IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-04-28 DOI: 10.1002/cbic.70344

Xue-Yan Wang, Yicheng Heng, Julian A Tanner, Simon Chi-Chin Shiu

引用次数: 0

Context-Dependent Chemoselectivity of Aromatic C-Methyltransferases. 芳香c -甲基转移酶的环境依赖性化学选择性。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-04-28 DOI: 10.1002/cbic.70294

Juliane Breiltgens, Ziruo Zou, Sascha Ferlaino, Jennifer N Andexer, Michael Müller

{"title":"Context-Dependent Chemoselectivity of Aromatic C-Methyltransferases.","authors":"Juliane Breiltgens, Ziruo Zou, Sascha Ferlaino, Jennifer N Andexer, Michael Müller","doi":"10.1002/cbic.70294","DOIUrl":"https://doi.org/10.1002/cbic.70294","url":null,"abstract":"S-adenosyl-l-methionine (SAM)-dependent methyltransferases (MTs) are generally classified as C-, O-, N-, S-, or halide MTs depending on their methyl acceptor. C-MTs catalyze selective methylation reactions of carbon nucleophiles and play a crucial role in the regulation and diversification of natural products. The control of chemoselectivity by these enzymes is poorly understood, especially with respect to the resonance of a nucleophilic neighboring group that activates the carbon methylation site. We investigated two aromatic C-MTs for the underlying mechanisms governing their chemo- and/or regioselectivity. The unprecedented in vitro dimethylation activity of SfmM2 and NapB5 was demonstrated using the native substrate l-tyrosine and substrates with a 2,4-dihydroxyacetophenone pattern, respectively. Substrate symmetry and the in situ SAM supply with removal of the competitive inhibitor S-adenosyl-l-homocysteine are favorable for dimethylation activity. Through NapB5 catalysis, we obtained C-(di-)methylated acetylphloroglucinol and flavonoid derivatives. We discovered that NapB5 catalyzes both C- and O-methylation of sterically demanding flavonoids. Here, chemoselectivity was modulated by the geometry of substrate binding through substrate selection or site-directed mutagenesis. Precise positioning of the acceptor nucleophile toward SAM is required to achieve regio- and chemoselectivity despite competing C- and O-nucleophilic sites. Thus, chemoselectivity is context-dependent, which opens new horizons for the diversification of natural products.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 8","pages":"e70294"},"PeriodicalIF":2.8,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Native Chemical Ligation at Phenylalanine via Ortho-Mercaptophenylalanine. 邻巯基苯丙氨酸在苯丙氨酸上的天然化学连接。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-04-28 DOI: 10.1002/cbic.70290

Christina R Forbes, Brice A Ludwig, Glenn P A Yap, Neal J Zondlo

{"title":"Native Chemical Ligation at Phenylalanine via Ortho-Mercaptophenylalanine.","authors":"Christina R Forbes, Brice A Ludwig, Glenn P A Yap, Neal J Zondlo","doi":"10.1002/cbic.70290","DOIUrl":"https://doi.org/10.1002/cbic.70290","url":null,"abstract":"Native chemical ligation (NCL) enables the synthesis of complex peptides and proteins. Prior work in NCL at phenylalanine (Phe) employed β-mercapto or β-seleno (alkyl) derivatives. Herein, we describe an alternative approach to NCL at Phe, via an aryl thiol on the novel Phe surrogate ortho-mercaptophenylalanine (2-mercaptophenylalanine). Commercially available Boc-2-iodo-phenylalanine was incorporated at the N-terminus of the peptide. A solid-phase copper mediated cross-coupling reaction with thioacetic acid was conducted on fully synthesized peptides with an N-terminal Boc-2-I-Phe to introduce, after TFA cleavage and deprotection, a nucleophilic aryl thiolate in the resultant N-terminal residue 2-mercaptophenylalanine (pKa = 5.1, substantially lower than alkyl thiols). Alternatively, 2-mercaptophenylalanine could be incorporated via the short synthesis of Boc-2-(S-tert-butyl)mercaptophenylalanine and coupling to peptide on resin. Peptides containing 2-mercaptophenylalanine rapidly underwent NCL reactions with peptides containing C-terminal thioesters. NCL reactions with the thioesters of Gly, Ala, Leu, and Phe were complete in 5 min1 h at room temperature at 0.52 mM peptide concentrations. Reactions with Val and Pro thioesters also proceeded in high yield, in 6 h and 12 h, respectively. NCL reactions with 2-mercaptophenylalanine also proceeded efficiently at pH 5. The peptide ligation product was desulfurized using nickel boride to generate phenylalanine. These results, using commercially available reagents and the possibility of amino acid synthesis on the solid phase which eliminates the requirement for solution-phase amino acid synthesis, represent a practical approach to NCL at phenylalanine.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 8","pages":"e70290"},"PeriodicalIF":2.8,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unspecific Peroxygenases-Catalyzed Oxidation of Pharmaceutical Compounds Considered Emerging Contaminants. 非特异性过氧酶-被认为是新兴污染物的药物化合物催化氧化。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-04-28 DOI: 10.1002/cbic.70351

