Mycobacterium tuberculosis pks12 produces a novel polyketide presented by CD1c to T cells.
Mycobacterium tuberculosis pks12 produces a novel polyketide presented by CD1c to T cells.
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DOI：
10.1084/jem.20041429
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发表时间：
2004-12-20
期刊：
影响因子：
--
通讯作者：
Moody DB
中科院分区：
文献类型：
--
作者：
Matsunaga I;Bhatt A;Young DC;Cheng TY;Eyles SJ;Besra GS;Briken V;Porcelli SA;Costello CE;Jacobs WR Jr;Moody DB
CD 1c介导的T细胞被分枝杆菌磷脂抗原激活，该抗原的碳水化合物结构精确地对应于哺乳动物甘露糖基β-1-磷酸多萜醇（MPD），但含有不寻常的脂质部分。在这里，我们表明，这种T细胞抗原是一个家庭的成员分支，烷烃脂质的长度不同（C30-34），并产生了医学上重要的分枝杆菌，如M。结核和M.牛卡介苗烷烃部分将这些分枝杆菌脂质抗原与哺乳动物MPD区分开来，并且是激活CD 1c限制性T细胞所必需的，但不能通过任何已知的脂质生物合成途径来解释。代谢标记和质谱分析表明，延长脂质使用交替的C2和C3单位，而不是C5异戊烯焦磷酸的机制。检查M.结核分枝杆菌基因组中发现了一个候选基因pks 12，该基因被预测编码结核分枝杆菌中最大的蛋白质。结核病，由12个催化结构域组成，对应于拟议途径中的关键步骤。基因缺失和互补表明，Pks 12是必要的抗原生产，但不影响合成真正的异戊烯醇。这些研究建立了一种以前未知类型的聚酮化合物的遗传和酶基础，称为mycoketide，它含有一种与真菌病原体相关的分子模式。
CD1c-mediated T cells are activated by a mycobacterial phospholipid antigen whose carbohydrate structure precisely corresponds to mammalian mannosyl β-1-phosphodolichol (MPD), but contains an unusual lipid moiety. Here, we show that this T cell antigen is a member of a family of branched, alkane lipids that vary in length (C30-34) and are produced by medically important mycobacteria such as M. tuberculosis and M. bovis Bacille-Calmette-Guerin. The alkane moiety distinguished these mycobacterial lipid antigens from mammalian MPDs and was necessary for activation of CD1c-restricted T cells, but could not be accounted for by any known lipid biosynthetic pathway. Metabolic labeling and mass spectrometric analyses suggested a mechanism for elongating lipids using alternating C2 and C3 units, rather than C5 isopentenyl pyrophosphate. Inspection of the M. tuberculosis genome identified one candidate gene, pks12, which was predicted to encode the largest protein in M. tuberculosis, consisting of 12 catalytic domains that correspond to key steps in the proposed pathway. Genetic deletion and complementation showed that Pks12 was necessary for antigen production, but did not affect synthesis of true isoprenols. These studies establish the genetic and enzymatic basis for a previously unknown type of polyketide, designated mycoketide, which contains a lipidic pathogen-associated molecular pattern.
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影响因子：
56.9
作者：
Moody, DB;Reinhold, BB;Porcelli, SA
通讯作者：
Porcelli, SA
影响因子：
56.9
作者：
Moody, DB;Young, DC;Brenner, MB
通讯作者：
Brenner, MB
影响因子：
4.8
作者：
Baulard, AR;Gurcha, SS;Besra, GS
通讯作者：
Besra, GS
影响因子：
4.1
作者：
Gurcha, SS;Baulard, AR;Besra, GS
通讯作者：
Besra, GS
影响因子：
2.8
作者：
Bardarov, S;Bardarov, S;Jacobs, WR
通讯作者：
Jacobs, WR