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Nature Jun 2022Branched fatty acid (FA) esters of hydroxy FAs (HFAs; FAHFAs) are recently discovered lipids that are conserved from yeast to mammals. A subfamily, palmitic acid esters...
Branched fatty acid (FA) esters of hydroxy FAs (HFAs; FAHFAs) are recently discovered lipids that are conserved from yeast to mammals. A subfamily, palmitic acid esters of hydroxy stearic acids (PAHSAs), are anti-inflammatory and anti-diabetic. Humans and mice with insulin resistance have lower PAHSA levels in subcutaneous adipose tissue and serum. PAHSA administration improves glucose tolerance and insulin sensitivity and reduces inflammation in obesity, diabetes and immune-mediated diseases. The enzyme(s) responsible for FAHFA biosynthesis in vivo remains unknown. Here we identified adipose triglyceride lipase (ATGL, also known as patatin-like phospholipase domain containing 2 (PNPLA2)) as a candidate biosynthetic enzyme for FAHFAs using chemical biology and proteomics. We discovered that recombinant ATGL uses a transacylation reaction that esterifies an HFA with a FA from triglyceride (TG) or diglyceride to produce FAHFAs. Overexpression of wild-type, but not catalytically dead, ATGL increases FAHFA biosynthesis. Chemical inhibition of ATGL or genetic deletion of Atgl inhibits FAHFA biosynthesis and reduces the levels of FAHFA and FAHFA-TG. Levels of endogenous and nascent FAHFAs and FAHFA-TGs are 80-90 per cent lower in adipose tissue of mice in which Atgl is knocked out specifically in the adipose tissue. Increasing TG levels by upregulating diacylglycerol acyltransferase (DGAT) activity promotes FAHFA biosynthesis, and decreasing DGAT activity inhibits it, reinforcing TGs as FAHFA precursors. ATGL biosynthetic transacylase activity is present in human adipose tissue underscoring its potential clinical relevance. In summary, we discovered the first, to our knowledge, biosynthetic enzyme that catalyses the formation of the FAHFA ester bond in mammals. Whereas ATGL lipase activity is well known, our data establish a paradigm shift demonstrating that ATGL transacylase activity is biologically important.
Topics: Acyltransferases; Adipose Tissue; Animals; Diglycerides; Esterification; Esters; Fatty Acids; Humans; Hydroxy Acids; Insulin Resistance; Mice; Triglycerides
PubMed: 35676490
DOI: 10.1038/s41586-022-04787-x -
Drug Development Research Feb 2019The rise of antibiotic resistance necessitates the search for new platforms for drug development. Prodrugs are common tools for overcoming drawbacks typically associated... (Review)
Review
The rise of antibiotic resistance necessitates the search for new platforms for drug development. Prodrugs are common tools for overcoming drawbacks typically associated with drug formulation and delivery, with ester prodrugs providing a classic strategy for masking polar alcohol and carboxylic acid functionalities and improving cell permeability. Ester prodrugs are normally designed to have simple ester groups, as they are expected to be cleaved and reactivated by a wide spectrum of cellular esterases. However, a number of pathogenic and commensal microbial esterases have been found to possess significant substrate specificity and can play an unexpected role in drug metabolism. Ester protection can also introduce antimicrobial properties into previously nontoxic drugs through alterations in cell permeability or solubility. Finally, mutation to microbial esterases is a novel mechanism for the development of antibiotic resistance. In this review, we highlight the important pathogenic and xenobiotic functions of microbial esterases and discuss the development and application of ester prodrugs for targeting microbial infections and combating antibiotic resistance. Esterases are often overlooked as therapeutic targets. Yet, with the growing need to develop new antibiotics, a thorough understanding of the specificity and function of microbial esterases and their combined action with ester prodrug antibiotics will support the design of future therapeutics.
Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Microbial; Esterases; Esters; Humans; Prodrugs; Protein Structure, Secondary; Protein Structure, Tertiary
PubMed: 30302779
DOI: 10.1002/ddr.21468 -
Molecules (Basel, Switzerland) Jan 2019Over the past few decades, transition metal catalysis has witnessed a rapid and extensive development. The discovery and development of cross-coupling reactions is... (Review)
Review
Over the past few decades, transition metal catalysis has witnessed a rapid and extensive development. The discovery and development of cross-coupling reactions is considered to be one of the most important advancements in the field of organic synthesis. The design and synthesis of well-defined and bench-stable transition metal pre-catalysts provide a significant improvement over the current catalytic systems in cross-coupling reactions, avoiding excess use of expensive ligands and harsh conditions for the synthesis of pharmaceuticals, agrochemicals and materials. Among various well-defined pre-catalysts, the use of Pd(II)-NHC, particularly, provided new avenues to expand the scope of cross-coupling reactions incorporating unreactive electrophiles, such as amides and esters. The strong σ-donation and tunable steric bulk of NHC ligands in Pd-NHC complexes facilitate oxidative addition and reductive elimination steps enabling the cross-coupling of broad range of amides and esters using facile conditions contrary to the arduous conditions employed under traditional catalytic conditions. Owing to the favorable catalytic activity of Pd-NHC catalysts, a tremendous progress was made in their utilization for cross-coupling reactions via selective acyl C⁻X (X=N, O) bond cleavage. This review highlights the recent advances made in the utilization of well-defined pre-catalysts for C⁻C and C⁻N bond forming reactions via selective amide and ester bond cleavage.
Topics: Amides; Catalysis; Chemistry Techniques, Synthetic; Esters; Ligands; Molecular Structure; Oxidation-Reduction; Palladium
PubMed: 30634382
DOI: 10.3390/molecules24020215 -
Archiv Der Pharmazie Nov 2022Based on a previously reported 1,4-dihydropyridinebutyrolactone virtual screening hit, nine lactone ring-opened ester and seven amide analogs were prepared. The analogs...
Based on a previously reported 1,4-dihydropyridinebutyrolactone virtual screening hit, nine lactone ring-opened ester and seven amide analogs were prepared. The analogs were designed to provide interactions with residues at the entrance of the ZA loop of the testis-specific bromodomain (ZA) channel to enhance the affinity and selectivity for the bromodomain and extra-terminal (BET) subfamily of bromodomains. Compound testing by AlphaScreen showed that neither the affinity nor the selectivity of the ester and lactam analogs was improved for BRD4-1 and the first bromodomain of the testis-specific bromodomain (BRDT-1). The esters retained affinity comparable to the parent compound, whereas the affinity for the amide analogs was reduced 10-fold. A representative benzyl ester analog was found to retain high selectivity for BET bromodomains as shown by a BROMOscan. X-ray analysis of the allyl ester analog in complex with BRD4-1 and BRDT-1 revealed that the ester side chain is located next to the ZA loop and solvent exposed.
Topics: Humans; Male; Amides; Cell Cycle Proteins; Esters; Nuclear Proteins; Structure-Activity Relationship; Transcription Factors; Lactones
PubMed: 35941525
DOI: 10.1002/ardp.202200288 -
Applied and Environmental Microbiology Jan 2020Steryl esters (SEs) are important storage compounds in many eukaryotes and are often prominent components of intracellular lipid droplets. Here, we demonstrate that...
Steryl esters (SEs) are important storage compounds in many eukaryotes and are often prominent components of intracellular lipid droplets. Here, we demonstrate that selected - and growing on sterols are also able to synthesize SEs and to sequester them in cytoplasmic lipid droplets. We found cholesteryl ester (CE) formation in members of the actinobacterial genera , , and , as well as several members of the proteobacterial order. CEs maximally accumulated under nitrogen-limiting conditions, suggesting that steryl ester formation plays a crucial role for storing excess energy and carbon under adverse conditions. RHA1 was able to synthesize phytosteryl and cholesteryl esters, the latter reaching up to 7% of its cellular dry weight and 69% of its lipid droplets. Purified lipid droplets from RHA1 contained CEs, free cholesterol, and triacylglycerols. In addition, we found formation of CEs in when it was grown with cholesterol plus an additional fatty acid substrate. This study provides a basis for the application of bacterial whole-cell systems in the biotechnological production of SEs for use in functional foods and cosmetics. Oleaginous bacteria exhibit great potential for the production of high-value neutral lipids, such as triacylglycerols and wax esters. This study describes the formation of steryl esters (SEs) as neutral lipid storage compounds in sterol-degrading oleaginous bacteria, providing a basis for biotechnological production of SEs using bacterial systems with potential applications in the functional food, nutraceutical, and cosmetic industries. We found cholesteryl ester (CE) formation in several sterol-degrading - and under nitrogen-limiting conditions, suggesting an important role of this process in storing energy and carbon under adverse conditions. In addition, grown on cholesterol accumulated CEs in the presence of an additional fatty acid substrate.
