importantly, a number of modification sites of these dopaminylated proteins were identified, attributed to the successful application of our chemical probe. Overall, these findings shed light on the significant association between cellular protein dopaminylation and cancer development, further suggesting that to block the installation of protein dopaminylation may become a promising anti-cancer strategy.

4.
Nat Commun ; 15(1): 4667, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38821952

RESUMO

Checkpoint kinase 1 (CHK1) is critical for cell survival under replication stress (RS). CHK1 inhibitors (CHK1i's) in combination with chemotherapy have shown promising results in preclinical studies but have displayed minimal efficacy with substantial toxicity in clinical trials. To explore combinatorial strategies that can overcome these limitations, we perform an unbiased high-throughput screen in a non-small cell lung cancer (NSCLC) cell line and identify thioredoxin1 (Trx1), a major component of the mammalian antioxidant-system, as a determinant of CHK1i sensitivity. We establish a role for redox recycling of RRM1, the larger subunit of ribonucleotide reductase (RNR), and a depletion of the deoxynucleotide pool in this Trx1-mediated CHK1i sensitivity. Further, the TrxR inhibitor auranofin, an approved anti-rheumatoid arthritis drug, shows a synergistic interaction with CHK1i via interruption of the deoxynucleotide pool. Together, we show a pharmacological combination to treat NSCLC that relies on a redox regulatory link between the Trx system and mammalian RNR activity.


Assuntos
Auranofina , Carcinoma Pulmonar de Células não Pequenas , Quinase 1 do Ponto de Checagem , Neoplasias Pulmonares , Oxirredução , Tiorredoxinas , Quinase 1 do Ponto de Checagem/metabolismo , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Humanos , Oxirredução/efeitos dos fármacos , Tiorredoxinas/metabolismo , Linhagem Celular Tumoral , Auranofina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/farmacologia , Ribonucleosídeo Difosfato Redutase/metabolismo , Ribonucleosídeo Difosfato Redutase/genética , Ribonucleotídeo Redutases/metabolismo , Ribonucleotídeo Redutases/antagonistas & inibidores , Sinergismo Farmacológico , Animais
5.
bioRxiv ; 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38766043

RESUMO

Serotonylation has been identified as a novel protein post-translational modification (PTM) for decades, where an isopeptide bond is formed between the glutamine residue and serotonin through transamination. Transglutaminase 2 (also known as TGM2 or TGase2) was proven to act as the main writer enzyme for this PTM and a number of key regulatory proteins (including small GTPases, fibronectin, fibrinogen, serotonin transporter, and histone H3) have been characterized as the substrates of serotonylation. However, due to the lack of pan-specific antibody for serotonylated glutamine, the precise enrichment and proteomic profiling of serotonylation still remain challenging. In our previous research, we developed an aryldiazonium probe to label protein serotonylation in a bioorthogonal manner. This chemical biology tool can be utilized alternatively for the antibody-free enrichment of serotonylated proteins, which depends on a pH-controlled chemoselective rapid azo-coupling reaction (CRACR). Here, we report the application of a photoactive aryldiazonium-biotin probe for the global profiling of serotonylation proteome in cancer cells. Thus, over 500 serotonylated proteins were identified from HCT 116 cells. Importantly, a number of modification sites of these serotonylated proteins were determine, attributed to the successful application of our chemical proteomic approach. Overall, these findings provided new insights into the significant association between cellular protein serotonylation and cancer development, further suggesting that to target TGM2-mediated monoaminylation may serve as a promising strategy for cancer therapeutics.

6.
bioRxiv ; 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38562869

RESUMO

Histone monoaminylation ( i . e ., serotonylation and dopaminylation) is an emerging category of epigenetic mark occurring on the fifth glutamine (Q5) residue of H3 N-terminal tail, which plays significant roles in gene transcription. Current analysis of histone monoaminylation is mainly based on site-specific antibodies and mass spectrometry, which either lacks high resolution or is time-consuming. In this study, we report the development of chemical probes for bioorthogonal labeling and enrichment of histone serotonylation and dopaminylation. These probes were successfully applied for the monoaminylation analysis of in vitro biochemical assays, cells, and tissue samples. The enrichment of monoaminylated histones by the probes further confirmed the crosstalk between H3Q5 monoaminylation and H3K4 methylation. Finally, combining the ex vivo and in vitro analyses based on the developed probes, we have shown that both histone serotonylation and dopaminylation are highly enriched in tumor tissues that overexpress transglutaminase 2 (TGM2) and regulate the three-dimensional architecture of cellular chromatin.

