Biochemical Journal最新文献_第10页

Engineering of CYP82Y1, a cytochrome P450 monooxygenase: a key enzyme in noscapine biosynthesis in opium poppy 细胞色素 P450 单加氧酶 CYP82Y1 的工程化：罂粟中诺卡品生物合成的关键酶

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2023-12-13 DOI: 10.1042/bcj20230243

Aghaali, Zahra, Naghavi, Mohammad Reza

{"title":"Engineering of CYP82Y1, a cytochrome P450 monooxygenase: a key enzyme in noscapine biosynthesis in opium poppy","authors":"Aghaali, Zahra, Naghavi, Mohammad Reza","doi":"10.1042/bcj20230243","DOIUrl":"https://doi.org/10.1042/bcj20230243","url":null,"abstract":"Protein engineering provides a powerful base for the circumvention of challenges tied with characteristics accountable for enzyme functions. CYP82Y1 introduces a hydroxyl group (−OH) into C1 of N-methylcanadine as the substrate to yield 1-hydroxy-N-methylcanadine. This chemical process has been found to be the gateway to noscapine biosynthesis. Owning to the importance of CYP82Y1 in this biosynthetic pathway, it has been selected as a target for enzyme engineering. The insertion of tags to the N- and C-terminal of CYP82Y1 was assessed for their efficiencies for improvement of the physiological performances of CYP82Y1. Although these attempts achieved some positive results, further strategies are required to dramatically enhance the CYP82Y1 activity. Here methods that have been adopted to achieve a functionally improved CYP82Y1 will be reviewed. In addition, the possibility of recruitment of other techniques having not yet been implemented in CYP82Y1 engineering, including the substitution of the residues located in the substrate recognition site, formation of the synthetic fusion proteins, and construction of the artificial lipid-based scaffold will be discussed. Given the fact that the pace of noscapine synthesis is constrained by the CYP82Y1-catalyzing step, the methods proposed here are capable of accelerating the rate of reaction performed by CYP82Y1 through improving its properties, resulting in the enhancement of noscapine accumulation.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"108 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138550625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Frequent loss-of-function mutations in the AMPK-α2 catalytic subunit suggest a tumour suppressor role in human skin cancers. AMPK-α2催化亚基频繁的功能缺失突变提示其在人类皮肤癌中具有肿瘤抑制作用。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2023-12-13 DOI: 10.1042/BCJ20230380

Fiona A Ross, Simon A Hawley, Fiona M Russell, Nicola Goodman, D Grahame Hardie

{"title":"Frequent loss-of-function mutations in the AMPK-α2 catalytic subunit suggest a tumour suppressor role in human skin cancers.","authors":"Fiona A Ross, Simon A Hawley, Fiona M Russell, Nicola Goodman, D Grahame Hardie","doi":"10.1042/BCJ20230380","DOIUrl":"10.1042/BCJ20230380","url":null,"abstract":"The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status activated by increases in AMP or ADP relative to ATP. Once activated, it phosphorylates targets that promote ATP-generating catabolic pathways or inhibit ATP-consuming anabolic pathways, helping to restore cellular energy balance. Analysis of human cancer genome studies reveals that the PRKAA2 gene (encoding the α2 isoform of the catalytic subunit) is often subject to mis-sense mutations in cancer, particularly in melanoma and non-melanoma skin cancers, where up to 70 mis-sense mutations have been documented, often accompanied by loss of the tumour suppressor NF1. Recently it has been reported that knockout of PRKAA2 in NF1-deficient melanoma cells promoted anchorage-independent growth in vitro, as well as growth as xenografts in immunodeficient mice in vivo, suggesting that AMPK-α2 can act as a tumour suppressor in that context. However, very few of the mis-sense mutations in PRKAA2 that occur in human skin cancer and melanoma have been tested to see whether they cause loss-of-function. We have addressed this by making most of the reported mutations and testing their activity when expressed in AMPK knockout cells. Of 55 different mis-sense mutations (representing 75 cases), 9 (12%) appeared to cause a total loss of activity, 18 (24%) a partial loss, 11 (15%) an increase in phenformin-stimulated kinase activity, while just 37 (49%) had no clear effect on kinase activity. This supports the idea that AMPK-α2 acts as a tumour suppressor in the context of human skin cancer.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1951-1968"},"PeriodicalIF":4.1,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10754287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92152588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Elucidating the interaction of C-terminal domain of Vaccinia-Related Kinase 2A (VRK2A) with B-cell lymphoma-extra Large (Bcl-xL) to decipher its anti-apoptotic role in cancer. 阐明疫苗相关激酶2A（VRK2A）的C末端结构域与B细胞大淋巴瘤（Bcl-xL）的相互作用，以阐明其在癌症中的抗凋亡作用。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2023-11-29 DOI: 10.1042/BCJ20230349

