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SummaryNormal hemostasis depends in part on the balance achieved between proaggregatory and prothrombotic platelet thromboxane A*, measured as its stable end-product thromboxane Bz (TXBz), and vascular prostacyclin (PGI~), which inhibits platelet aggregation and is antithrombotic. Cvstathionine-Bsvnthase deficiencv is characterized by a high frequkncy of thro1;lbokmbolic disease. w e therefore studied, in vitro, the effects of homocysteine and related compounds on platelet TXBp and vascular PGIz formation.In paired samples of platelet rich plasma, which had been preincubated with L-homocystine (1 mM), mean production of the two platelet cyclooxygenase products, TXBz and 12-hydroxy-5, 8,lO-heptadecatrienoic acid increased significantly from control levels 113.6% + 1.9 to 19.8% + 2.1 ( P < 0.02) TXBz and 29.8% + 4.2 to 39.4% + 4.1 ( P < 0.01) HHTI. In the presence of D,Lhomocysteine (1 mM), mean platelet TXBz and 12-hydroxy-5,8,10-heptadecatrienoic acid production was also significantly increased 112.7% +-1.5 to 16.9% + 1.5 ( P < 0.01) TXBz and 27% + 4 to 31% The homocystinurias occur as a result of genetically determined defects in the metabolism of homocysteine (15). The most common etiology, cystathionine-P-synthase deficiency, results in a decrease in the rate of conversion of homocysteine to cystathionine and is generally accompanied by hyperðionine&ia. Deficiencies in the remethylation of homocysteine to methionine cause homocystinemia accompanied by hypomethioninemia but are much less common. In all these disorders, accumulated homocysteine is oxidized to homocystine, which is found in excessive amounts in blood and urine.Cystathionine-P-synthase dificiency is characterized by ectopia lentis, skeletal deformities, central nervous system abnormalities and a high frequency of thromboembolic disease. Atherosclerosis and occlusion of major vessels such as myocardial, cerebral, renal and pulmonary arteries and veins may occur as early as the first decade, often with fatal results (15).Studies on other disorders with a high incidence of thrombotic complications suggest that normal heGostasis depends in part on the balance achieved between proaggregatory and prothrombotic platelet thromboxane A2 and vascular prostacyclin, which inhibits platelet aggregation and is thus antithrombotic (14). We therefore undertook an in vitro study of the effects of homocysteine and related compounds on platelet thromboxane and vascular prostacyclin formation. MATERIALS AND METHODSEvaluation of platelet arachidonic acid metabolism after incubation in vitro with homocystine, homocysteine, cystine, cysteine, or methionine. Blood samples were obtained after informed consent from control subjects using a two-syringe technique and 9 volumes of blood to 1 volume citrate-phosphate-dextrose solution. Plateletrich plasma (PRP) was obtained by centrifugation of the samples at 200 X g for 20 min. PRP from each control was divided into three aliquots. Hank's balanced salt solution (HBSS) was added to one aliquot as a control, whereas L-homoc...

Two of the three known metabolic pathways to serine and glycine have been shown to be present in prototrophic yeast strains, i.e., the phosphorylated pathway from glycolytic intermediates and the glyoxylate pathway from tricarboxylic acid cycle intermediates. Two serine-glycine auxotrophs ( ser1 and ser2 ) were found to be blocked in the phosphoglycerate pathway. The ser1 gene controls l -glutamate:phosphohydroxypyruvate transaminase biosynthesis, and the ser2 gene controls phosphoserine phosphatase biosynthesis. The other pathway to glycine, from isocitrate, is repressed by growth in glucose media, specifically, at isocitrate lyase and at the alanine:glyoxylate transaminase. This pathway is derepressed by growth to stationary phase in glucose media yielding high activity of these enzymes. The phosphorylated pathway appears to be the principal biosynthetic pathway to serine and glycine during growth on sugar media. Strains which are serine-glycine dependent in glucose media became capable of serine-glycine independent growth on acetate media. These results describe a method of physiological control of a secondary metabolic pathway allowing a single lesion in the principal biosynthetic pathway to produce auxotrophy. This may be termed conditional auxotrophy.