Towards the development of an enzyme replacement therapy for the metabolic disorder propionic acidemia

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• 作者：Mahnaz Darvish-Damavandi ; Han Kiat Ho ; Tse Siang Kang ; ^{tsesiang@gmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：PA ; propionic acidemia ; PCC ; propionyl coenzyme-A carboxylase ; PP-CoA ; propionyl coenzyme-A ; CPPs ; cell penetrating peptides ; MTS ; mitochondria targeting sequences ; ERT ; enzyme replacement therapy ; MPP ; mitochondrial processing peptidase ; LAD ; lipoamine dehydrogenase ; PCCA ; PCCα subunit ; PCCB ; PCCβ subunit ; His-tag ; six histidines tag ; UPLC-MS/MS ; ultra performance liquid chromatography tandem mass spectrometry ; CoA ; coenzyme-A
• 刊名：Molecular Genetics and Metabolism Reports
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：8
• 期：Complete
• 页码：51-60
• 全文大小：1300 K

文摘

Propionic acidemia (PA) is a life-threatening disease caused by the deficiency of a mitochondrial biotin-dependent enzyme known as propionyl coenzyme-A carboxylase (PCC). This enzyme is responsible for degrading the metabolic intermediate, propionyl coenzyme-A (PP-CoA), derived from multiple metabolic pathways. Currently, except for drastic surgical and dietary intervention that can only provide partial symptomatic relief, no other form of therapeutic option is available for this genetic disorder. Here, we examine a novel approach in protein delivery by specifically targeting and localizing our protein candidate of interest into the mitochondrial matrix of the cells. In order to test this concept of delivery, we have utilized cell penetrating peptides (CPPs) and mitochondria targeting sequences (MTS) to form specific fusion PCC protein, capable of translocating and localizing across cell membranes. In vitro delivery of our candidate fusion proteins, evaluated by confocal images and enzymatic activity assay, indicated effectiveness of this strategy. Therefore, it holds immense potential in creating a new paradigm in site-specific protein delivery and enzyme replacement therapeutic for PA.