Metabolism of phenylalanine in mice homozygous for the gene ‘dilute lethal’

Abstract

Mice homozygous for d(l) have been suggested as models for phenylketonuria. We found: (1) the concentration of phenylalanine in the blood was normal at all ages examined; (2) phenylalanine hydroxylase activity in the liver in vitro equalled that in unaffected littermates; (3) the apparent K(m) values for phenylalanine and cofactor respectively in d(l)/d(l) mice were the same as in their normal littermates; (4) inhibition of the overall reaction by the particulate fraction, excess of substrate, excess of cofactor or phenylpyruvic acid showed no difference between d(l)/d(l) mice and their unaffected littermates; (5) phenylalanine injected in vivo had equal, small, effects on phenylalanine hydroxylase activity of the liver measured in vitro in the two groups of mice. An explanation of the findings of other workers, based on the natural history of the disease process, is tentatively put forward.

The inactivation of phenylalanine hydroxylase by 2-amino-4-hydroxy-6,7-dimethyltetrahydropteridine and the aerobic oxidation of the latter. The effects of catalase, dithiothreitol and reduced nicotinamide–adenine dinucleotide

“…Only in the presence of sufficient amounts of catalase is there a direct relationship between the amount of tyrosine formed and the concentration of the co- factor. The effect of time of incubation on the amount of tyrosine formed has been reported elsewhere (Woolf et al 1970). Effect of dithiothreitol.…”

“…Immediately after the reaotion the tyrosine was determined in a sample of the deproteinized supernatant (Woolf et al 1970) by Phillips' (1967) modification of the method of Waalkes & Udenfriend (1957), by using an Aminco-Bowman spectrofluorimeter at an exciting wavelength of 465nm and measuring the emission at 550nm. In each experiment all values were corrected for a control blank that contained the appropriate liver extract boiled for 3min and incubated under the same conditions; hence the contributions of the tyrosine contained in the liver and that formed non-enzymically during the incubation were eliminated from the determination.…”

Myelin

“…The deficiencies accord with the decreased body weight of the mutant and probably reflect undernutrition as a result of the motor disability. The differences which have been reported in phenylalanine metabolism (Rauch and Yost, 1963;Zannoni et al, 1966) also appear to reflect relative starvation in the homozygous dilute lethal mouse (Woolf et al, 1970).…”

Myelin

“…The deficiencies accord with the decreased body weight of the mutant and probably reflect undernutrition as a result of the motor disability. The differences in phenylalanine metabolism that have been reported (Rauch and Yost, 1963;Zannoni et al, 1966) also appear to reflect relative starvation in the homozygous dilute lethai mouse (Woolf et al, 1970):…”