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Activities of pyruvate decarboxylase (PDC), alpha-ketoglutarate decarboxylase (KGDC) and both the pyruvate and alpha-ketoglutarate dehydrogenase complexes (PDH complex and KGDH complex) were measured, and kinetic properties of PDC were studied in fibroblasts derived from normal individuals and from a 2-yr-old girl with congenital lactic acidemia and severe retardation of growth and development. The activities of PDC, KGDC, PDH complex, and KGDH complex in the patient were 1.12 +/- 0.12, 2.33 +/- 0.42, 9.00 +/- 0.50, and 16.46 +/- 1.57 and in controls 3.10 +/- 0.16, 5.36 +/- 0.56, 24.13 +/- 1.61 and 44.95 +/- 3.72 nmole/mg protein/hr. The optimum pH (6.0) and Michaelis constants (Km) for pyruvate of PDC (1.0-1.6 X 10(-5) M) were similar in fibroblasts of the patient and controls. PDC activity was more sensitive to denaturation by heat in the fibroblasts of the patient than those from controls, while heat denaturation curves of KGDC were similar in the patient and control. Higher concentrations of thiamine pyrophosphate (TPP) were required to protect PDC from heat denaturation in the patient. TPP was more easily removed from PDC in the patient than in the control by washing the fibroblasts with alkaline buffer. These results suggest that the PDC enzyme of the patient is in an altered molecular form, to which TPP is loosely bound. This particular constellation of abnormalities has not previously been reported in patients with lactic acidemia.
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