González-Salgado Amaia, Steinmann Michael, Major Louise L, Sigel Erwin, Reymond Jean-Louis, Smith Terry K, Bütikofer Peter
Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
Biomedical Sciences Research Complex, University of St Andrews, North Haugh, St. Andrews, Fife, United Kingdom.
Eukaryot Cell. 2015 Jun;14(6):616-24. doi: 10.1128/EC.00038-15. Epub 2015 Apr 17.
myo-Inositol is a building block for all inositol-containing phospholipids in eukaryotes. It can be synthesized de novo from glucose-6-phosphate in the cytosol and endoplasmic reticulum. Alternatively, it can be taken up from the environment via Na(+)- or H(+)-linked myo-inositol transporters. While Na(+)-coupled myo-inositol transporters are found exclusively in the plasma membrane, H(+)-linked myo-inositol transporters are detected in intracellular organelles. In Trypanosoma brucei, the causative agent of human African sleeping sickness, myo-inositol metabolism is compartmentalized. De novo-synthesized myo-inositol is used for glycosylphosphatidylinositol production in the endoplasmic reticulum, whereas the myo-inositol taken up from the environment is used for bulk phosphatidylinositol synthesis in the Golgi complex. We now provide evidence that the Golgi complex-localized T. brucei H(+)-linked myo-inositol transporter (TbHMIT) is essential in bloodstream-form T. brucei. Downregulation of TbHMIT expression by RNA interference blocked phosphatidylinositol production and inhibited growth of parasites in culture. Characterization of the transporter in a heterologous expression system demonstrated a remarkable selectivity of TbHMIT for myo-inositol. It tolerates only a single modification on the inositol ring, such as the removal of a hydroxyl group or the inversion of stereochemistry at a single hydroxyl group relative to myo-inositol.
肌醇是真核生物中所有含肌醇磷脂的组成成分。它可以在细胞质和内质网中由6-磷酸葡萄糖从头合成。或者，它可以通过与钠离子或氢离子偶联的肌醇转运体从环境中摄取。虽然与钠离子偶联的肌醇转运体仅存在于质膜中，但与氢离子偶联的肌醇转运体则存在于细胞内细胞器中。在人类非洲昏睡病的病原体布氏锥虫中，肌醇代谢是分区进行的。从头合成的肌醇用于内质网中糖基磷脂酰肌醇的产生，而从环境中摄取的肌醇则用于高尔基体中大量磷脂酰肌醇的合成。我们现在提供证据表明，定位于高尔基体的布氏锥虫氢离子偶联肌醇转运体（TbHMIT）在布氏锥虫血流形式中是必不可少的。通过RNA干扰下调TbHMIT的表达会阻断磷脂酰肌醇的产生，并抑制培养物中寄生虫的生长。在异源表达系统中对该转运体的表征表明，TbHMIT对肌醇具有显著的选择性。它仅能耐受肌醇环上的单一修饰，例如相对于肌醇去除一个羟基或单个羟基的立体化学反转。
