Metabolic Correction of Triose Phosphate Isomerase Deficiencyin Vitroby Complementation

Abstract Inherited deficiency of triose phosphate isomerase (TPI), the enzyme that catalyses the interconversion of dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate, is characterised by an accumulation of intracellular DHAP and markedly reduced enzyme activity in cells and tissues, resulting in progressive, usually fatal neuromuscular dysfunction. Since specific enzyme replacement for TPI deficiency is not currently available, the secretion and recapture of the missing enzyme was investigated in a co-culture model comprising K562 human erythroleukaemia cells and lymphoblastoid cells taken from a TPI deficient patient. A sevenfold reduction in intracellular DHAP with concomitant increase in intracellular TPI activity from 7.25±0.1 to 197.2±10 units/mg protein was achieved for co-cultured lymphoblastoid cells. These novel results confirm the existence of a transport mechanism which permits transfer of active TPI from K562 cells to deficient cells, and may have important implications for developing different therapeutic approaches for TPI deficiency and other metabolic disorders of glycolysis.