Evidence for Transfer of Enzyme Product as the Basis of Metabolic Cooperation between Tissue Culture Fibroblasts of Lesch-Nyhan Disease and Normal Cells

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Abstract
Tissue culture fibroblasts derived from patients with Lesch-Nyhan disease (congenital hyperuricosuria) have a reduced IMP:pyrophosphate phosphoribosyltransferase (EC 2.4.2.8) activity and therefore incorporate, as detected by radioautography, much smaller amounts of tritiated hypoxanthine or guanine into cell nuclei and cytoplasm than do normal cells. However, Lesch-Nyhan cells grown in close contact with normal fibroblasts incorporate these purines. This phenomenon, which requires cell to cell contact for correction of the mutant phenotype, has been called metabolic cooperation. After separation of Lesch-Nyhan cells from normal cells, there is a prompt reversion to the mutant phenotype although the transferase is stable under these conditions for many hours. These results are most compatible with the transfer from normal to mutant fibroblasts of the product of the normal enzyme, a nucleotide or a nucleotide derivative, rather than the transfer of the transferase or informational macromolecules leading to the synthesis of the enzyme. Metabolic cooperation may provide a mechanism for maintaining normal cell function in the heterozygote in vivo . Evidence has been presented previously that selection of normal cells, presumably during embryogenesis, also provides a means for achieving normal function in the heterozygote.