Rashmi Puja, Shubhankar Dutta, Kakoli Bose

{"title":"Elucidating the interaction of C-terminal domain of Vaccinia-Related Kinase 2A (VRK2A) with B-cell lymphoma-extra Large (Bcl-xL) to decipher its anti-apoptotic role in cancer.","authors":"Rashmi Puja, Shubhankar Dutta, Kakoli Bose","doi":"10.1042/BCJ20230349","DOIUrl":"10.1042/BCJ20230349","url":null,"abstract":"Vaccinia-Related Kinase 2 (VRK2) is an anti-apoptotic Ser/Thr kinase that enhances drug sensitivity in cancer cells. This protein exists in two isoforms: VRK2A, the longer variant, and VRK2B, which lacks the C-terminal region and transmembrane domain. While the therapeutic importance of VRK2 family proteins is known, the specific roles of VRK2A and its interplay with apoptotic regulator Bcl-xL (B-cell lymphoma-extra Large) remain elusive. Bcl-xL regulates cell death by interacting with BAX (B-cell lymphoma-2 Associated X-protein), controlling its cellular localization and influencing BAX-associated processes and signaling pathways. As VRK2A interacts with the Bcl-xL-BAX complex, comprehending its regulatory engagement with Bcl-xL presents potential avenues for intervening in diseases. Using a multi-disciplinary approach, this study provides information on the cellular localization of VRK2A and establishes its interaction with Bcl-xL in the cellular milieu, pinpointing the interacting site and elucidating its anti-apoptotic property within the complex. Furthermore, this study also put forth a model that highlights the importance of VRK2A in stabilizing the ternary complex, formed with Bcl-xL and BAX, thereby impeding BAX dissociation and hence apoptosis. Therefore, further investigations associated with this important revelation will provide cues for designing cancer therapeutics in the future.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1871-1885"},"PeriodicalIF":4.1,"publicationDate":"2023-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71520352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Elevated atmospheric carbon dioxide and plant immunity to fungal pathogens: do the risks outweigh the benefits? 大气中二氧化碳浓度升高和植物对真菌病原体的免疫力:弊大于利吗?

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2023-11-29 DOI: 10.1042/BCJ20230152

Freya Smith, Estrella Luna

{"title":"Elevated atmospheric carbon dioxide and plant immunity to fungal pathogens: do the risks outweigh the benefits?","authors":"Freya Smith, Estrella Luna","doi":"10.1042/BCJ20230152","DOIUrl":"10.1042/BCJ20230152","url":null,"abstract":"Anthropogenic emissions have caused atmospheric carbon dioxide (CO2) concentrations to double since the industrial revolution. Although this could benefit plant growth from the 'CO2 fertilisation' effect, recent studies report conflicting impacts of elevated CO2 (eCO2) on plant-pathogen interactions. Fungal pathogens are the leading cause of plant disease. Since climate change has been shown to affect the distribution and virulence of these pathogens, it is important to understand how their plant hosts may also respond. This review assesses existing reports of positive, negative, and neutral effects of eCO2 on plant immune responses to fungal pathogen infection. The interaction between eCO2 and immunity appears specific to individual pathosystems, dependent on environmental context and driven by the interactions between plant defence mechanisms, suggesting no universal effect can be predicted for the future. This research is vital for assessing how plants may become more at risk under climate change and could help to guide biotechnological efforts to enhance resistance in vulnerable species. Despite the importance of understanding the effects of eCO2 on plant immunity for protecting global food security, biodiversity, and forests in a changing climate, many plant-pathogen interactions are yet to be investigated. In addition, further research into the effects of eCO2 in combination with other environmental factors associated with climate change is needed. In this review, we highlight the risks of eCO2 to plants and point to the research required to address current unknowns.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"480 22","pages":"1791-1804"},"PeriodicalIF":4.1,"publicationDate":"2023-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10657175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136396021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Catalysis of non-canonical protein ubiquitylation by the ARIH1 ubiquitin ligase. ARIH1泛素连接酶对非规范蛋白泛素化的催化作用。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2023-11-29 DOI: 10.1042/BCJ20230373

Nicholas Purser, Ishita Tripathi-Giesgen, Jerry Li, Daniel C Scott, Daniel Horn-Ghetko, Kheewoong Baek, Brenda A Schulman, Arno F Alpi, Gary Kleiger

