Abstract
Fumarylacetoacetate hydrolase (FAH) is the last enzyme in the degradation pathway of the amino acids tyrosine and phenylalanine in mammals that catalyzes the hydrolysis of 4-fumarylacetoacetate into acetoacetate and fumarate. Mutations of the FAH gene are associated with hereditary tyrosinemia type I (HT1), resulting in reduced protein stability, misfolding, accelerated degradation and deficiency in functional proteins. Identifying E3 ligases, which are necessary for FAH protein stability and degradation, is essential. In this study, we demonstrated that the FAH protein level is elevated in liver cancer tissues compared to that in normal tissues. Further, we showed that the FAH protein undergoes 26S proteasomal degradation and its protein turnover is regulated by the anaphase-promoting complex/cyclosome-Cdh1 (APC/C)Cdh1 E3 ubiquitin ligase complex. APC/CCdh1 acts as a negative stabilizer of FAH protein by promoting FAH polyubiquitination and decreases the half-life of FAH protein. Thus, we envision that Cdh1 might be a key factor in the maintenance of FAH protein level to regulate FAH-mediated physiological functions.
Highlights
Tyrosine degradation is a crucial five step pathway in animals that breaks down the aromatic amino acids obtained from diet and protein breakdown [1]
Our results showed that out of 26 liver cancer patients, 14 patients showed significantly high expression of Fumarylacetoacetate hydrolase (FAH) in tumor tissues when compared to the normal tissues (Figure 1A). 7 patients showed moderate expression of FAH in tumor tissues compared to that in normal tissues (Figure 1B) and 5 patients showed non-significant changes in the expression of FAH protein between tumor and normal tissues (Figure 1C)
The results showed slight upregulation of the FAH gene in tumor tissue when compared with normal tissues (Supplementary Figure S2)
Summary
Tyrosine degradation is a crucial five step pathway in animals that breaks down the aromatic amino acids obtained from diet and protein breakdown [1]. FAH is an enzyme encoded by the FAH gene located on chromosome 15q25.1 containing 14 exons, spanning over 35 kb of DNA [2,3,4]. It is a cytosolic homodimer with two 46-kDa subunits conformed by a 120-residue N-terminal domain (N-term) and a 300-residue C-terminal domain (C-term). The loss of FAH activity, which is responsible for phenylalanine and tyrosine degradation, would be lethal to humans. In the absence of FAH, metabolites such as maleylacetoacetate (MAA), fumarylacetoacetate (FAA) and succinylacetone (SUAC) accumulate during tyrosine degradation. In a mammalian cell assay, FAA has been shown to have mutagenic activity to induce cell cycle arrest at G2/M and apoptosis [8]
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