Acyl chain selection couples the consumption and synthesis of phosphoinositides.
Acyl chain selection couples the consumption and synthesis of phosphoinositides.
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DOI：
10.15252/embj.2021110038
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发表时间：
2022-09-15
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哺乳动物组织中的磷脂酰肌醇(PIPn)富含硬脂酰基/花生四烯酰基(C38：4)，但其功能意义尚不清楚。我们使用代谢示踪剂(肌醇、葡萄糖和水的同位素制剂)来研究细胞系中PIPn的合成，在这些细胞系中，这种浓缩被保存到不同的相对程度。我们表明，从葡萄糖合成的PI最初富含较短/更饱和的酰基链，但随后迅速重塑为C38：4物种。PI也是通过独特的“循环途径”合成的，该途径利用现有的前体，并对合成C38：4-PA和-PI表现出很高的选择性。在磷脂酶-C的受体激活过程中，这种再循环途径被迅速刺激，既允许保留C38：4主干，也允许PIPn消耗与其重新合成紧密耦合，从而保持池的大小。这些结果表明，PIPn特殊的酰基链组成的一个性质是分子密码，通过与其他脂质代谢途径相同的中间体池(DG、PA和CDP-DG)，促进从PIP2到PI的代谢通道。磷脂酰肌醇的合成途径被发现，揭示了复杂的功能适应。
Phosphoinositides (PIPn) in mammalian tissues are enriched in the stearoyl/arachidonoyl acyl chain species (“C38:4”), but its functional significance is unclear. We have used metabolic tracers (isotopologues of inositol, glucose and water) to study PIPn synthesis in cell lines in which this enrichment is preserved to differing relative extents. We show that PIs synthesised from glucose are initially enriched in shorter/more saturated acyl chains, but then rapidly remodelled towards the C38:4 species. PIs are also synthesised by a distinct ‘re‐cycling pathway’, which utilises existing precursors and exhibits substantial selectivity for the synthesis of C38:4‐PA and ‐PI. This re‐cycling pathway is rapidly stimulated during receptor activation of phospholipase‐C, both allowing the retention of the C38:4 backbone and the close coupling of PIPn consumption to its resynthesis, thus maintaining pool sizes. These results suggest that one property of the specific acyl chain composition of PIPn is that of a molecular code, to facilitate ‘metabolic channelling’ from PIP2 to PI via pools of intermediates (DG, PA and CDP‐DG) common to other lipid metabolic pathways. Pathways of phosphatidylinositol synthesis are uncovered to reveal intricate functional adaptation.