caa a22 4500 467932808 CHVBK 20180406152948.0 cr unu---uuuuu 170328e20060201xx s 000 0 eng 10.1007/s10545-006-0225-z doi (NATIONALLICENCE)springer-10.1007/s10545-006-0225-z Inefficient cleavage of palmitoyl-protein thioesterase (PPT) substrates by aminothiols: Implications for treatment of infantile neuronal ceroid lipofuscinosis [Elektronische Daten] [J.-Y. Lu, S. Hofmann] Summary: Infantile neuronal ceroid lipofuscinosis (INCL, also known as infantile Batten disease) is a devastating neurodegenerative disorder caused by deficiency in the lysosomal enzyme palmitoyl-protein thioesterase (PPT, or CLN1), which functions to remove long-chain fatty acids from cysteine residues in proteins. A previous study suggested that the drug cysteamine, a simple aminothiol used in the treatment of cystinosis, may have utility in the treatment of INCL. In the current study, we compared the catalytic rate constants for the conversion of palmitoyl-CoA (a PPT substrate) and cystine (which accumulates in cystinosis) by cysteamine. We found that while cysteamine can react with palmitoyl-CoA, the rate constant is 103-fold less than the reaction with cystine. Structure-activity studies suggested that it is the thiolate ion that is reactive in the cleavage reaction and that the amino group probably facilitates lysosomal entry. A modest effect of cysteamine (and two related aminothiols, WR 1065 and dimethylaminoethanethiol, DMAET) on PPT substrate accumulation in INCL lymphoblasts was observed. However, at optimum concentration a paradoxical increase in saposin immunoreactivity was seen, indicating possible lysosomal dysfunction. Improvements are needed in the design of small molecules for the treatment of INCL disease. SSIEM and Springer, 2006 Lu J.-Y Department of Internal Medicine and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA aut Hofmann S. Department of Internal Medicine and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA aut Journal of Inherited Metabolic Disease Kluwer Academic Publishers 29/1(2006-02-01), 119-126 0141-8955 29:1<119 2006 29 10545 https://doi.org/10.1007/s10545-006-0225-z text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10545-006-0225-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Lu J.-Y Department of Internal Medicine and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA aut NATIONALLICENCE 700 1- Hofmann S. Department of Internal Medicine and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA aut NATIONALLICENCE 773 0- Journal of Inherited Metabolic Disease Kluwer Academic Publishers 29/1(2006-02-01), 119-126 0141-8955 29:1<119 2006 29 10545 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer