E3 Ubiquitin Ligase APC/CCdh1 Regulation of Phenylalanine Hydroxylase Stability and Function

Abstract

Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by the dysfunction of the enzyme phenylalanine hydroxylase (PAH). Alterations in the level of PAH leads to the toxic accumulation of phenylalanine in the blood and brain. Protein degradation mediated by ubiquitination is a principal cellular process for maintaining protein homeostasis. Therefore, it is important to identify the E3 ligases responsible for PAH turnover and proteostasis. Here, we report that anaphase-promoting complex/cyclosome-Cdh1 (APC/C)Cdh1 is an E3 ubiquitin ligase complex that interacts and promotes the polyubiquitination of PAH through the 26S proteasomal pathway. Cdh1 destabilizes and declines the half-life of PAH. In contrast, the CRISPR/Cas9-mediated knockout of Cdh1 stabilizes PAH expression and enhances phenylalanine metabolism. Additionally, our current study demonstrates the clinical relevance of PAH and Cdh1 correlation in hepatocellular carcinoma (HCC). Overall, we show that PAH is a prognostic marker for HCC and Cdh1 could be a potential therapeutic target to regulate PAH-mediated physiological and metabolic disorders.

A Minimal Subset of Seven Genes Associated with Tumor Hepatocyte Differentiation Predicts a Poor Prognosis in Human Hepatocellular Carcinoma

“…PAH (phenylalanine hydroxylase, an enzyme which catalyzes the conversion of phenylalanine to tyrosine) has been associated with phenylketonuria, an autosomal recessive metabolic disorder. In HCC, a low expression of PAH has been reported as a prognostic marker for a poor prognosis [ 51 ].…”

Research progress and application of the CRISPR/Cas9 gene-editing technology based on hepatocellular carcinoma

“…In addition, researchers also revealed by CRISPR/Cas9 tool that eukaryotic elongation factor 2, chromosome condensin I complex subunit G (NCAPG), zinc finger protein 384 (ZNF384), the enzyme phenylalanine hydroxylase (PAH), epigenetic-related genes (ERG), telomerase reverse transcriptase (TERT), and hexokinase 1 (HK1) could be applied to serve as predictive and prognostic biomarkers for HCC. Consequently, these biomarkers could provide a personalized and timely scheme for early diagnosis and prognosis therapy of HCC, as well as offered potential therapeutic targets for HCC patients and potential pathways for drug development [ 9 , 93 , [132] , [133] , [134] , [135] , [136] ].…”

Effect of Copper Sulphate Pollution and Its Antidote Penicillamine on Serum and Brain Tissues Markers of Albino Rats

“…The following parameters were assayed serum tyrosinase was determined using (ab185435 kit) colorimetric assay method 15 , Serum Copper ions were determined using colorimetric assay kit at 580 nm according to 17 , Serum Fasting glucose levels were determined using (ab65333 kit) according to 16 , TAC in brain tissue was determined using (Cat. No-E-BC-K136-S) according to colorimetric assay adapted to 18 and MDA in brain tissue assayed using (ab118970) according to a method adapted to 19 .…”