Abstract
Extract: The amounts of 14C-labeled lysine, arginine, and ornithine taken up by isolated granulocytes of 11 patients with lysinuric protein intolerance (LPI) and of 16 control subjects were measured. Transport against a concentration gradient was evident in all. The initial 5-min uptake was measured in a series of substrate concentrations varying from 0.025—4.0 mM. One transport system was seemingly present for all three amino acids. The rates of transport into the granulocytes in the patients and control subjects were comparable. The Vmax, in millimoles × kilogram of cell water−1 × 5 min−1, ranged only from 0.30—0.38 in the patients and from 0.32—0.34 in the control subjects. The Km values were 0.06 aqd 0.06 mM for lysine, 0.05 and 0.06 for arginine, and 0.10 and 0.09 mM for ornithine in the patients and control subjects, respectively.
The transport of the nonmetabolizable diamino acid analog, homoarginine, into liver slices of three patients and five control subjects was also studied. There was no clear difference in the time course of uptake at 0.05 mM homoarginine concentration in the medium. In kinetic studies of two patients and three control subjects, at least two transport systems were evident. The “large capacity, low affinity” system had Vmax of 0.43 and 3.08 mmol × kg cell water−1 × 15 min−1 and Km of 0.18 and 2.49 mM in the patients and control subjects, respectively. The “small capacity, high affinity” system had Vmax of 0.07 and 0.14 mmol × kg cell water−1 × 15 min−1 and Km of 0.03 and 0.05 mM, respectively. The Vmax of the large capacity, low affinity system in the patients was only [fraction 1 over 7] of that in the control subjects, showing clearly impaired diamino acid uptake by the liver cells in LPI.
Speculation: In LPI diamino acids show depressed plasma concentrations, probably because of their impaired intestinal absorption and increased renal loss. If my findings on the kinetically abnormal diamino acid transport in liver slices of the patients are valid in vivo, the intestinal, renal, and hepatic defects must result in ornithine deficiency in the liver cells. As ornithine is the molecule on which urea is formed in the urea cycle, this deficiency will incapacitate the urea cycle and result in hyperammonemia. This mechanism is consistent with the basic chemical characteristics of LPI, the hyperdibasic aminoaciduria, and hyperammonemia after amino nitrogen loading. The defect of hepatic diamino acid transport is suggested to distinguish LPI from other diseases with low plasma diamino acid concentrations, the classic cystinuria, and the nonhyperammonemic hyperdibasic aminoacidurias.
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Simell, O. Diamino Acid Transport into Granulocytes and Liver Slices of Patients with Lysinuric Protein Intolerance. Pediatr Res 9, 504–508 (1975). https://doi.org/10.1203/00006450-197505000-00008
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DOI: https://doi.org/10.1203/00006450-197505000-00008