7.
Biochim Biophys Acta Proteins Proteom ; 1872(4): 141017, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38641087

RESUMO

The diversity and dynamics of proteins play essential roles in maintaining the basic constructions and functions of cells. The abundance of functional proteins is regulated by the transcription and translation processes, while the alternative splicing enables the same gene to generate distinct protein isoforms of different lengths. Beyond the transcriptional and translational regulations, post-translational modifications (PTMs) are able to further expand the diversity and functional scope of proteins. PTMs have been shown to make significant changes in the surface charges, structures, activation states, and interactome of proteins. Due to the functional complexity, highly dynamic nature, and low presence percentage, the study of protein PTMs remains challenging. Here we summarize and discuss the major chemical biology tools and chemical proteomics approaches to enrich and investigate the protein PTM of interest.


Assuntos
Processamento de Proteína Pós-Traducional , Proteômica , Proteômica/métodos , Humanos , Proteínas/metabolismo , Proteínas/química , Animais
8.
Cell Commun Signal ; 21(1): 249, 2023 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-37735413

RESUMO

Histones undergo a plethora of post-translational modifications (PTMs) that regulate nucleosome and chromatin dynamics and thus dictate cell fate. Several evidences suggest that the accumulation of epigenetic alterations is one of the key driving forces triggering aberrant cellular proliferation, invasion, metastasis and chemoresistance pathways. Recently a novel class of histone "non-enzymatic covalent modifications" (NECMs), correlating epigenome landscape and metabolic rewiring, have been described. These modifications are tightly related to cell metabolic fitness and are able to impair chromatin architecture. During metabolic reprogramming, the high metabolic flux induces the accumulation of metabolic intermediate and/or by-products able to react with histone tails altering epigenome homeostasis. The accumulation of histone NECMs is a damaging condition that cancer cells counteracts by overexpressing peculiar "eraser" enzymes capable of removing these modifications preserving histones architecture. In this review we explored the well-established NECMs, emphasizing the role of their corresponding eraser enzymes. Additionally, we provide a parterre of drugs aiming to target those eraser enzymes with the intent to propose novel routes of personalized medicine based on the identification of epi-biomarkers which might be selectively targeted for therapy. Video Abstract.


Assuntos
Histonas , Neoplasias , Humanos , Neoplasias/genética , Homeostase , Cromatina , Epigênese Genética
9.
Cancer Biol Ther ; 24(1): 2240084, 2023 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-37498047

RESUMO

Recent evidence has shown that the human microbiome is associated with various diseases, including cancer. The salivary microbiome, fecal microbiome, and circulating microbial DNA in blood plasma have all been used experimentally as diagnostic biomarkers for many types of cancer. The microbiomes present within local tissue, other regions, and tumors themselves have been shown to promote and restrict the development and progression of cancer, most often by affecting cancer cells or the host immune system. These microbes have also been shown to impact the efficacy of various cancer therapies, including radiation, chemotherapy, and immunotherapy. Here, we review the research advances focused on how microbes impact these different facets and why they are important to the clinical care of cancer. It is only by better understanding the roles these microbes play in the diagnosis, development, progression, and treatment of cancer, that we will be able to catch and treat cancer early.


Assuntos
Microbiota , Neoplasias , Humanos , Neoplasias/diagnóstico , Neoplasias/terapia , Imunoterapia
10.
Nat Commun ; 14(1): 3549, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-37322069

RESUMO

The Holliday junction (HJ) is a DNA intermediate of homologous recombination, involved in many fundamental physiological processes. RuvB, an ATPase motor protein, drives branch migration of the Holliday junction with a mechanism that had yet to be elucidated. Here we report two cryo-EM structures of RuvB, providing a comprehensive understanding of HJ branch migration. RuvB assembles into a spiral staircase, ring-like hexamer, encircling dsDNA. Four protomers of RuvB contact the DNA backbone with a translocation step size of 2 nucleotides. The variation of nucleotide-binding states in RuvB supports a sequential model for ATP hydrolysis and nucleotide recycling, which occur at separate, singular positions. RuvB's asymmetric assembly also explains the 6:4 stoichiometry between the RuvB/RuvA complex, which coordinates HJ migration in bacteria. Taken together, we provide a mechanistic understanding of HJ branch migration facilitated by RuvB, which may be universally shared by prokaryotic and eukaryotic organisms.


