ACS Bio & Med Chem Au最新文献

{"title":"Hidden β-γ Dehydrogenation Products in Long-Chain Fatty Acid Oxidation Unveiled by NMR: Implications on Lipid Metabolism.","authors":"Simone Fabbian, Beatrice Masciovecchio, Elisabetta Schievano, Gabriele Giachin","doi":"10.1021/acsbiomedchemau.4c00140","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00140","url":null,"abstract":"<p><p>We present a comprehensive analysis of the initial α,β-dehydrogenation step in long-chain fatty acid β-oxidation (FAO). We focused on palmitoyl-CoA oxidized by two mitochondrial acyl-CoA dehydrogenases, very-long-chain acyl-CoA dehydrogenase (VLCAD) and acyl-CoA dehydrogenase family member 9 (ACAD9), both implicated in mitochondrial diseases. By combining MS and NMR, we identified the (2<i>E</i>)-hexadecenoyl-CoA as the expected α-β-dehydrogenation product and also the <i>E</i> and <i>Z</i> stereoisomers of 3-hexadecenoyl-CoA: a \"γ-oxidation\" product. This finding reveals an alternative catalytic pathway in mitochondrial FAO, suggesting a potential regulatory role for ACAD9 and VLCAD during fatty acid metabolism.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 2","pages":"262-267"},"PeriodicalIF":3.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12006827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hidden β-γ Dehydrogenation Products in Long-Chain Fatty Acid Oxidation Unveiled by NMR: Implications on Lipid Metabolism","authors":"Simone Fabbian,&nbsp;Beatrice Masciovecchio,&nbsp;Elisabetta Schievano and Gabriele Giachin*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0014010.1021/acsbiomedchemau.4c00140","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00140https://doi.org/10.1021/acsbiomedchemau.4c00140","url":null,"abstract":"<p >We present a comprehensive analysis of the initial α,β-dehydrogenation step in long-chain fatty acid β-oxidation (FAO). We focused on palmitoyl-CoA oxidized by two mitochondrial acyl-CoA dehydrogenases, very-long-chain acyl-CoA dehydrogenase (VLCAD) and acyl-CoA dehydrogenase family member 9 (ACAD9), both implicated in mitochondrial diseases. By combining MS and NMR, we identified the (2<i>E</i>)-hexadecenoyl-CoA as the expected α-β-dehydrogenation product and also the <i>E</i> and <i>Z</i> stereoisomers of 3-hexadecenoyl-CoA: a “γ-oxidation” product. This finding reveals an alternative catalytic pathway in mitochondrial FAO, suggesting a potential regulatory role for ACAD9 and VLCAD during fatty acid metabolism.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 2","pages":"262–267 262–267"},"PeriodicalIF":3.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00140","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143833093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Noncanonical Iron and 2-Oxoglutarate Dependent Enzymes Involved in C–C and C–N Bond Formation in Biosynthetic Pathways","authors":"Yaoyao Shen,&nbsp;Anyi Sun,&nbsp;Yisong Guo* and Wei-chen Chang*,&nbsp;","doi":"10.1021/acsbiomedchemau.5c0000110.1021/acsbiomedchemau.5c00001","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00001https://doi.org/10.1021/acsbiomedchemau.5c00001","url":null,"abstract":"<p >Iron and 2-oxoglutarate dependent (Fe/2OG) enzymes utilize an Fe^IV═O species to catalyze the functionalization of otherwise chemically inert C–H bonds. In addition to the more familiar canonical reactions of hydroxylation and chlorination, they also catalyze several other types of reactions that contribute to the diversity and complexity of natural products. In the past decade, several new Fe/2OG enzymes that catalyze C–C and C–N bond formation have been reported in the biosynthesis of structurally complex natural products. Compared with hydroxylation and chlorination, the catalytic cycles of these Fe/2OG enzymes involve distinct mechanistic features to enable noncanonical reaction outcomes. This Review summarizes recent discoveries of Fe/2OG enzymes involved in C–C and C–N bond formation with a focus on reaction mechanisms and their roles in natural product biosynthesis.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 2","pages":"238–261 238–261"},"PeriodicalIF":3.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.5c00001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Noncanonical Iron and 2-Oxoglutarate Dependent Enzymes Involved in C-C and C-N Bond Formation in Biosynthetic Pathways.","authors":"Yaoyao Shen, Anyi Sun, Yisong Guo, Wei-Chen Chang","doi":"10.1021/acsbiomedchemau.5c00001","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00001","url":null,"abstract":"<p><p>Iron and 2-oxoglutarate dependent (Fe/2OG) enzymes utilize an Fe^IV=O species to catalyze the functionalization of otherwise chemically inert C-H bonds. In addition to the more familiar canonical reactions of hydroxylation and chlorination, they also catalyze several other types of reactions that contribute to the diversity and complexity of natural products. In the past decade, several new Fe/2OG enzymes that catalyze C-C and C-N bond formation have been reported in the biosynthesis of structurally complex natural products. Compared with hydroxylation and chlorination, the catalytic cycles of these Fe/2OG enzymes involve distinct mechanistic features to enable noncanonical reaction outcomes. This Review summarizes recent discoveries of Fe/2OG enzymes involved in C-C and C-N bond formation with a focus on reaction mechanisms and their roles in natural product biosynthesis.