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Biomedical subjects

L I Woolf

Publications and source records attributed to L I Woolf.

At least 37 records · Page 2Linked to original sources
PubMed1976

Krabbe's leukodystrophy without globoid cells.

Krabbe's infantile cerebral sclerosis with a prolonged course was present in a boy who became increasingly hypertonic during infancy and had an increased protein level in the spinal fluid. At 4 years he showed significant growth failure, profound mental retardation, spastic quadriplegia, bilateral optic atrophy, and depressed tendon reflexes. Conduction velocity in motor fibers of the median nerve had become progressively impaired. Autopsy at 5 years 10 months showed severe leukodystrophy with demyelination and gliosis. No stored breakdown products or globoid cells were seen in the brain. Galactosyl ceramide beta-galactosidase was virtually absent, and hardly any myelin was demonstrable on chemical and electron microscopic studies. The presence of globoid cells may not be essential for the pathologic diagnosis of Krabbe's leukodystrophy in the presence of appropriate enzyme deficiency.

Brain↗
PubMed1976

Arterial plasma amino acids in patients with serious postoperative infection and in patients with major fractures.

Arterial plasma amino acids were measured in 27 patients with serious septic complications after operation, 15 patients following reduction of femoral shaft fractures and nine control patients on the first and third days following uneventful major abdominal surgery. Amino acid concentrations in the controls were similar to those which have been reported during early starvation. The amino acid patterns seen in all groups did not resemble that previously observed following glucocorticoid administration. In the patients with infection, mean phenylalanine concentration (108.0 +/- 46.9 mumoles per liter) was significantly greater than in the controls on the first (p greater than 0.001) or third (p less than 0.001) postoperative days. Four of the septic patients with hyperphenylalaninemia also had elevated arterial methionine concentrations. These observations suggest that many of the patients with sepsis had seriously impaired liver metabolism. In patients with fractures, the concentrations of ornithine (p less than 0.001), taurine (p less than 0.05), and aspartic acid (p less than 0.05) were lower than in controls. No other significant differences of amino acid concentrations were observed. It is difficult to relate these differences to a specific metabolic abnormality.

Abdomen, Acute↗
PubMed1975

Phenylketonuria as a balanced polymorphism: the nature of the heterozygote advantage.

Mothers of children with phenylketonuria have a significantly lower miscarriage rate than a matched control population in Ireland and west Scotland. This protective effect of the gene against some factor causing foetal death would seem to constitute a heterozygote advantage which might account for the previously observed polymorphism for phenylketonuria. It is suggested that the decrease in foetal mortality is mediated by the higher concentration of phenylalanine in the heterozygous mother's blood, but that this is not a simple nutritional effect of an increased supply of an essential amino acid leading to increased protein deposition.

Abortion, Spontaneous↗
PubMed1974

The isolation and properties of phenylalanine hydroxylase from rat liver.

Phenylalanine hydroxylase was prepared from rat liver and purified 200-fold to about 90% purity. All the enzymic activity of the liver appeared in a single protein of mol.wt. approx. 110000, but omission of dithiothreitol and of a preliminary filtration step to remove lipids resulted in partial conversion into a second enzymically active protein of mol.wt. approx. 250000. The K(m) and V(max.) values of the enzyme for phenylalanine, p-fluorophenylalanine and dimethyltetrahydropterin were measured; p-chlorophenylalanine inhibited the enzyme by competing with phenylalanine. Disc gel electrophoresis at pH7.2 showed a single protein band containing all the enzymic activity, but at pH8.7 the enzyme dissociated into two inactive fragments of similar but not identical molecular weight. The molecule of phenylalanine hydroxylase contained two atoms of iron, one atom of copper and one molecule of FAD; molybdenum was absent. Treatment with chelating agents showed that both non-haem iron and copper were necessary for enzymic activity. The molecule contained five thiol groups, and thiol-binding reagents inhibited the enzyme. Catalase or peroxidase enhanced enzymic activity fivefold; it is postulated that catalase (or other peroxidase) plays a part in the hydroxylation reaction independent of the protection by catalase of enzyme and cofactor from inactivation by a hydroperoxide.