Assuntos
DNA Cruciforme , Proteínas de Escherichia coli , DNA Cruciforme/metabolismo , DNA Helicases/metabolismo , Proteínas de Escherichia coli/metabolismo , Proteínas de Bactérias/metabolismo , Escherichia coli/genética , DNA/metabolismo , Nucleotídeos/metabolismo , Catálise
11.
Res Sq ; 2023 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-37205570

RESUMO

Checkpoint kinase 1 (CHK1) is critical for cell survival under replication stress (RS). CHK1 inhibitors (CHK1i's) in combination with chemotherapy have shown promising results in preclinical studies but minimal efficacy with substantial toxicity in clinical trials. To explore novel combinational strategies that can overcome these limitations, we performed an unbiased high-throughput screen in a non-small cell lung cancer (NSCLC) cell line and identified thioredoxin1 (Trx1), a major component of the mammalian antioxidant-system, as a novel determinant of CHK1i sensitivity. We established a role for redox recycling of RRM1, the larger subunit of ribonucleotide reductase (RNR), and a depletion of the deoxynucleotide pool in this Trx1-mediated CHK1i sensitivity. Further, the TrxR1 inhibitor auronafin, an anti-rheumatoid arthritis drug, shows a synergistic interaction with CHK1i via interruption of the deoxynucleotide pool. Together, these findings identify a new pharmacological combination to treat NSCLC that relies on a redox regulatory link between the Trx system and mammalian RNR activity.

12.
Int J Mol Sci ; 24(8)2023 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-37108572

RESUMO

DJ-1 (also known as PARK7) is a multifunctional enzyme in human beings that is highly conserved and that has also been discovered in diverse species (ranging from prokaryotes to eukaryotes). Its complex enzymatic and non-enzymatic activities (such as anti-oxidation, anti-glycation, and protein quality control), as well as its role as a transcriptional coactivator, enable DJ-1 to serve as an essential regulator in multiple cellular processes (e.g., epigenetic regulations) and make it a promising therapeutic target for diverse diseases (especially cancer and Parkinson's disease). Due to its nature as a Swiss army knife enzyme with various functions, DJ-1 has attracted a large amount of research interest, from different perspectives. In this review, we give a brief summary of the recent advances with respect to DJ-1 research in biomedicine and psychology, as well as the progress made in attempts to develop DJ-1 into a druggable target for therapy.


Assuntos
Doença de Parkinson , Humanos , Proteína Desglicase DJ-1/metabolismo , Estresse Oxidativo
13.
Nat Rev Chem ; 7(4): 234-255, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37117416

RESUMO

The ability to manipulate the chemical composition of proteins and peptides has been central to the development of improved polypeptide-based therapeutics and has enabled researchers to address fundamental biological questions that would otherwise be out of reach. Protein ligation, in which two or more polypeptides are covalently linked, is a powerful strategy for generating semisynthetic products and for controlling polypeptide topology. However, specialized tools are required to efficiently forge a peptide bond in a chemoselective manner with fast kinetics and high yield. Fortunately, nature has addressed this challenge by evolving enzymatic mechanisms that can join polypeptides using a diverse set of chemical reactions. Here, we summarize how such nature-inspired protein ligation strategies have been repurposed as chemical biology tools that afford enhanced control over polypeptide composition.


Assuntos
Peptídeos , Proteínas , Proteínas/química , Peptídeos/química
14.
ACS Appl Mater Interfaces ; 15(13): 17113-17122, 2023 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-36946793

RESUMO

Electro-responsive dynamic hydrogels, which possess robust mechanical properties and precise spatiotemporal resolution, have a wide range of applications in biomedicine and energy science. However, it is still challenging to design and prepare electro-responsive hydrogels (ERHs) which have all of these properties. Here, we report one such class of ERHs with these features, based on the direct current voltage (DCV)-induced rearrangement of sodium dodecyl sulfate (SDS) micelles, where the rearrangement can tune the hydrogel networks that are originally maintained by the SDS micelle-assisted hydrophobic interactions. An enlarged mesh size is demonstrated for these ERHs after DCV treatment. Given the unique structure and properties of these ERHs, hydrophobic cargo (thiostrepton) has been incorporated into the hydrogels and is released upon DCV loading. Additionally, these hydrogels are highly stretchable (>6000%) and tough (507 J/m2), showing robust mechanical properties. Moreover, these hydrogels have a high spatiotemporal resolution. As the cross-links within our ERHs are enabled by the non-covalent (i.e., hydrophobic) interactions, these hydrogels are self-healing and malleable. Considering the robust mechanical properties, precise spatiotemporal resolution, dynamic nature (e.g., injectable and self-healing), and on-demand drug delivery ability, this class of ERHs will be of great interest in the fields of wearable bioelectronics and smart drug delivery systems.


