Mitochondrial phosphatidylethanolamine metabolism

描述（由申请人提供）：磷脂酰乙醇胺（PE）在生物学中的重要性是多方面的。PE通常是生物膜中含量第二丰富的磷脂成分，因此在细胞自主和亚细胞区隔化中起着重要作用。此外，PE是其他主要脂质的前体，对多种特定生物功能至关重要。在真核生物中，PE的合成可以通过四种不同的途径进行，其中一种途径是由位于线粒体内膜内的磷脂酰丝氨酸脱羧酶1进行的。有趣的是，尽管产生PE有四种不同的途径，但在小鼠中，卵磷脂酰丝氨酸脱羧酶1的缺失在胚胎期是致命的。关于磷脂酰丝氨酸脱羧酶1的机制知之甚少，该途径所需的大多数脂质运输步骤仍然不清楚，线粒体中产生的PE如何支持线粒体功能尚未完全解决。该应用程序的首要目标是开始填补我们对这一重要生物合成途径的知识中的众多空白。在第一个具体目标中，我们将确定功能重要的结构

DESCRIPTION (provided by applicant): The importance of phosphatidylethanolamine (PE) in biology is multi-faceted. PE is typically the second most abundant phospholipid component in biological membranes and thus plays a fundamental role in cellular autonomy and subcellular compartmentalization. In addition, PE is a precursor for other major lipids and is critical for a diverse range of specific biological functions. In eukaryotes, PE synthesis can occur via four separate pathways one of which is performed by phosphatidylserine decarboxylase 1 which resides in the inner mitochondrial membrane. Intriguingly, even though there are four distinct pathways to make PE, deletion of phosphatidylserine decarboxylase 1 is embryonically lethal in mice. Not much is known about the phosphatidylserine decarboxylase 1 mechanism, most of the lipid trafficking steps required for this pathway remain obscure, and how PE produced in mitochondria supports mitochondrial function is incompletely resolved. The overarching goal of this application is to begin filling in the numerous gaps in our knowledge about this essential biosynthetic pathway. In the first specific aim, we will identify functionally important structural motifs in phosphatidylserine decarboxylase 1. The catalytically active form of phosphatidylserine decarboxylase 1 is generated by an autocatalytic event that generates a large membrane anchored ??subunit that non-covalently interacts with the enzymatically essential small ? subunit. How phosphatidylserine decarboxylase 1 achieves specificity is not known, but a potential substrate binding motif in the ? subunit has been identified by homology modeling. One goal of Aim 1 is to test the generated homology model and define the substrate binding motif. Another major effort in Aim 1 is to utilize chemical crosslinking to identify the interactio surface between the ? and ? subunits. The goal of this mapping exercise is to determine if the ? /?? interaction is critical for phosphatidylserine decarboxylase 1 activity, and if so, how. Phosphatidylserine decarboxylase 1 is embedded in the mitochondrial inner membrane and it is known that PE produced outside of mitochondria is unable to compensate for the absence of PE made in mitochondria. In Aim 2, we will exploit a novel short-circuit strategy to obtain a more comprehensive understanding of mitochondrial PE metabolism. Specifically, we will determine the ability of PE produced in the outer membrane to access the inner membrane, molecularly characterize trafficking steps required for mitochondrial PE production, and pinpoint if the synthetic lethal interaction between the mitochondrial PE and cardiolipin biosynthetic pathways reflects a defect in an essential inner membrane or outer membrane function. By obtaining a more comprehensive understanding of mitochondrial PE metabolism, novel therapeutic targets may be identified for those diseases in which PE has been implicated, including Alzheimer's and prion disease, and for the numerous pathological states, including cancer, associated with derangements in cardiolipin metabolism.