{"title":"Catalysis of non-canonical protein ubiquitylation by the ARIH1 ubiquitin ligase.","authors":"Nicholas Purser, Ishita Tripathi-Giesgen, Jerry Li, Daniel C Scott, Daniel Horn-Ghetko, Kheewoong Baek, Brenda A Schulman, Arno F Alpi, Gary Kleiger","doi":"10.1042/BCJ20230373","DOIUrl":"10.1042/BCJ20230373","url":null,"abstract":"Protein ubiquitylation typically involves isopeptide bond formation between the C-terminus of ubiquitin to the side-chain amino group on Lys residues. However, several ubiquitin ligases (E3s) have recently been identified that ubiquitylate proteins on non-Lys residues. For instance, HOIL-1 belongs to the RING-in-between RING (RBR) class of E3s and has an established role in Ser ubiquitylation. Given the homology between HOIL-1 and ARIH1, an RBR E3 that functions with the large superfamily of cullin-RING E3 ligases (CRLs), a biochemical investigation was undertaken, showing ARIH1 catalyzes Ser ubiquitylation to CRL-bound substrates. However, the efficiency of ubiquitylation was exquisitely dependent on the location and chemical environment of the Ser residue within the primary structure of the substrate. Comprehensive mutagenesis of the ARIH1 Rcat domain identified residues whose mutation severely impacted both oxyester and isopeptide bond formation at the preferred site for Ser ubiquitylation while only modestly affecting Lys ubiquitylation at the physiological site. The results reveal dual isopeptide and oxyester protein ubiquitylation activities of ARIH1 and set the stage for physiological investigations into this function of emerging importance.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1817-1831"},"PeriodicalIF":4.1,"publicationDate":"2023-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10657180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49688624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

PHF1 compartmentalizes PRC2 via phase separation. PHF1通过相分离来划分PRC2。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2023-11-29 DOI: 10.1042/BCJ20230040

Genzhe Lu, Pilong Li

引用次数: 0

Enzyme function and evolution through the lens of bioinformatics. 从生物信息学的角度看酶的功能和进化。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2023-11-29 DOI: 10.1042/BCJ20220405

Antonio J M Ribeiro, Ioannis G Riziotis, Neera Borkakoti, Janet M Thornton

{"title":"Enzyme function and evolution through the lens of bioinformatics.","authors":"Antonio J M Ribeiro, Ioannis G Riziotis, Neera Borkakoti, Janet M Thornton","doi":"10.1042/BCJ20220405","DOIUrl":"10.1042/BCJ20220405","url":null,"abstract":"Enzymes have been shaped by evolution over billions of years to catalyse the chemical reactions that support life on earth. Dispersed in the literature, or organised in online databases, knowledge about enzymes can be structured in distinct dimensions, either related to their quality as biological macromolecules, such as their sequence and structure, or related to their chemical functions, such as the catalytic site, kinetics, mechanism, and overall reaction. The evolution of enzymes can only be understood when each of these dimensions is considered. In addition, many of the properties of enzymes only make sense in the light of evolution. We start this review by outlining the main paradigms of enzyme evolution, including gene duplication and divergence, convergent evolution, and evolution by recombination of domains. In the second part, we overview the current collective knowledge about enzymes, as organised by different types of data and collected in several databases. We also highlight some increasingly powerful computational tools that can be used to close gaps in understanding, in particular for types of data that require laborious experimental protocols. We believe that recent advances in protein structure prediction will be a powerful catalyst for the prediction of binding, mechanism, and ultimately, chemical reactions. A comprehensive mapping of enzyme function and evolution may be attainable in the near future.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"480 22","pages":"1845-1863"},"PeriodicalIF":4.1,"publicationDate":"2023-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10754289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138290201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Loss of the methylarginine reader function of SND1 confers resistance to hepatocellular carcinoma. SND1甲基精氨酸读写器功能的丧失赋予了对肝细胞癌的耐药性。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2023-11-29 DOI: 10.1042/BCJ20230384

Tanner Wright, Yalong Wang, Sabrina A Stratton, Manu Sebastian, Bin Liu, David G Johnson, Mark T Bedford