Topics: Bacteria; Esters; Lipid Droplets; Steroids; Sterols
PubMed: 31704679
DOI: 10.1128/AEM.02353-19 -
International Journal of Molecular... Dec 2021Resveratrol butyrate ester (RBE) complexes have demonstrated higher antioxidant capacity and anti-fat accumulation activity in previous studies. In this study, silica...
Resveratrol butyrate ester (RBE) complexes have demonstrated higher antioxidant capacity and anti-fat accumulation activity in previous studies. In this study, silica gel, high-performance liquid chromatography, and 1H nuclear magnetic resonance were used for separation and identification of RBE complex components. With the exception of resveratrol, five different structures of ester derivatives were separated from silica gel: 3,4'-di-O-butanoylresveratrol (ED2, 18.8%), 3-O-butanoylresveratrol (ED4, 35.7%), 4'-O-butanoylresveratrol (ED5, 4.4%), 3,5,4'-tri-O-butanoylresveratrol (ED6, 1.5%), and 3,5-di-O-butanoylresveratrol (ED7, 0.7%). Among the ester derivatives obtained, ED2 and ED4 were the main ester derivatives in the RBE complex. Thus, the cellular antioxidant activities of the RBE mixture, ED2, and ED4 were evaluated. Results showed that the antioxidant capacity of ED2 and ED4 was higher than that of the RBE mixture, demonstrating that the number and position of butyrate esterification sites are related to cell survival rate and antioxidant capacity. This study is the first to report the successful isolation, structural identification, and cellular biological antioxidant activity of RBE complex derivatives, which are key characteristics for the potential practical application of RBE complexes.
Topics: Antioxidants; Butyrates; Chromatography, High Pressure Liquid; Esters; Hep G2 Cells; Humans; Proton Magnetic Resonance Spectroscopy; Resveratrol
PubMed: 34948341
DOI: 10.3390/ijms222413539 -
Bioorganic & Medicinal Chemistry Jan 2023In cancer cells, glutaminolysis is the primary source of biosynthetic precursors. Recent efforts to develop amino acid analogues to inhibit glutamine metabolism in...
In cancer cells, glutaminolysis is the primary source of biosynthetic precursors. Recent efforts to develop amino acid analogues to inhibit glutamine metabolism in cancer have been extensive. Our lab recently discovered many L-γ-methyleneglutamic acid amides that were shown to be as efficacious as tamoxifen or olaparib in inhibiting the cell growth of MCF-7, SK-BR-3, and MDA-MB-231 breast cancer cells after 24 or 72 h of treatment. None of these compounds inhibited the cell growth of nonmalignant MCF-10A breast cells. These L-γ-methyleneglutamic acid amides hold promise as novel therapeutics for the treatment of multiple subtypes of breast cancer. Herein, we report our synthesis and evaluation of two series of tert-butyl ester and ethyl ester prodrugs of these L-γ-methyleneglutamic acid amides and the cyclic metabolite and its tert-butyl esters and ethyl esters on the three breast cancer cell lines MCF-7, SK-BR-3, and MDA-MB-231 and the nonmalignant MCF-10A breast cell line. These esters were found to suppress the growth of the breast cancer cells, but they were less potent compared to the L-γ-methyleneglutamic acid amides. Pharmacokinetic (PK) studies were carried out on the lead L-γ-methyleneglutamic acid amide to establish tissue-specific distribution and other PK parameters. Notably, this lead compound showed moderate exposure to the brain with a half-life of 0.74 h and good tissue distribution, such as in the kidney and liver. Therefore, the L-γ-methyleneglutamic acid amides were then tested on glioblastoma cell lines BNC3 and BNC6 and head and neck cancer cell lines HN30 and HN31. They were found to effectively suppress the growth of these cancer cell lines after 24 or 72 h of treatment in a concentration-dependent manner. These results suggest broad applications of the L-γ-methyleneglutamic acid amides in anticancer therapy.
