Regulation of phosphatidic acid phosphatase during lipogenesis in the oleaginous yeast Yarrowia lipolytica Phosphatidic acid phosphatase in Yarrowia lipolytica

摘要 磷脂酸磷酸酶（PAP）催化的生物合成中的关键步骤， 三酰基甘油（TAG），其是磷脂酸（PA）的去磷酸化， 甘油二酯（DAG）。通过其反应的性质，PAP控制PA和TAG的细胞水平。 在酿酒酵母中，缺失PAH 1编码的PAP酶（即Scpah 1 Δ突变体） 导致细胞TAG水平降低90%。此外，PA在Scpah 1 Δ中的蓄积 导致磷脂生物合成基因的去抑制， 磷脂量增加，表现为核膜/ER膜的扩张。 人类PAP酶（脂蛋白）的失调与几种疾病有关，如肥胖症 和脂肪代谢障碍。在这个竞争性的拨款申请中，我们将确定编码 PAP活性在Y.脂肪分解，并检查其在脂质代谢中的作用（具体目标1）。Y.氏酵母 暴露于高葡萄糖量的细胞进入脂肪生成期， 诱导。这导致TAG在细胞中的积累，其可高达90%。 的总脂肪。我们将研究Y的作用和调节。Lipolytica PAP酶在这 代谢（具体目标2）。

Abstract Phosphatidic acid phosphatase (PAP) catalyzes the committed step in the biosynthesis of triacylglycerol (TAG) which is the dephosphorylation of phosphatidic acid (PA) to yield diacylglycerol (DAG). By the nature of its reaction PAP controls the cellular levels of PA and TAG. In Saccharomyces cerevisiae, deletion of the PAH1-encoded PAP enzyme (i.e. Scpah1Δ mutant) causes a 90 % reduction in cellular TAG levels. Also, the accumulation of PA in the Scpah1Δ causes the derepression of the phospholipid biosynthetic genes which results in increased phospholipid amounts and is manifested by the expansion of the nuclear/ER membrane. Deregulation of the human PAP enzymes, lipins, is associated with several diseases, like obesity and lipodystrophy. In this competitive grant application, we will identify the genes that encode for PAP activity in Y. lipolytica and examine their role in lipid metabolism (specific aim 1). Y. lipolytica cells exposed to high glucose amounts enter a lipogenic phase where TAG biosynthesis is induced. This results in the accumulation of TAG in the cells which can become as high as 90% of the total lipids. We will examine the role and regulation of the Y. lipolytica PAP enzymes in this metabolism (specific aim 2).