Gunter Maubach, Michelle C. C. Lim, Michael Naumann
{"title":"发现跨王国的β-D-甘露庚糖生物合成酶：ALPK1/NF-κB 依赖性免疫反应的新型激动剂","authors":"Gunter Maubach, Michelle C. C. Lim, Michael Naumann","doi":"10.1038/s41392-024-02003-y","DOIUrl":null,"url":null,"abstract":"<p>A recent study by Tang et al. <sup>1</sup> in <i>Science</i> reveals the cross-kingdom widespread occurrence of functional nucleotide-diphosphate (NDP)-heptose biosynthetic enzymes (HBEs) that accounts for the synthesis of NDP-heptoses to activate the alpha-protein kinase 1 (ALPK1)-dependent innate immune response. This study not only highlights the importance of the metabolite β-D-<i>manno</i>-heptose as pathogen-associated molecular patterns (PAMPs) but also raises the question of possibly other biological roles, especially in the different kingdoms (Fig. 1).</p><figure><figcaption><b data-test=\"figure-caption-text\">Fig. 1</b></figcaption><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-024-02003-y/MediaObjects/41392_2024_2003_Fig1_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure 1\" aria-describedby=\"Fig1\" height=\"511\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-024-02003-y/MediaObjects/41392_2024_2003_Fig1_HTML.png\" width=\"685\"/></picture><p>New findings on NDP-heptoses as agonists for the immune response. Small molecule metabolites such as ADP-heptose are synthesized by HBEs exhibiting isomerase, kinase, phosphatase, and nucleotidyltransferase activities. Of note, three subgroups of HBEs with nucleotidyltransferase activity (HENases) exist, exhibiting solely this activity or combined with kinase, or isomerase/kinase activities. In bacteria, where HBEs were first reported, they catalyzed the four-step biosynthesis of ADP-heptose starting from D-sedoheptulose 7-phosphate. Functional HBEs are prevalent in bacteria, archaea, viruses, and some eukaryotes. The authors discovered the presence of a widely conserved arginine residue at the fifth N-terminal position of the (F/L)XXGXSTT motif (STT<sub>R5</sub>) in HENases that enable them to synthesize also CDP- and UDP-heptoses. A striking feature of the NDP-heptoses is their ability to act as immunostimulants. Pathogenic organisms deliver NDP-heptoses into mammalian cells, where they are detected by ALPK1, triggering its kinase activity. The ensuing TIFA phosphorylation initiates a signaling cascade to activate NF-κB, leading to the release of cytokines and chemokines that result in the recruitment of immune cells. In addition, NDP-heptoses could also serve as building blocks for protein glycosylation, or the production of LPS or antibiotics. The figure is created with BioRender.com</p><span>Full size image</span><svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-chevron-right-small\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></figure>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":40.8000,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of biosynthetic enzymes for β-D-manno-heptoses across kingdoms: novel agonists for ALPK1/NF-κB-dependent immune response\",\"authors\":\"Gunter Maubach, Michelle C. C. 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This study not only highlights the importance of the metabolite β-D-<i>manno</i>-heptose as pathogen-associated molecular patterns (PAMPs) but also raises the question of possibly other biological roles, especially in the different kingdoms (Fig. 1).</p><figure><figcaption><b data-test=\\\"figure-caption-text\\\">Fig. 1</b></figcaption><picture><source srcset=\\\"//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-024-02003-y/MediaObjects/41392_2024_2003_Fig1_HTML.png?as=webp\\\" type=\\\"image/webp\\\"/><img alt=\\\"figure 1\\\" aria-describedby=\\\"Fig1\\\" height=\\\"511\\\" loading=\\\"lazy\\\" src=\\\"//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-024-02003-y/MediaObjects/41392_2024_2003_Fig1_HTML.png\\\" width=\\\"685\\\"/></picture><p>New findings on NDP-heptoses as agonists for the immune response. Small molecule metabolites such as ADP-heptose are synthesized by HBEs exhibiting isomerase, kinase, phosphatase, and nucleotidyltransferase activities. Of note, three subgroups of HBEs with nucleotidyltransferase activity (HENases) exist, exhibiting solely this activity or combined with kinase, or isomerase/kinase activities. In bacteria, where HBEs were first reported, they catalyzed the four-step biosynthesis of ADP-heptose starting from D-sedoheptulose 7-phosphate. Functional HBEs are prevalent in bacteria, archaea, viruses, and some eukaryotes. The authors discovered the presence of a widely conserved arginine residue at the fifth N-terminal position of the (F/L)XXGXSTT motif (STT<sub>R5</sub>) in HENases that enable them to synthesize also CDP- and UDP-heptoses. A striking feature of the NDP-heptoses is their ability to act as immunostimulants. Pathogenic organisms deliver NDP-heptoses into mammalian cells, where they are detected by ALPK1, triggering its kinase activity. The ensuing TIFA phosphorylation initiates a signaling cascade to activate NF-κB, leading to the release of cytokines and chemokines that result in the recruitment of immune cells. In addition, NDP-heptoses could also serve as building blocks for protein glycosylation, or the production of LPS or antibiotics. 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Discovery of biosynthetic enzymes for β-D-manno-heptoses across kingdoms: novel agonists for ALPK1/NF-κB-dependent immune response
A recent study by Tang et al. 1 in Science reveals the cross-kingdom widespread occurrence of functional nucleotide-diphosphate (NDP)-heptose biosynthetic enzymes (HBEs) that accounts for the synthesis of NDP-heptoses to activate the alpha-protein kinase 1 (ALPK1)-dependent innate immune response. This study not only highlights the importance of the metabolite β-D-manno-heptose as pathogen-associated molecular patterns (PAMPs) but also raises the question of possibly other biological roles, especially in the different kingdoms (Fig. 1).
Fig. 1
New findings on NDP-heptoses as agonists for the immune response. Small molecule metabolites such as ADP-heptose are synthesized by HBEs exhibiting isomerase, kinase, phosphatase, and nucleotidyltransferase activities. Of note, three subgroups of HBEs with nucleotidyltransferase activity (HENases) exist, exhibiting solely this activity or combined with kinase, or isomerase/kinase activities. In bacteria, where HBEs were first reported, they catalyzed the four-step biosynthesis of ADP-heptose starting from D-sedoheptulose 7-phosphate. Functional HBEs are prevalent in bacteria, archaea, viruses, and some eukaryotes. The authors discovered the presence of a widely conserved arginine residue at the fifth N-terminal position of the (F/L)XXGXSTT motif (STTR5) in HENases that enable them to synthesize also CDP- and UDP-heptoses. A striking feature of the NDP-heptoses is their ability to act as immunostimulants. Pathogenic organisms deliver NDP-heptoses into mammalian cells, where they are detected by ALPK1, triggering its kinase activity. The ensuing TIFA phosphorylation initiates a signaling cascade to activate NF-κB, leading to the release of cytokines and chemokines that result in the recruitment of immune cells. In addition, NDP-heptoses could also serve as building blocks for protein glycosylation, or the production of LPS or antibiotics. The figure is created with BioRender.com
期刊介绍：
Signal Transduction and Targeted Therapy is an open access journal that focuses on timely publication of cutting-edge discoveries and advancements in basic science and clinical research related to signal transduction and targeted therapy.
Scope: The journal covers research on major human diseases, including, but not limited to:
Cancer,Cardiovascular diseases,Autoimmune diseases,Nervous system diseases.
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