Assuntos
Hidrogéis , Dispositivos Eletrônicos Vestíveis , Hidrogéis/química , Liberação Controlada de Fármacos , Sistemas de Liberação de Medicamentos , Micelas
15.
Macromol Rapid Commun ; 44(8): e2300008, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36807445

RESUMO

Gas-releasing/scavenging hydrogels have wide applications in biomedical and industrial fields. However, the covalently crosslinked nature of these existing materials makes them difficult to degrade or recycle, leading to a waste of raw materials and aggravating environmental pollution. Herein, a new class of pH-responsive and recyclable hydrogels with versatile gas-releasing and scavenging properties is reported, utilizing pH changes to reversibly control disassembly and reassembly of the hydrogel network. The initial hydrogels are constructed via the one-pot radical polymerization and contain dynamic molecular networks based on hydrophobic interactions, which can disassemble when the materials are placed in low pH solutions. The disassembled copolymer chains can reform hydrogels, following supplementation with fresh mineral salts and micelle monomers in neutral solutions. Moreover, the mineral salts used to reform hydrogels can function as gas donors or scavengers, endowing these hydrogels with versatile gas-releasing and consuming properties. Overall, this research provides a facile and environmentally friendly method to recycle hydrogels with gas-releasing and gas-scavenging properties, which have potential applications in diverse fields, including wound healing, wastewater management, and gas therapy for diseases.


Assuntos
Hidrogéis , Sais , Hidrogéis/química , Polímeros/química , Concentração de Íons de Hidrogênio , Minerais
16.
Nat Chem ; 15(2): 177-184, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36690833

RESUMO

Cycloaddition reactions are among the most widely used reactions in chemical synthesis. Nature achieves these cyclization reactions with a variety of enzymes, including Diels-Alderases that catalyse concerted 4 + 2 cycloadditions, but biosynthetic enzymes with 2 + 2 cyclase activity have yet to be discovered. Here we report that PloI4, a ß-barrel-fold protein homologous to the exo-selective 4 + 2 cyclase that functions in the biosynthesis of pyrroindomycins, catalyses competitive 2 + 2 and 4 + 2 cycloaddition reactions. PloI4 is believed to catalyse an endo-4 + 2 cycloaddition in the biosynthesis of pyrrolosporin A; however, when the substrate precursor of pyrroindomycins was treated with PloI4, an exo-2 + 2 adduct was produced in addition to the exo- and endo-4 + 2 adducts. Biochemical characterizations, computational analyses, (co)crystal structures and mutagenesis outcomes have allowed the catalytic versatility of PloI4 to be rationalized. Mechanistic studies involved the directed engineering of PloI4 to variants that produced the exo-4 + 2, endo-4 + 2 or exo-2 + 2 product preferentially. This work illustrates an enzymatic thermal 2 + 2 cycloaddition and provides evidence of a process through which an enzyme evolves along with its substrate for specialization and activity improvement.


Assuntos
Reação de Cicloadição , Catálise
17.
Imeta ; 2(1): e73, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38868335

RESUMO

Rather than a "short-term tenant," the tumor microbiome has been shown to play a vital role as a "permanent resident," affecting carcinogenesis, cancer development, metastasis, and cancer therapies. As the tumor microbiome has great potential to become a target for the early diagnosis and treatment of cancer, recent research on the relevance of the tumor microbiota has attracted a wide range of attention from various scientific fields, resulting in remarkable progress that benefits from the development of interdisciplinary technologies. However, there are still a great variety of challenges in this emerging area, such as the low biomass of intratumoral bacteria and unculturable character of some microbial species. Due to the complexity of tumor microbiome research (e.g., the heterogeneity of tumor microenvironment), new methods with high spatial and temporal resolution are urgently needed. Among these developing methods, multi-omics technologies (combinations of genomics, transcriptomics, proteomics, and metabolomics) are powerful approaches that can facilitate the understanding of the tumor microbiome on different levels of the central dogma. Therefore, multi-omics (especially single-cell omics) will make enormous impacts on the future studies of the interplay between microbes and tumor microenvironment. In this review, we have systematically summarized the advances in multi-omics and their existing and potential applications in tumor microbiome research, thus providing an omics toolbox for investigators to reference in the future.