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 2","pages":"238-261"},"PeriodicalIF":3.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12006828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biosynthetic Pathways of Alaremycin and Its Derivative: Inhibitors of Porphobilinogen Synthase in Porphyrin Biosynthesis from <i>Streptomyces</i> sp. A012304.","authors":"Mio Okui, Yuki Noto, Jun Kawaguchi, Noritaka Iwai, Masaaki Wachi","doi":"10.1021/acsbiomedchemau.5c00045","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00045","url":null,"abstract":"<p><p>The antibiotic alaremycin (5-acetamido-4-oxo-5-hexenoic acid, <b>1</b>), isolated from <i>Streptomyces</i> sp. A012304, structurally resembles 5-aminolevulinic acid (ALA), a precursor in porphyrin biosynthesis, and inhibits porphobilinogen synthase, the enzyme responsible for catalyzing the first common step of this pathway. In our previous study, the biosynthetic gene cluster responsible for alaremycin production-composed of <i>almA</i> (ALA synthase homologue), <i>almB</i> (<i>N</i>-acetyltransferase), <i>almC</i> (oxidoreductase), and <i>almE</i> (MFS-type transporter)-was identified, and a potential biosynthetic pathway was proposed. In this study, the biosynthetic pathway of <b>1</b> was confirmed by detecting intermediates using the liquid chromatography-mass spectrometry/MS (LC-MS/MS) analysis of extracts from <i>Escherichia coli</i> cells transformed with the biosynthetic genes, followed by <i>in vitro</i> reconstitution of the biosynthetic reactions using purified enzymes. AlmA catalyzed the condensation of l-serine and succinyl-CoA to produce 5-amino-6-hydroxy-4-oxohexanoic acid (<b>2</b>), AlmB catalyzed the <i>N</i>-acetylation of <b>2</b> to produce 5-acetamido-6-hydroxy-4-oxohexanoic acid (<b>3</b>), and AlmC catalyzed the dehydration of <b>3</b> to form <b>1</b>. The AlmC-catalyzed reaction may involve a two-step mechanism including reduction by NADH and oxidation by Fe³⁺. Additionally, a novel derivative of <b>1</b> was identified in the culture broth of the producer strain, and its structure was determined as 5,6-dihydroalaremycin (5-acetamido-4-oxohexanoic acid, <b>4</b>). It was revealed that <b>4</b> is synthesized via the same biosynthetic pathway but with AlmA and AlmB utilizing l-alanine as the amino acid precursor instead of l-serine.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 2","pages":"310-319"},"PeriodicalIF":3.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12006855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biosynthetic Pathways of Alaremycin and Its Derivative: Inhibitors of Porphobilinogen Synthase in Porphyrin Biosynthesis from Streptomyces sp. A012304","authors":"Mio Okui,&nbsp;Yuki Noto,&nbsp;Jun Kawaguchi,&nbsp;Noritaka Iwai and Masaaki Wachi*,&nbsp;","doi":"10.1021/acsbiomedchemau.5c0004510.1021/acsbiomedchemau.5c00045","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00045https://doi.org/10.1021/acsbiomedchemau.5c00045","url":null,"abstract":"<p >The antibiotic alaremycin (5-acetamido-4-oxo-5-hexenoic acid, <b>1</b>), isolated from <i>Streptomyces</i> sp. A012304, structurally resembles 5-aminolevulinic acid (ALA), a precursor in porphyrin biosynthesis, and inhibits porphobilinogen synthase, the enzyme responsible for catalyzing the first common step of this pathway. In our previous study, the biosynthetic gene cluster responsible for alaremycin production─composed of <i>almA</i> (ALA synthase homologue), <i>almB</i> (<i>N</i>-acetyltransferase), <i>almC</i> (oxidoreductase), and <i>almE</i> (MFS-type transporter)─was identified, and a potential biosynthetic pathway was proposed. In this study, the biosynthetic pathway of <b>1</b> was confirmed by detecting intermediates using the liquid chromatography–mass spectrometry/MS (LC-MS/MS) analysis of extracts from <i>Escherichia coli</i> cells transformed with the biosynthetic genes, followed by <i>in vitro</i> reconstitution of the biosynthetic reactions using purified enzymes. AlmA catalyzed the condensation of <span>l</span>-serine and succinyl-CoA to produce 5-amino-6-hydroxy-4-oxohexanoic acid (<b>2</b>), AlmB catalyzed the <i>N</i>-acetylation of <b>2</b> to produce 5-acetamido-6-hydroxy-4-oxohexanoic acid (<b>3</b>), and AlmC catalyzed the dehydration of <b>3</b> to form <b>1</b>. The AlmC-catalyzed reaction may involve a two-step mechanism including reduction by NADH and oxidation by Fe³⁺. Additionally, a novel derivative of <b>1</b> was identified in the culture broth of the producer strain, and its structure was determined as 5,6-dihydroalaremycin (5-acetamido-4-oxohexanoic acid, <b>4</b>). It was revealed that <b>4</b> is synthesized via the same biosynthetic pathway but with AlmA and AlmB utilizing <span>l</span>-alanine as the amino acid precursor instead of <span>l</span>-serine.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 2","pages":"310–319 310–319"},"PeriodicalIF":3.