Alina Torres-Aguirre, Azucena López-López, Mayra Avelar, Miguel Alcalde, Marcela Ayala

引用次数: 0

Heterologous Production of Barnesin A, an NRPS-PKS Hybrid Containing a Rare Vinylogous Arginine Moiety. 含有罕见葡萄精氨酸片段的NRPS-PKS杂交种Barnesin A的异源生产。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-04-28 DOI: 10.1002/cbic.70305

Sven Balluff, Marie Dayras, Christine Beemelmanns

{"title":"Heterologous Production of Barnesin A, an NRPS-PKS Hybrid Containing a Rare Vinylogous Arginine Moiety.","authors":"Sven Balluff, Marie Dayras, Christine Beemelmanns","doi":"10.1002/cbic.70305","DOIUrl":"10.1002/cbic.70305","url":null,"abstract":"Natural products containing vinylogous amino acids are rarely found in nature and often possess significant biological activity. Barnesin A was the first NP reported from an anaerobic bacterium (Sulfurospirillum barnesii) postulated to be biosynthesized by a nonribosomal peptide synthetase (NRPS) polyketide synthases (PKS) hybrid. Containing a vinylogous arginine moiety, the lipodipeptide exhibited nanomolar inhibitory activity against cysteine proteases. While a putative NRPS-PKS hybrid biosynthetic gene cluster (brn) was identified and a trans-acting acyltransferase (trans-AT) domain was postulated, experimental validation remained an open question. Here, we report the production of barnesin A by heterologous expression of the trans-AT domain-dependent NRPS-PKS gene cluster in Escherichia coli. Our findings indicate that the native primary metabolism-derived malonyl CoA-acyl carrier protein transacylase homolog (FabD) functions as a trans-AT in the biosynthesis pathway, while the NRPS-PKS megaenzyme exhibited strict selectivity toward its native phosphopantetheinyl transferase. Metabolome mining further allowed for the description of previously unreported barnesin congeners. The results of this study enabled the establishment of a biosynthetic platform for the generation of novel lipopeptidic vinylogous protease inhibitors.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 8","pages":"e70305"},"PeriodicalIF":2.8,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13096860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147727780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Binding Mode Analysis of Antifouling Compounds Targeting Tyrosinase and Acetylcholinesterase by Saturation Transfer Difference NMR Spectroscopy. 以酪氨酸酶和乙酰胆碱酯酶为靶点的防污化合物的结合模式分析。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-04-28 DOI: 10.1002/cbic.70311

Ana Sara Gomes, Mariana Andrade, Diana I S P Resende, Sara M Cravo, Emília Sousa, Marta Correia-da-Silva

{"title":"Binding Mode Analysis of Antifouling Compounds Targeting Tyrosinase and Acetylcholinesterase by Saturation Transfer Difference NMR Spectroscopy.","authors":"Ana Sara Gomes, Mariana Andrade, Diana I S P Resende, Sara M Cravo, Emília Sousa, Marta Correia-da-Silva","doi":"10.1002/cbic.70311","DOIUrl":"10.1002/cbic.70311","url":null,"abstract":"Ecofriendly and sustainable antifouling (AF) compounds are required to replace toxic additives in maritime AF coatings. Our group has developed synthetic AF compounds with anti-settlement activity toward Mytilus galloprovincialis mussel with nontoxic properties against this target organism. Some compounds have shown to be capable of modulating the activity of key enzymes involved in mussel settlement, namely, tyrosinase and acetylcholinesterase (AChE). The saturation transfer difference nuclear magnetic resonance (STD-NMR) technique is a powerful ligand-based approach to disclose the moieties responsible for binding to macromolecules in solution. This work aimed to study the binding mode of two AF compounds, a xanthone and a polyphenol, with tyrosinase and AChE, respectively, by using STD-NMR. The obtained results showed that the tyrosinase inhibitor exhibited an epitope map based on the hydroxylated aromatic ring, whereas the AChE inhibitor established interactions with both the aromatic ring and the aliphatic moiety. Further competition assays with established inhibitors, namely, kojic acid for tyrosinase and eserine for AChE, suggested that the xanthone derivative engages tyrosinase in a competitive manner, whereas the polyphenol interacts with AChE at sites distinct from the catalytic active site. These structural insights will help the rational design for optimized AF agents by targeting tyrosinase and AChE.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 8","pages":"e70311"},"PeriodicalIF":2.8,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13096763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147727800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanistic Insight into Conformational Control of Enzyme Activity by Genetically Encoded Metal-Responsive Switches. 基因编码金属响应开关对酶活性构象控制的机制研究。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-04-28 DOI: 10.1002/cbic.70349