18.
Molecules ; 27(20)2022 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-36296526

RESUMO

Cancer vaccines have been considered promising therapeutic strategies and are often constructed from whole cells, attenuated pathogens, carbohydrates, peptides, nucleic acids, etc. However, the use of whole organisms or pathogens can elicit unwanted immune responses arising from unforeseen reactions to the vaccine components. On the other hand, synthetic vaccines, which contain antigens that are conjugated, often with carrier proteins, can overcome these issues. Therefore, in this review we have highlighted the synthetic approaches and discussed several bioconjugation strategies for developing antigen-based cancer vaccines. In addition, the major synthetic biology approaches that were used to develop genetically modified cancer vaccines and their progress in clinical research are summarized here. Furthermore, to boost the immune responses of any vaccines, the addition of suitable adjuvants and a proper delivery system are essential. Hence, this review also mentions the synthesis of adjuvants and utilization of biomaterial scaffolds, which may facilitate the design of future cancer vaccines.


Assuntos
Vacinas Anticâncer , Neoplasias , Ácidos Nucleicos , Humanos , Biologia Sintética , Desenvolvimento de Vacinas , Vacinas Sintéticas , Neoplasias/prevenção & controle , Adjuvantes Imunológicos/farmacologia , Antígenos , Peptídeos/química , Carboidratos , Proteínas de Transporte , Materiais Biocompatíveis
19.
Chembiochem ; 23(22): e202200473, 2022 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-36125775

RESUMO

Bufadienolides are toxic components widely found in amphibious toads that exhibit a wide range of biological activities. Guided by UPLC-QTOF-MS analysis, several 3-epi-bufadienolides with unique structures were isolated from the bile of the Asiatic toad, Bufo gargarizans. However, the enzymatic machinery of this epimerization in toads and its significance in chemical ecology remains poorly understood. Herein, we firstly compared the toxicities of two typical bufadienolides, bufalin (featuring a 14ß-hydroxyl) and resibufogenin (containing a 14, 15-epoxy group), with their corresponding 3-epi isomers in a zebrafish model. The results of the toxicology assays showed that the ratio of maximum non-toxic concentrations of these two pairs of compounds are 256 and 96 times, respectively, thereby indicating that 3-hydroxyl epimerization leads to a significant decrease in toxicity. Aiming to investigate the biotransformation of 3-epi bufadienolides in toads, we applied liver lysate to transform bufalin and found that it could stereoselectively catalyze the conversion of bufalin into its 3α-hydroxyl epimer. Following this, we cloned and characterized a short-chain dehydrogenase/reductase, HSE-1, from the toad liver cDNA library and verified its 3(ß→α)-hydroxysteroid epimerization activity. To the best of our knowledge, this is the first hydroxyl epimerase identified from amphibians that regulates the toxicity of animal-derived natural products.


Assuntos
Bufanolídeos , Redutases-Desidrogenases de Cadeia Curta , Animais , Bufo bufo/metabolismo , Redutases-Desidrogenases de Cadeia Curta/metabolismo , Peixe-Zebra , Bufanolídeos/toxicidade , Bufanolídeos/química , Bufanolídeos/metabolismo , Catálise
20.
Front Oncol ; 12: 933407, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35936744

RESUMO

Accumulating recent evidence indicates that the human microbiome plays essential roles in pathophysiological states, including cancer. The tumor microbiome, an emerging concept that has not yet been clearly defined, has been proven to influence both cancer development and therapy through complex mechanisms. Small molecule metabolites produced by the tumor microbiome through unique biosynthetic pathways can easily diffuse into tissues and penetrate cell membranes through transporters or free diffusion, thus remodeling the signaling pathways of cancer and immune cells by interacting with biomacromolecules. Targeting tumor microbiome metabolism could offer a novel perspective for not only understanding cancer progression but also developing new strategies for the treatment of multiple cancer types. Here, we summarize recent advances regarding the role the tumor microbiome plays as a game changer in cancer biology. Specifically, the metabolites produced by the tumor microbiome and their potential effects on the cancer development therapy are discussed to understand the importance of the microbial metabolism in the tumor microenvironment. Finally, new anticancer therapeutic strategies that target tumor microbiome metabolism are reviewed and proposed to provide new insights in clinical applications.

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