Mycobacteria that cause tuberculosis have retained ancestrally acquired genes for the biosynthesis of chemically diverse terpene nucleosides.

IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences
PLoS Biology Pub Date : 2024-09-30 eCollection Date: 2024-09-01 DOI:10.1371/journal.pbio.3002813
Jacob A Mayfield, Sahadevan Raman, Alexandrea K Ramnarine, Vivek K Mishra, Annie D Huang, Sandrine Dudoit, Jeffrey Buter, Tan-Yun Cheng, David C Young, Yashodhan M Nair, Isobel G Ouellet, Braden T Griebel, Shuyi Ma, David R Sherman, Ludovic Mallet, Kyu Y Rhee, Adriaan J Minnaard, D Branch Moody
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引用次数: 0

Abstract

Mycobacterium tuberculosis (Mtb) releases the unusual terpene nucleoside 1-tuberculosinyladenosine (1-TbAd) to block lysosomal function and promote survival in human macrophages. Using conventional approaches, we found that genes Rv3377c and Rv3378c, but not Rv3376, were necessary for 1-TbAd biosynthesis. Here, we introduce linear models for mass spectrometry (limms) software as a next-generation lipidomics tool to study the essential functions of lipid biosynthetic enzymes on a whole-cell basis. Using limms, whole-cell lipid profiles deepened the phenotypic landscape of comparative mass spectrometry experiments and identified a large family of approximately 100 terpene nucleoside metabolites downstream of Rv3378c. We validated the identity of previously unknown adenine-, adenosine-, and lipid-modified tuberculosinol-containing molecules using synthetic chemistry and collisional mass spectrometry, including comprehensive profiling of bacterial lipids that fragment to adenine. We tracked terpene nucleoside genotypes and lipid phenotypes among Mycobacterium tuberculosis complex (MTC) species that did or did not evolve to productively infect either human or nonhuman mammals. Although 1-TbAd biosynthesis genes were thought to be restricted to the MTC, we identified the locus in unexpected species outside the MTC. Sequence analysis of the locus showed nucleotide usage characteristic of plasmids from plant-associated bacteria, clarifying the origin and timing of horizontal gene transfer to a pre-MTC progenitor. The data demonstrated correlation between high level terpene nucleoside biosynthesis and mycobacterial competence for human infection, and 2 mechanisms of 1-TbAd biosynthesis loss. Overall, the selective gain and evolutionary retention of tuberculosinyl metabolites in modern species that cause human TB suggest a role in human TB disease, and the newly discovered molecules represent candidate disease-specific biomarkers.

导致结核病的分枝杆菌保留了从祖先那里获得的生物合成化学性质多样的萜烯核苷的基因。
结核分枝杆菌(Mtb)释放出不寻常的萜烯核苷 1-结核苷基腺苷(1-TbAd),阻断溶酶体功能,促进人类巨噬细胞的存活。利用传统方法,我们发现基因 Rv3377c 和 Rv3378c 是 1-TbAd 生物合成所必需的,但 Rv3376 不是。在这里,我们引入了线性质谱模型(limms)软件,作为新一代脂质组学工具,用于研究全细胞脂质生物合成酶的基本功能。利用 limms,全细胞脂质图谱深化了比较质谱实验的表型图谱,并确定了 Rv3378c 下游约 100 个萜烯核苷代谢物的大家族。我们利用合成化学和碰撞质谱法验证了先前未知的腺嘌呤、腺苷和脂质修饰的含结核苷醇分子的身份,包括全面剖析了以腺嘌呤为片段的细菌脂质。我们追踪了结核分枝杆菌复合体(MTC)物种中的萜烯核苷基因型和脂质表型,无论这些物种是否进化到能有效感染人类或非人类哺乳动物。尽管 1-TbAd 生物合成基因被认为仅限于 MTC,但我们在 MTC 以外的意外物种中发现了该基因座。对该基因座的序列分析表明,核苷酸的使用具有来自植物相关细菌质粒的特征,从而明确了横向基因转移到前 MTC 祖先的起源和时间。数据显示了高水平萜烯核苷生物合成与分枝杆菌感染人类的能力之间的相关性,以及 1-TbAd 生物合成丧失的两种机制。总之,在导致人类结核病的现代物种中,结核苷代谢物的选择性增殖和进化保留表明了其在人类结核病中的作用,新发现的分子代表了候选的疾病特异性生物标记物。
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来源期刊
PLoS Biology
PLoS Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-BIOLOGY
CiteScore
15.40
自引率
2.00%
发文量
359
审稿时长
3-8 weeks
期刊介绍: PLOS Biology is the flagship journal of the Public Library of Science (PLOS) and focuses on publishing groundbreaking and relevant research in all areas of biological science. The journal features works at various scales, ranging from molecules to ecosystems, and also encourages interdisciplinary studies. PLOS Biology publishes articles that demonstrate exceptional significance, originality, and relevance, with a high standard of scientific rigor in methodology, reporting, and conclusions. The journal aims to advance science and serve the research community by transforming research communication to align with the research process. It offers evolving article types and policies that empower authors to share the complete story behind their scientific findings with a diverse global audience of researchers, educators, policymakers, patient advocacy groups, and the general public. PLOS Biology, along with other PLOS journals, is widely indexed by major services such as Crossref, Dimensions, DOAJ, Google Scholar, PubMed, PubMed Central, Scopus, and Web of Science. Additionally, PLOS Biology is indexed by various other services including AGRICOLA, Biological Abstracts, BIOSYS Previews, CABI CAB Abstracts, CABI Global Health, CAPES, CAS, CNKI, Embase, Journal Guide, MEDLINE, and Zoological Record, ensuring that the research content is easily accessible and discoverable by a wide range of audiences.
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