Payal, Jonathan Thirman, Katherine A Edmonds, Sandip Mishra, Nathan Blackwell, Yasmine S Zubi, Benoît Roux, Jared C Lewis

{"title":"Mechanistic Insight into Conformational Control of Enzyme Activity by Genetically Encoded Metal-Responsive Switches.","authors":"Payal, Jonathan Thirman, Katherine A Edmonds, Sandip Mishra, Nathan Blackwell, Yasmine S Zubi, Benoît Roux, Jared C Lewis","doi":"10.1002/cbic.70349","DOIUrl":"https://doi.org/10.1002/cbic.70349","url":null,"abstract":"We previously introduced a genetically encoded, metal-responsive system for reversible control of protein function based on metal chelation by bipyridylalanine (BpyAla) residues. The efficacy of this linking group approach was demonstrated in two structurally and functionally distinct enzymes, Pyrococcus furiosus prolyl oligopeptidase (Pfu POP) and Photinus pyralis luciferase (Pluc). Here, we investigate the mechanistic basis of this switching in Pfu POP. Fluorescence-based metal competition assays and molecular dynamics (MD) simulations were conducted to quantify Ni(II) binding affinity and evaluate the structural response to Bpy2Ni(II) complex formation. 19F NMR spectroscopy and MD simulations further indicate that linking group-controlled conformational changes near the catalytic triad, particularly within the loop containing H592, drive the observed activity modulation upon metal binding. These findings establish that genetically encoded metal-binding motifs can regulate enzyme function through subtle, localized conformational changes, providing a versatile platform for engineering responsive protein systems in synthetic biology, biosensing, and programmable catalysis.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 8","pages":"e70349"},"PeriodicalIF":2.8,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13109687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Toward Sustainability: Intensification of Light-Driven Whole Cell Biocatalysis. 迈向可持续性：光驱动全细胞生物催化的强化。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-04-28 DOI: 10.1002/cbic.70320

Lenny Malihan-Yap, Pablo Domínguez de Maria, Robert Kourist

{"title":"Toward Sustainability: Intensification of Light-Driven Whole Cell Biocatalysis.","authors":"Lenny Malihan-Yap, Pablo Domínguez de Maria, Robert Kourist","doi":"10.1002/cbic.70320","DOIUrl":"https://doi.org/10.1002/cbic.70320","url":null,"abstract":"Photobiocatalysis with photoautotrophic whole cells has demonstrated strong potential for producing chiral molecules and platform chemicals using sustainable inputs such as light, water and CO2 under mild reaction conditions. Coupling enzymatic transformations directly to natural photosynthesis enables higher atom efficiency compared with heterotrophic systems. However, large-scale application remains challenging, particularly due to light attenuation in photobioreactors. In this review, we summarize recent advances in whole-cell photobiotransformations with emphasis on process conditions. We also discuss strategies for intensifying photobiocatalysis through improved reactor design and new immobilization materials, along with developments in fast-growing photoautotrophic strains. Sustainability analyses indicate that organic electron donors represent only one factor influencing environmental performance, and simply replacing them with photosynthetic water splitting does not inherently yield a carbon-negative process. Nonetheless, our calculations show that when high substrate loadings are combined with wastewater use and optimized downstream processing, photosynthesis-driven biotechnology can offer substantial reductions in CO2 emissions.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 8","pages":"e70320"},"PeriodicalIF":2.8,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13101868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reconstitution of Archaeal Membrane Lipid Biosynthesis in Bacterial and Eukaryotic Hosts. 细菌和真核生物宿主中古细菌膜脂生物合成的重构。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-04-28 DOI: 10.1002/cbic.202500981

