Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.14 (ATP synthase)
 7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Batten disease, or juvenile neuronal ceroid-lipofuscinosis, is an autosomal-recessive hereditary disorder that leads to blindness, severe neurological degeneration, and premature death. The disease is characterized by massive accumulation of lysosomal storage bodies in most tissues. A significant constituent of the storage material is a protein that appears to be almost identical to a small hydrophobic inner mitochondrial membrane protein, subunit c of ATP synthase. The protein isolated from the storage bodies contains an epsilon-N-trimethyl-L-lysine (TML) residue at amino acid position 43. The presence of TML in the stored protein suggests that one of the lysine residues in subunit c is normally trimethylated, and this trimethylation may act as a signal to initiate degradation of the protein. Free TML produced by the degradation of TML-containing proteins is the first intermediate in the carnitine biosynthetic pathway. It is possible that trimethylated subunit c is a major source of the free TML used in carnitine biosynthesis. If this is the case, one would predict that the genetic defect resulting in the accumulation of TML containing subunit c would also reduce systemic levels of free TML and carnitine. To evaluate this possibility, plasma TML and carnitine levels were measured in affected human subjects, heterozygous carriers, and normal controls. Both TML and carnitine levels were significantly depressed in the affected individuals. This suggests that subunit c is normally a major source of TML for carnitine biosynthesis. In Batten disease, failure to degrade the TML-containing form of subunit c is probably responsible for the reduction in plasma TML and carnitine levels.
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PMID:Decreased plasma carnitine and trimethyl-L-lysine levels associated with lysosomal accumulation of a trimethyl-L-lysine containing protein in Batten disease. 898 35

Niemann-Pick type C1 (NPC1) disease is a fatal hereditary disorder characterized by a defect in cholesterol trafficking and progressive neurodegeneration. Although the NPC1 gene has been identified, the molecular mechanism responsible for neuronal dysfunction in brains of patients with NPC1 disease remains unknown. This study demonstrates that the amount of cholesterol within mitochondria membranes is significantly elevated in NPC1 mouse brains and neural cells. In addition, the mitochondrial membrane potential, the activity of ATP synthase, and henceforth the level of ATP are markedly decreased in NPC1 mouse brains and neurons. Importantly, reducing the level of cholesterol within mitochondrial membranes using methyl-beta-cyclodextrin can restore the activity of ATP synthase. Finally, NPC1 neurons show an impaired neurite outgrowth, which can be rescued by exogenous ATP. These results suggest that mitochondrial dysfunctions and subsequent ATP deficiency, which are induced by altered cholesterol metabolism in mitochondria, may be responsible for neuronal impairment in NPC1 disease.
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PMID:Altered cholesterol metabolism in Niemann-Pick type C1 mouse brains affects mitochondrial function. 1564 30