Young David C, Layre Emilie, Pan Shih-Jung, Tapley Asa, Adamson John, Seshadri Chetan, Wu Zhongtao, Buter Jeffrey, Minnaard Adriaan J, Coscolla Mireia, Gagneux Sebastien, Copin Richard, Ernst Joel D, Bishai William R, Snider Barry B, Moody D Branch
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Smith Building Room 538, 1 Jimmy Fund Way, Boston, MA 02115, USA.
K-RITH, KwuZulu-Natal Research Institute for Tuberculosis & HIV, Nelson R. Mandela School of Medicine-University of Kwazulu-Natal, K-RITH Tower Building, 719 Umbilo Road, Durban, 4001 Private Bag X7, Congela-Durban 4001, South Africa.
Chem Biol. 2015 Apr 23;22(4):516-526. doi: 10.1016/j.chembiol.2015.03.015.
Although small molecules shed from pathogens are widely used to diagnose infection, such tests have not been widely implemented for tuberculosis. Here we show that the recently identified compound, 1-tuberculosinyladenosine (1-TbAd), accumulates to comprise >1% of all Mycobacterium tuberculosis lipid. In vitro and in vivo, two isomers of TbAd were detected that might serve as infection markers. Using mass spectrometry and nuclear magnetic resonance, we established the structure of the previously unknown molecule, N(6)-tuberculosinyladenosine (N(6)-TbAd). Its biosynthesis involves enzymatic production of 1-TbAd by Rv3378c followed by conversion to N(6)-TbAd via the Dimroth rearrangement. Intact biosynthetic genes are observed only within M. tuberculosis complex bacteria, and TbAd was not detected among other medically important pathogens, environmental bacteria, and vaccine strains. With no substantially similar known molecules in nature, the discovery and in vivo detection of two abundant terpene nucleosides support their development as specific diagnostic markers of tuberculosis.
尽管病原体释放的小分子被广泛用于诊断感染，但此类检测尚未在结核病诊断中广泛应用。在此，我们表明，最近鉴定出的化合物1-结核分枝杆菌素腺苷（1-TbAd）积累量占结核分枝杆菌所有脂质的1%以上。在体外和体内，检测到两种TbAd异构体，它们可能作为感染标志物。利用质谱和核磁共振，我们确定了此前未知分子N(6)-结核分枝杆菌素腺苷（N(6)-TbAd）的结构。其生物合成过程包括由Rv3378c酶促生成1-TbAd，然后通过迪姆罗特重排转化为N(6)-TbAd。完整的生物合成基因仅在结核分枝杆菌复合群细菌中观察到，在其他重要医学病原体、环境细菌和疫苗菌株中未检测到TbAd。由于自然界中不存在基本相似的已知分子，两种丰富的萜烯核苷的发现及其在体内的检测支持将它们开发为结核病的特异性诊断标志物。