Wenzhuo Li, Yizhou Luo, Shizhe Zhang, Jinze Li, Zhilai Hong, Tong Si, Wei Liu

{"title":"Reconstitution of Archaeal Membrane Lipid Biosynthesis in Bacterial and Eukaryotic Hosts.","authors":"Wenzhuo Li, Yizhou Luo, Shizhe Zhang, Jinze Li, Zhilai Hong, Tong Si, Wei Liu","doi":"10.1002/cbic.202500981","DOIUrl":"https://doi.org/10.1002/cbic.202500981","url":null,"abstract":"The membrane lipids of archaea differ from those of bacteria and eukarya in backbone stereochemical configuration, chemical linkage type, and hydrophobic chain structure, a fundamental dichotomy termed the lipid divide. Synthetic biology and metabolic engineering have enabled reconstruction of archaeal lipid biosynthesis pathways in bacterial and eukaryotic hosts, yielding production levels reaching 30% of membrane phospholipids in Escherichia coli and 6.5% of total cellular lipids in Saccharomyces cerevisiae. These achievements required coordinated expression of core archaeal enzymes combined with enhanced isoprenoid precursor supply. A recurring finding is that bacterial and eukaryotic enzymes exhibit remarkable substrate promiscuity toward archaeal lipid precursors, enabling biosynthesis of archaetidylglycerol, archaetidylethanolamine, and archaetidylinositol without requiring archaeal enzymes. This review examines the biosynthetic pathways, host systems, and engineering strategies underlying these advances. We consider how heterologous reconstitution informs longstanding questions about membrane evolution and the nature of the last universal common ancestor. Engineered strains with hybrid archaeal-bacterial membranes not only remain viable but also exhibit enhanced stress tolerance, demonstrating that the lipid divide does not preclude membrane coexistence while enabling biotechnological applications from stress-tolerant cell factories to archaeosome-based delivery systems.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 8","pages":"e202500981"},"PeriodicalIF":2.8,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of Secondary Nucleation Inhibitors of Amyloid-β Aggregation by Cellular Selection of a SICLOPPS Library. SICLOPPS文库筛选鉴定淀粉样蛋白-β聚集的二级成核抑制剂。

IF 2.8 4区生物学

ChemBioChem Pub Date : 2026-04-28 DOI: 10.1002/cbic.202500908

ByungUk Lee, Brian Flood, Emma Potter, Tina Wang

{"title":"Identification of Secondary Nucleation Inhibitors of Amyloid-β Aggregation by Cellular Selection of a SICLOPPS Library.","authors":"ByungUk Lee, Brian Flood, Emma Potter, Tina Wang","doi":"10.1002/cbic.202500908","DOIUrl":"10.1002/cbic.202500908","url":null,"abstract":"Alzheimer's disease is characterized by the accumulation of amyloid beta (Aβ) aggregates. Soluble oligomers Aβ oligomeric intermediates (AβOs) generated during aggregation are hypothesized to be a neurotoxic species. Many cyclic peptides have been developed to inhibit Aβ aggregation but primarily target Aβ monomers and fibrils; few cyclic peptides selectively recognize AβOs. We selected a library of >107 cyclic peptides generated by the widely used split-intein mediated circular ligation of peptides and proteins (SICLOPPS) strategy for binders of AβOs. These selections identified cyclo-CRLISFF, which significantly delayed Aβ42 aggregation in vitro but displayed a mechanism inconsistent with inhibitors selectively targeting AβOs. To resolve this discrepancy, we tested whether intermediates formed during SICLOPPS cyclic peptide generation might also possess AβO binding activity. Our experiments showed that the CRLISFF sequence was active as an intein-bound intermediate which selectively targeted AβOs by inhibiting the secondary nucleation step of the Aβ42 aggregation cascade. This intermediate has not been previously examined in studies employing SICLOPPS and may present a convoluting factor when using this technology to generate cyclic peptide libraries. The CRLISFF motif also retained activity when transplanted onto an unrelated protein scaffold, suggesting that SICLOPPS sequences may be compatible with peptide grafting strategies used to create protein-based binders.","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 8","pages":"e202500908"},"PeriodicalIF":2.8,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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