Topics: Humans; Female; Amides; Prodrugs; Esters; Amino Acids; Breast Neoplasms; Cell Line, Tumor
PubMed: 36603398
DOI: 10.1016/j.bmc.2022.117137 -
Journal of Experimental Botany May 2022Wax esters are high-value compounds used as feedstocks for the production of lubricants, pharmaceuticals, and cosmetics. Currently, they are produced mostly from fossil... (Review)
Review
Wax esters are high-value compounds used as feedstocks for the production of lubricants, pharmaceuticals, and cosmetics. Currently, they are produced mostly from fossil reserves using chemical synthesis, but this cannot meet increasing demand and has a negative environmental impact. Natural wax esters are also obtained from Simmondsia chinensis (jojoba) but comparably in very low amounts and expensively. Therefore, metabolic engineering of plants, especially of the seed storage lipid metabolism of oil crops, represents an attractive strategy for renewable, sustainable, and environmentally friendly production of wax esters tailored to industrial applications. Utilization of wax ester-synthesizing enzymes with defined specificities and modulation of the acyl-CoA pools by various genetic engineering approaches can lead to obtaining wax esters with desired compositions and properties. However, obtaining high amounts of wax esters is still challenging due to their negative impact on seed germination and yield. In this review, we describe recent progress in establishing non-food-plant platforms for wax ester production and discuss their advantages and limitations as well as future prospects.
Topics: Esters; Lubricants; Metabolic Engineering; Plants, Genetically Modified; Waxes
PubMed: 35560197
DOI: 10.1093/jxb/erac046 -
Molecules (Basel, Switzerland) Oct 2018Amide bonds are the most prevalent structures found in organic molecules and various biomolecules such as peptides, proteins, DNA, and RNA. The unique feature of amide... (Review)
Review
Amide bonds are the most prevalent structures found in organic molecules and various biomolecules such as peptides, proteins, DNA, and RNA. The unique feature of amide bonds is their ability to form resonating structures, thus, they are highly stable and adopt particular three-dimensional structures, which, in turn, are responsible for their functions. The main focus of this review article is to report the methodologies for the activation of the unactivated amide bonds present in biomolecules, which includes the enzymatic approach, metal complexes, and non-metal based methods. This article also discusses some of the applications of amide bond activation approaches in the sequencing of proteins and the synthesis of peptide acids, esters, amides, and thioesters.
Topics: Acids; Amides; Biological Products; Esters; Molecular Conformation
PubMed: 30322008
DOI: 10.3390/molecules23102615 -
Chemical & Pharmaceutical Bulletin 2017A series of cinnamic acid derivatives, amides (1-12) and esters (13-22), were synthesized, and structure-activity relationships for antioxidant activity, and monoamine...
Synthesis of Amide and Ester Derivatives of Cinnamic Acid and Its Analogs: Evaluation of Their Free Radical Scavenging and Monoamine Oxidase and Cholinesterase Inhibitory Activities.
A series of cinnamic acid derivatives, amides (1-12) and esters (13-22), were synthesized, and structure-activity relationships for antioxidant activity, and monoamine oxidases (MAO) A and B, acetylcholinesterase, and butyrylcholinesterase (BChE) inhibitory activities were analyzed. Among the synthesized compounds, compounds 1-10, 12-18, and rosmarinic acid (23), which contained catechol, o-methoxyphenol or 5-hydroxyindole moieties, showed potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity. Compounds 9-11, 15, 17-22 showed potent and selective MAO-B inhibitory activity. Compound 20 was the most potent inhibitor of MAO-B. Compounds 18 and 21 showed moderate BChE inhibitory activity. In addition, compound 18 showed potent antioxidant activity and MAO-B inhibitory activity. In a comparison of the cinnamic acid amides and esters, the amides exhibited more potent DPPH free radical scavenging activity, while the esters showed stronger inhibitory activities against MAO-B and BChE. These results suggested that cinnamic acid derivatives such as compound 18, p-coumaric acid 3,4-dihydroxyphenethyl ester, and compound 20, p-coumaric acid phenethyl ester, may serve as lead compounds for the development of novel MAO-B inhibitors and candidate lead compounds for the prevention or treatment of Alzheimer's disease.
Topics: Acetylcholinesterase; Amides; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Cinnamates; Dose-Response Relationship, Drug; Esters; Horses; Humans; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Structure-Activity Relationship
PubMed: 29093288
DOI: 10.1248/cpb.c17-00416