Abstract
Recently Hillman and Otto showed tiglic acid to inhibit glycine-serine interconversion in fibroblasts from a patient with β-ketothiolase deficiency and normal cells. In order to elucidate the mechanism of these phenomena, the effects of tiglyl CoA and related compounds on partially purified rabbit liver serine hydroxymethyltransferase (SHMT) were investigated. The rate of conversion of serine to glycine was measured as described by Schirch. Using SHMT 27. 7 units/ml, serine 16mM, and dl-L-tetrahydrofolate 0.32mM, the concentration of tiglyl CoA and % inhibition (N=5, Mean ±S. E. M.) of the enzyme activity were 2.5mM 15±1.5, 5.0mM 28±2.4, 7.5mM 40±2.8, 10mM 41±3.3. Isovaleryl CoA, n-valeryl CoA, crotonyl CoA and isobutyryl CoA also showed inhibitory effects, but at a lesser degree than tiglyl CoA. n-Butyryl CoA, propionyl CoA and CoA inhibited only slightly. Tiglate, isovalerate, n-valerate, crotonate, isobutyrate and β-methylcrotonate at a concentration of 30mM were incapable of inhibiting SHMT activity. Tiglyl CoA inhibition showed competitive kinetics with tetrahydrofolate, but not serine. The findings suggest that impaired glycine-serine metabolism in the ketotic hyperglycinemia syndrome may, at least in part, result from inhibition of SHMT by high intracellular concentration of Tiglyl CoA.
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Ho, C., Hillman, R. & Dodge, P. STUDIES ON KETOTIC HYPERGLYCINEMIA-INHIBITORS OF SERINE HYDROXYMETHYL TRANSFERASE. Pediatr Res 8, 433 (1974). https://doi.org/10.1203/00006450-197404000-00559
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DOI: https://doi.org/10.1203/00006450-197404000-00559