ABSTRACT
Patients with homocystinuria due to cystathionine synthase deficiency do not have free homocystine in the liver when it is present in high concentrations in the plasma and the urine. The liver of these patients is capable of maintaining normal concentrations of cystine at a time when the plasma cystine concentration is severely reduced. There is an increase in the methionine concentration of the liver which is reduced to normal concentrations during pyridoxine therapy.
Subject(s)
Amino Acids, Sulfur/metabolism , Cystathionine beta-Synthase/deficiency , Homocystinuria/metabolism , Hydro-Lyases/deficiency , Liver/metabolism , Pyridoxine/therapeutic use , Cystathionine beta-Synthase/metabolism , Homocystinuria/drug therapy , Homocystinuria/etiology , Humans , Liver/drug effects , Liver/enzymology , Male , Pyridoxine/pharmacologyABSTRACT
The metabolic response of patients with homocystinuria due to cystabhionine synthase deficiency to oral loads of homocysteine indicates: that even severely affected patients with homocystinuria have pools of cystine in their tissues; that control of sulfur amino acid metabolism favors increased concentrations of methionine rather than homocystine in the plasma; and that even patients who apparently are not B-6-responsive respond differently to the loads of homocysteine when challenged during B-6-treatment compared with their response before B-6 treatment. Loading tests with homocysteine indicate that B-6 treatment be of some benefit even in individuals who do not have an obvious biochemical response to such therapy.
Subject(s)
Cystathionine beta-Synthase/deficiency , Cysteine , Homocysteine , Homocystinuria/metabolism , Hydro-Lyases/deficiency , Pyridoxine/pharmacology , Cysteine/metabolism , Cystine/blood , Cystinuria , Disulfides/blood , Disulfides/urine , Female , Homocysteine/metabolism , Homocystine/blood , Homocystine/urine , Humans , Male , Pyridoxine/therapeutic use , Time FactorsABSTRACT
The thermostability of cystathionine synthase and the effect of pyridoxal phosphate (PLP) on this thermostability were investigated in extracts of normal human liver and in extracts of liver, both before and during pyridoxine (vitamin B6) therapy, from members of a family with three clinically and biochemically typical, B6-responsive, synthase-deficient sibs. Incubation of crude extracts of normal liver at 55 degrees (preincubation) for 3-4 min before assay consistently resulted in a more than 2-fold increase in specific activity (activation) of cystathionine synthase (Fig. 1). With periods of preincubation longer than 4 min, thermal inactivation occurred. When PLP was added to the preincubation mixture, slightly more activation occurred in the first 3-4 min, and there was no observable loss of activity for an additional 25 min. The activation phenomenon was not observed in extracts of liver which had been obtained from three synthase-deficient sibs before therapy with vitamin B6 (Index of activation, Table 1). When extracts of liver obtained during vitamin B6 therapy were studied, however, significant activation was observed. Synthase activity in extracts of liver from the patients' parents, obligate heterozygotes for synthase deficiency, and from a potentially heterozygous sister demonstrated activation similar to that found in control liver extracts. With periods of preincubation longer than 5 min, the inactivation of synthase in liver extracts from patients receiving pyridoxine-HCl occurred at the same rate as in liver extracts from heterozygotes and from normal subjects (Index of inactivation, Table 1). PLP completely prevented heat inactivation of enzyme from normal liver.
