A dPhelicate intracellular balance among protein synthesis, folding, and degradation is essential to maintaining protein homeostasis or proteostasis, and it is challenged by genetic and environmental factors. Molecular chaperones and the ubiquitin proteasome system (UPS) play a vital role in proteostasis for normal cellular function. As part of protein quality control, molecular chaperones recognize misfolded proteins and assist in their refolding. Proteins that are beyond repair or refolding undergo degradation, which is largely mediated by the UPS. The importance of protein quality control is becoming ever clearer, but it can also be a disease-causing mechanism. Diseases such as nylalanine hydroxylase (PAH) and fumarylacetoacetate hydroxylase (FAH) are two highly regulated liver enzymes that catalyze the rate-limiting step in phenylalanine and tyrosine metabolism. Mammalian PAH (phenylalanine 4-monooxygenase, E.C. 1.14.16.1) catalyzes the stereospecific hydroxylation of L-phenylketonuria (PKU) and hereditary alanine into L-tyrosinemia-I (HT1) are caused due to mutations in PAH and FAH  usingene, resulting in reduced protein stability, misfolding, accelerated degradatitetrahydrobiopterin (BH4), non-heme iron, and deficiency in functional proteins. Misfolded or partially unfolded proteins do not necessarily lose their functional activity completely. Thus, partially functional proteins can be rescued from degradation by molecular chaperones and deubiquitinating enzymes (DUBs). Deubiquitination is an important mechanism of the UPS that can reverseioxygen as co-substrates in the cytosol of the liver and kidney. PAH facilitates oxidation of excess L-phenylalanine into carbon dioxide and water, and is the major enzyme degrading 75% of L-phenylalanine from the degradation of a substrateiet. PAH assembles as a homotetrameric protein by covalently removing its attached ubiquitin molecule. In this review, we discuss the importance of molecular chaperones and DUBs in reducing the severity of PKU and HT1 by stabilizing and rescuing mutant proteins, each subunit composed of N-terminal regulatory domain for allosteric activation by Phe, a central catalytic domain, and C-terminal helix responsible for tetramer formation.