Animals↗
PubMed1974

The isolation and properties of phenylalanine hydroxylase from human liver.

Phenylalanine hydroxylase was prepared from human foetal liver and purified 800-fold; it appeared to be essentially pure. The phenylalanine hydroxylase activity of the liver was confined to a single protein of mol.wt. approx. 108000, but omission of a preliminary filtration step resulted in partial conversion into a second enzymically active protein of mol.wt. approx. 250000. Human adult and full-term infant liver also contained a single phenylalanine hydroxylase with molecular weights and kinetic parameters the same as those of the foetal enzyme; foetal, newborn and adult phenylalanine hydroxylase are probably identical. The K(m) values for phenylalanine and cofactor were respectively one-quarter and twice those found for rat liver phenylalanine hydroxylase. As with the rat enzyme, human phenylalanine hydroxylase acted also on p-fluorophenylalanine, which was inhibitory at high concentrations, and p-chlorophenylalanine acted as an inhibitor competing with phenylalanine. Iron-chelating and copper-chelating agents inhibited human phenylalanine hydroxylase. Thiol-binding reagents inhibited the enzyme but, as with the rat enzyme, phenylalanine both stabilized the human enzyme and offered some protection against these inhibitors. It is hoped that isolation of the normal enzyme will further the study of phenylketonuria.

Adult↗
PubMed1971

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.

1. Phenylalanine hydroxylase is inhibited by its cofactor, 6,7-dimethyltetrahydropterin. The rate of inactivation, which is irreversible, increases with the concentration of cofactor. 2. Catalase, in sufficient amount relative to cofactor, prevents this inactivation. More tyrosine is formed in the presence of added catalase. 3. Dithiothreitol in the presence of liver extract also prevents inactivation of the enzyme by the cofactor and stimulates hydroxylation of phenylalanine, probably by protecting the cofactor from oxidation and regenerating it from a dihydropterin reaction product. Dithiothreitol restores linearity of rate at very low enzyme concentrations. 4. Dimethyltetrahydropterin is unstable when the solution is exposed to air but is stabilized by dithiothreitol the aerobic oxidation of which is greatly accelerated by dimethyltetrahydropterin. 5. NADH together with liver extract stabilizes the cofactor but not phenylalanine hydroxylase. 6. It is suggested that either hydrogen peroxide or an organic peroxide formed by oxidation in air of the cofactor is the substance attacking phenylalanine hydroxylase, dithiothreitol and cofactor.

Air↗
PubMed1971

The non-enzymic hydroxylation of phenylalanine to tyrosine by 2-amino-4-hydroxy-6,7-dimethyl-5,6,7,8-tetrahydropteridine.

1. Phenylalanine is converted into tyrosine by incubation in air with 6,7-dimethyltetrahydropterin, which is a cofactor for the enzymic hydroxylation. This can cause serious inaccuracies in assays of phenylalanine hydroxylase. 2. The non-enzymic reaction is not specific for l-phenylalanine. 3. m-Tyrosine, o-tyrosine and dihydroxyphenylalanines are formed in addition to p-tyrosine; their chromatographic separation and assay are described. 4. l-[(14)C]Phenylalanine as purchased or soon after purification contains p- and m-tyrosine, both of which can cause errors in the assay of phenylalanine hydroxylase. 5. Catalase prevents the non-enzymic hydroxylation. Thiol compounds in low concentrations stimulate the reaction but in high concentrations are inhibitory. Fe(2+) and metal complexing agents have small stimulatory effects. 6. The mechanism of the non-enzymic reaction and its possible relation to the enzymic hydroxylation of phenylalanine are discussed; it is suggested that phenylalanine is attacked by a peroxide of the cofactor.

Air↗
PubMed1970

Metabolism of phenylalanine in mice homozygous for the gene 'dilute lethal'.

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.

Animals↗