Mahawar Usha, Wattenberg Binks
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Bioessays. 2025 Sep;47(9):e70036. doi: 10.1002/bies.70036. Epub 2025 Jun 23.
Sphingolipids are a structurally unique, widespread, and diverse family of lipids. Serine palmitoyltransferase (SPT) is the first and rate-limiting enzyme required for the synthesis of all sphingolipids. Not unexpectedly, SPT is highly regulated. SPT is a multi-subunit enzyme, the level of activity of which is controlled by the regulatory subunits known as the ORMDLs. Here, we discuss how the regulation of SPT activity is accomplished by multiple mechanisms, underscoring the importance of this regulation. A rapid homeostatic regulation of SPT, monitoring cellular sphingolipid levels, is mediated by the direct binding of the central sphingolipid ceramide to the SPT/ORMDL complex. This acute regulation is overlaid by a longer-term regulation in which ORMDL is removed from the remainder of the SPT complex and trafficked for degradation, resulting in enhanced SPT activity. A third level of regulation is conferred by the inclusion of specific isoforms of the subunits of SPT into the complex. The isoform composition of the SPT complex dictates both the sensitivity of the complex to levels of cellular sphingolipid and the molecular species of sphingoid backbone that are produced. Here we discuss the mechanisms, interplay, and physiological roles of these three levels of regulation of sphingolipid biosynthesis.
鞘脂是一类结构独特、分布广泛且种类多样的脂质家族。丝氨酸棕榈酰转移酶（SPT）是所有鞘脂合成所需的首个且限速的酶。不出所料，SPT受到高度调控。SPT是一种多亚基酶，其活性水平由被称为ORMDLs的调节亚基控制。在此，我们讨论SPT活性是如何通过多种机制实现调控的，强调这种调控的重要性。对SPT的一种快速稳态调控，即监测细胞内鞘脂水平，是由核心鞘脂神经酰胺与SPT/ORMDL复合物的直接结合介导的。这种急性调控之上叠加着一种长期调控，其中ORMDL从SPT复合物的其余部分脱离并被转运用于降解，从而导致SPT活性增强。第三种调控水平是由将SPT亚基的特定异构体纳入复合物所赋予的。SPT复合物的异构体组成决定了该复合物对细胞内鞘脂水平的敏感性以及所产生的鞘氨醇骨架的分子种类。在此我们讨论鞘脂生物合成这三种调控水平的机制、相互作用及生理作用。