{"title":"Loss of the methylarginine reader function of SND1 confers resistance to hepatocellular carcinoma.","authors":"Tanner Wright, Yalong Wang, Sabrina A Stratton, Manu Sebastian, Bin Liu, David G Johnson, Mark T Bedford","doi":"10.1042/BCJ20230384","DOIUrl":"10.1042/BCJ20230384","url":null,"abstract":"Staphylococcal nuclease Tudor domain containing 1 (SND1) protein is an oncogene that 'reads' methylarginine marks through its Tudor domain. Specifically, it recognizes methylation marks deposited by protein arginine methyltransferase 5 (PRMT5), which is also known to promote tumorigenesis. Although SND1 can drive hepatocellular carcinoma (HCC), it is unclear whether the SND1 Tudor domain is needed to promote HCC. We sought to identify the biological role of the SND1 Tudor domain in normal and tumorigenic settings by developing two genetically engineered SND1 mouse models, an Snd1 knockout (Snd1 KO) and an Snd1 Tudor domain-mutated (Snd1 KI) mouse, whose mutant SND1 can no longer recognize PRMT5-catalyzed methylarginine marks. Quantitative PCR analysis of normal, KO, and KI liver samples revealed a role for the SND1 Tudor domain in regulating the expression of genes encoding major acute phase proteins, which could provide mechanistic insight into SND1 function in a tumor setting. Prior studies indicated that ectopic overexpression of SND1 in the mouse liver dramatically accelerates the development of diethylnitrosamine (DEN)-induced HCC. Thus, we tested the combined effects of DEN and SND1 loss or mutation on the development of HCC. We found that both Snd1 KO and Snd1 KI mice were partially protected against malignant tumor development following exposure to DEN. These results support the development of small molecule inhibitors that target the SND1 Tudor domain or the use of upstream PRMT5 inhibitors, as novel treatments for HCC.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1805-1816"},"PeriodicalIF":4.4,"publicationDate":"2023-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10860161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71410432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Plant adaptation to climate change. 植物对气候变化的适应。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2023-11-29 DOI: 10.1042/BCJ20220580

Christine H Foyer, Ilse Kranner

引用次数: 0

Leukotriene B4 receptor 1 (BLT1) does not mediate disease progression in a mouse model of liver fibrosis. 白三烯B4受体1 (BLT1)在小鼠肝纤维化模型中不介导疾病进展。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2023-11-28 DOI: 10.1042/BCJ20230422

Erin Coyne, Yilin Nie, Desiree Abdurrachim, Charlene Lin Zhi Ong, Yongqi Zhou, Asad Abu Bakar Ali, Stacey Meyers, Jeff Grein, Wendy Blumenschein, Brendan Gongol, Yang Liu, Cedric Lorenz Hugelshofer, Ester Carballo-Jane, Saswata Talukdar

{"title":"Leukotriene B4 receptor 1 (BLT1) does not mediate disease progression in a mouse model of liver fibrosis.","authors":"Erin Coyne, Yilin Nie, Desiree Abdurrachim, Charlene Lin Zhi Ong, Yongqi Zhou, Asad Abu Bakar Ali, Stacey Meyers, Jeff Grein, Wendy Blumenschein, Brendan Gongol, Yang Liu, Cedric Lorenz Hugelshofer, Ester Carballo-Jane, Saswata Talukdar","doi":"10.1042/BCJ20230422","DOIUrl":"10.1042/BCJ20230422","url":null,"abstract":"MASH is a prevalent liver disease that can progress to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and ultimately death, but there are no approved therapies. Leukotriene B4 (LTB4) is a potent pro-inflammatory chemoattractant that drives macrophage and neutrophil chemotaxis, and genetic loss or inhibition of its high affinity receptor, leukotriene B4 receptor 1 (BLT1), results in improved insulin sensitivity and decreased hepatic steatosis. To validate the therapeutic efficacy of BLT1 inhibition in an inflammatory and pro-fibrotic mouse model of MASH and fibrosis, mice were challenged with a choline-deficient, L-amino acid defined high fat diet and treated with a BLT1 antagonist at 30 or 90 mg/kg for 8 weeks. Liver function, histology, and gene expression were evaluated at the end of the study. Treatment with the BLT1 antagonist significantly reduced plasma lipids and liver steatosis but had no impact on liver injury biomarkers or histological endpoints such as inflammation, ballooning, or fibrosis compared to control. Artificial intelligence-powered digital pathology analysis revealed a significant reduction in steatosis co-localized fibrosis in livers treated with the BLT1 antagonist. Liver RNA-seq and pathway analyses revealed significant changes in fatty acid, arachidonic acid, and eicosanoid metabolic pathways with BLT1 antagonist treatment, however, these changes were not sufficient to impact inflammation and fibrosis endpoints. Targeting this LTB4-BLT1 axis with a small molecule inhibitor in animal models of chronic liver disease should be considered with caution, and additional studies are warranted to understand the mechanistic nuances of BLT1 inhibition in the context of MASH and liver fibrosis.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138443690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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