We plan to continue the identification and characterization of transport systems whereby amino acids generated by physiological proteolysis in the lysosome are released from that organelle, and perhaps captured by it. The system by which cystine is released from leucocyte lysosomes in non-cystinotics (Gahl et al.) we have now confirmed for the human skin fibroblast. We will continue its comparison with a newly discovered system for transport of cationic amino acids, and explore how the latter system may allow a therapeutic removal of cystine from the lysosome by treatment of the cystinotic patient with selected sulfhydryl compounds such as cysteamine. We hope to generate mixed disulfides of cysteine in vivo with the proposed therapeutic agent, a result apparently obtained with cysteamine. These mixed disulfides should then also escape from the lysosome by a transport system not defective in the cystinotic. We will seek to identify suspected mediating systems by which dipolar and anionic amino acids escape. For this purpose, our work so far persuades us that for sufficient precision we will need to purify lysosomes well beyond the stage of the granular fraction which has served so far. The identification of the set of amino acid transport systems serving lysosomal function will we hope enhance understanding of that function, and may identify other congenital lysosomal transport defects as yet unknown. We hope the study will also help us understand how amino acids and proteins are targeted for integration into lysosomal membrane structures.
| Christensen, H N (1990) Role of amino acid transport and countertransport in nutrition and metabolism. Physiol Rev 70:43-77 |
| Christensen, H N (1989) Distinguishing amino acid transport systems of a given cell or tissue. Methods Enzymol 173:576-616 |
| Christensen, H N (1988) Amino acid transport systems of lysosomes: possible substitute utility of a surviving transport system for one congenitally defective or absent. Biosci Rep 8:121-9 |
