Ap. Doskeland et T. Flatmark, RECOMBINANT HUMAN PHENYLALANINE-HYDROXYLASE IS A SUBSTRATE FOR THE UBIQUITIN-CONJUGATING ENZYME-SYSTEM, Biochemical journal, 319, 1996, pp. 941-945
Mammalian phenylalanine hydroxylase (PAH) catalyses the conversion of
L-phenylalanine to L-tyrosine in the presence of dioxygen and tetrahyd
robiopterin; it is a highly regulated enzyme. Little is known about th
e rates of synthesis and degradation of PAH in vivo. The enzyme has be
en reported to have a half-life of approx. 2 days in rat liver and 7-8
h in rat hepatoma cells, but the mechanism of its degradation is not
known. In the present study it is shown that the tetrameric form of th
e recombinant wild-type human enzyme is a substrate for the ubiquitin-
conjugating enzyme system in the cytosolic fraction of rat testis. Our
findings support the conclusion that multi-/poly-ubiquitination of hu
man PAH plays a key role in the turnover of this cytosolic liver enzym
e and provides a mechanism for the increased turnover observed for a n
umber of recombinant mutant forms of the enzyme related to the metabol
ic disorder phenylketonuria, when expressed in eukaryotic cells.