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.5c00045","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering Cell-Specific Protein Delivery Vehicles for Erythroid Lineage Cells","authors":"Mekedlawit T. Setegne,&nbsp;Aidan T. Cabral,&nbsp;Anushri Tiwari,&nbsp;Fangfang Shen,&nbsp;Hawa Racine Thiam and Laura M. K. Dassama*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0009810.1021/acsbiomedchemau.4c00098","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00098https://doi.org/10.1021/acsbiomedchemau.4c00098","url":null,"abstract":"<p >Biologics such as proteins, peptides, and oligonucleotides are powerful ligands to modulate challenging drug targets that lack readily accessible and “ligandable” pockets. However, the limited membrane permeance of biologics severely restricts their intracellular applications. Moreover, different cell types may exhibit varying levels of impermeability, and some delivery vehicles might be more sensitive to this variance. Erythroid lineage cells are especially challenging to deliver cargo to because of their unique cytoskeleton and the absence of endocytosis in mature erythrocytes. We recently employed a cell permeant miniature protein to deliver bioPROTACs to human umbilical cord blood derived erythroid progenitor cells (HUDEP-2) and primary hematopoietic stem (CD34⁺) cells (Shen et al., <cite><i>ACS Cent. Sci.</i></cite> <span>2022</span>, <em>8</em>, 1695−1703). While successful, the low efficiency of delivery and lack of cell-type specificity limit use of bioPROTACs <i>in vivo</i>. In this work, we thoroughly evaluated the performance of various recently reported cell penetrating peptides (CPPs), CPP additives, bacterial toxins, and contractile injection systems for their ability to deliver cargo to erythroid precursor cells. We also explored how targeting receptors enriched on the erythroid cell surface might improve the efficiencies and specificities of these delivery vehicles. Our results reveal that certain vehicles exhibit improved efficiencies when directed to cell surface receptors while others do not benefit from this targeting strategy. Together, these findings advance our understanding of protein delivery to challenging cell types and illustrate some of the intricacies of cell-surface receptor targeting.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 2","pages":"268–282 268–282"},"PeriodicalIF":3.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00098","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering Cell-Specific Protein Delivery Vehicles for Erythroid Lineage Cells.","authors":"Mekedlawit T Setegne, Aidan T Cabral, Anushri Tiwari, Fangfang Shen, Hawa Racine Thiam, Laura M K Dassama","doi":"10.1021/acsbiomedchemau.4c00098","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00098","url":null,"abstract":"<p><p>Biologics such as proteins, peptides, and oligonucleotides are powerful ligands to modulate challenging drug targets that lack readily accessible and \"ligandable\" pockets. However, the limited membrane permeance of biologics severely restricts their intracellular applications. Moreover, different cell types may exhibit varying levels of impermeability, and some delivery vehicles might be more sensitive to this variance. Erythroid lineage cells are especially challenging to deliver cargo to because of their unique cytoskeleton and the absence of endocytosis in mature erythrocytes. We recently employed a cell permeant miniature protein to deliver bioPROTACs to human umbilical cord blood derived erythroid progenitor cells (HUDEP-2) and primary hematopoietic stem (CD34⁺) cells (Shen et al., ACS Cent. Sci.2022, 8, 1695-1703). While successful, the low efficiency of delivery and lack of cell-type specificity limit use of bioPROTACs <i>in vivo</i>. In this work, we thoroughly evaluated the performance of various recently reported cell penetrating peptides (CPPs), CPP additives, bacterial toxins, and contractile injection systems for their ability to deliver cargo to erythroid precursor cells. We also explored how targeting receptors enriched on the erythroid cell surface might improve the efficiencies and specificities of these delivery vehicles. Our results reveal that certain vehicles exhibit improved efficiencies when directed to cell surface receptors while others do not benefit from this targeting strategy. Together, these findings advance our understanding of protein delivery to challenging cell types and illustrate some of the intricacies of cell-surface receptor targeting.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 2","pages":"268-282"},"PeriodicalIF":3.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12006860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Celebrating 5 Years of the ACS Au Journal Family.","authors":"Paul D Goring, Amelia Newman, Christopher W Jones, Shelley D Minteer","doi":"10.1021/acsbiomedchemau.5c00042","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00042","url":null,"abstract":"","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 2","pages":"235-237"},"PeriodicalIF":3.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12006849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Celebrating 5 Years of the ACS Au Journal Family","authors":"Paul D. Goring,&nbsp;Amelia Newman,&nbsp;Christopher W. Jones* and Shelley D. Minteer*,&nbsp;","doi":"10.1021/acsbiomedchemau.5c0004210.1021/acsbiomedchemau.5c00042","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00042https://doi.org/10.1021/acsbiomedchemau.5c00042","url":null,"abstract":"","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 2","pages":"235–237 235–237"},"PeriodicalIF":3.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.5c00042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}