PDF(Pubmed)
Abstract：
The serine peptidase CLPP is conserved among bacteria, chloroplasts, and mitochondria. In humans and mice, its loss causes Perrault syndrome, which presents with growth deficits, infertility, deafness, and ataxia. In the filamentous fungus Podospora anserina, CLPP loss leads to longevity. CLPP substrates are selected by CLPX, an AAA+ unfoldase. CLPX is known to target delta-aminolevulinic acid synthase (ALAS) to promote pyridoxal phosphate (PLP) binding. CLPX may also influence cofactor association with other enzymes. Here, the evaluation of P. anserina metabolomics highlighted a reduction in arginine/histidine levels. In Mus musculus cerebellum, reductions in arginine/histidine and citrulline occurred with a concomitant accumulation of the heme precursor protoporphyrin IX. This suggests that the increased biosynthesis of 5-carbon (C5) chain deltaALA consumes not only C4 succinyl-CoA and C1 glycine but also specific C5 delta amino acids. As enzymes responsible for these effects, the elevated abundance of CLPX and ALAS is paralleled by increased OAT (PLP-dependent, ornithine delta-aminotransferase) levels. Possibly as a consequence of altered C1 metabolism, the proteome profiles of P. anserina CLPP-null cells showed strong accumulation of a methyltransferase and two mitoribosomal large subunit factors. The reduced histidine levels may explain the previously observed metal interaction problems. As the main nitrogen-storing metabolite, a deficiency in arginine would affect the urea cycle and polyamine synthesis. Supplementation of arginine and histidine might rescue the growth deficits of CLPP-mutant patients.
摘要：
丝氨酸肽酶CLPP在细菌中保守，叶绿体,和线粒体.在人类和老鼠中，它的损失导致Perrault综合征,这带来了增长赤字，不孕症,耳聋,和共济失调.在丝状真菌中，CLPP损失导致寿命。CLPP底物由CLPX选择，AAA+展开酶。已知CLPX靶向δ-氨基乙酰丙酸合酶(ALAS)以促进磷酸吡哆醛(PLP)结合。CLPX还可以影响辅因子与其他酶的结合。这里,对安塞拉氏菌代谢组学的评估强调了精氨酸/组氨酸水平的降低。小脑小肌，精氨酸/组氨酸和瓜氨酸的减少伴随着血红素前体原卟啉IX的积累。这表明5-碳(C5)链deltaALA的增加的生物合成不仅消耗C4琥珀酰-CoA和C1甘氨酸,而且消耗特定的C5δ氨基酸。作为负责这些影响的酶，CLPX和ALAS丰度的升高与OAT的增加(PLP依赖性，鸟氨酸δ-转氨酶）水平。可能是C1代谢改变的结果，羊丝虫CLPP无效细胞的蛋白质组特征显示一个甲基转移酶和两个丝体大亚基因子的强烈积累。降低的组氨酸水平可以解释先前观察到的金属相互作用问题。作为主要的储氮代谢产物，精氨酸的缺乏会影响尿素循环和多胺的合成。补充精氨酸和组氨酸可能会挽救CLPP突变患者的生长缺陷。
