The TMEM189 gene encodes plasmanylethanolamine desaturase which introduces the characteristic vinyl ether double bond into plasmalogens
The TMEM189 gene encodes plasmanylethanolamine desaturase which introduces the characteristic vinyl ether double bond into plasmalogens
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DOI：
10.1073/pnas.1917461117
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发表时间：
2020-04-07
影响因子：
11.1
通讯作者：
Watschinger, Katrin
中科院分区：
文献类型：
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作者：
Werner, Ernst R.;Keller, Markus A.;Watschinger, Katrin
人体中甘油磷脂的重要部分由缩醛磷脂组成，特别是在脑、心脏和免疫细胞膜中。在阿尔茨海默氏症和慢性阻塞性肺病等疾病中观察到这些脂质的下降。缩醛磷脂含有特征性的1-O-alk-1'-enyl ether（乙烯基醚）双键，赋予这些脂质特殊的生物物理、生物化学和化学性质。然而，其生物合成的遗传学尚未完全了解，因为尚未鉴定出编码血浆乙醇胺去饱和酶（E.C. 1.14.99.19目前的工作确定该基因为跨膜蛋白189（TMEM189）。在人HAP 1细胞中TMEM 189基因的失活导致血浆乙醇胺去饱和酶活性的完全丧失，血浆缩醛原水平的强烈降低，血浆乙醇胺底物的积累，并导致这些细胞不能从标记的烷基甘油形成标记的缩醛原。TMEM189蛋白的瞬时表达，而不是其他选择的去饱和酶，恢复了这种缺陷。TMEM 189蛋白含有一个保守的蛋白基序（pfam 10520），该基序具有八个保守的组氨酸，该基序为另一种类型的植物去饱和酶所共有，但不为其他哺乳动物蛋白所共有。这些组氨酸中的每一个对于血浆乙醇胺去饱和酶活性是必需的。失活的Tmem189基因纯合子小鼠缺乏血浆乙醇胺去饱和酶活性，其组织中的血浆酶原水平显著降低。这些结果将TMEM 189基因分配给血浆乙醇胺去饱和酶，并表明先前表征的TMEM 189缺陷型小鼠的表型可能是由缺乏缩醛磷脂引起的。
A significant fraction of the glycerophospholipids in the human body is composed of plasmalogens, particularly in the brain, cardiac, and immune cell membranes. A decline in these lipids has been observed in such diseases as Alzheimer's and chronic obstructive pulmonary disease. Plasmalogens contain a characteristic 1-O-alk-1'-enyl ether (vinyl ether) double bond that confers special biophysical, biochemical, and chemical properties to these lipids. However, the genetics of their biosynthesis is not fully understood, since no gene has been identified that encodes plasmanylethanolamine desaturase (E.C. 1.14.99.19), the enzyme introducing the crucial alk-1'-enyl ether double bond. The present work identifies this gene as transmembrane protein 189 (TMEM189). Inactivation of the TMEM189 gene in human HAP1 cells led to a total loss of plasmanylethanolamine desaturase activity, strongly decreased plasmalogen levels, and accumulation of plasmanylethanolamine substrates and resulted in an inability of these cells to form labeled plasmalogens from labeled alkylglycerols. Transient expression of TMEM189 protein, but not of other selected desaturases, recovered this deficit. TMEM189 proteins contain a conserved protein motif (pfam10520) with eight conserved histidines that is shared by an alternative type of plant desaturase but not by other mammalian proteins. Each of these histidines is essential for plasmanylethanolamine desaturase activity. Mice homozygous for an inactivated Tmem189 gene lacked plasmanylethanolamine desaturase activity and had dramatically lowered plasmalogen levels in their tissues. These results assign the TMEM189 gene to plasmanylethanolamine desaturase and suggest that the previously characterized phenotype of Tmem189-deficient mice may be caused by a lack of plasmalogens.