Glutamate dehydrogenase contributes to leucine sensing in the regulation of autophagy

Amino acids, leucine in particular, are known to inhibit autophagy, at least in part by their ability to stimulate MTOR-mediated signaling. Evidence is presented showing that glutamate dehydrogenase, the central enzyme in amino acid catabolism, contributes to leucine sensing in the regulation of autophagy. The data suggest a dual mechanism by which glutamate dehydrogenase activity modulates autophagy, i.e., by activating MTORC1 and by limiting the formation of reactive oxygen specie

Development of adamantan-1-yl-methoxy-functionalized 1-deoxynojirimycin derivatives as selective inhibitors of glucosylceramide metabolism in man

In this article, we present a straightforward synthesis of adamantan-1-yl-methoxy-functionalized 1-deoxynojirimycin derivatives. The used synthetic routes are flexible and can be used to create a wide variety of lipophilic mono- and difunctionalized 1-deoxynojirimycin derivatives. The compounds reported here are lipophilic iminosugar based on lead compound 4, a potent inhibitor of the three enzymes involved in the metabolism of the glycosphingolipid glucosylceramide. Iminosugar-based inhibitors of glucosylceramide synthase, one of these three enzymes, have attracted increasing interest over the past decade due to the crucial role of this enzyme in glycosphingolipid biosynthesis. Combined with the fact that an increasing number of pathological processes are being linked to excessive glycosphingolipid levels, glucosylceramide synthase becomes a very attractive therapeutic and research target. Our results presented here demonstrate that relocating the lipophilic moiety from the nitrogen atom to other positions on the 1-deoxynojirimycin ring system does not lead to a more potent or selective inhibitor of glucosylceramide synthase. The beta-aza-C-glycoside analogue (17) retained the best inhibitory potency for glucosylceramide synthase and is a more potent inhibitor than the therapeutic agent N-butyl-1-deoxynojirimycin (3), marketed as treatment for Gaucher disease under the commercial name Zavesc

Lysosomal glycosphingolipid catabolism by acid ceramidase: formation of glycosphingoid bases during deficiency of glycosidases

Glycosphingoid bases are elevated in inherited lysosomal storage disorders with deficient activity of glycosphingolipid catabolizing glycosidases. We investigated the molecular basis of the formation of glucosylsphingosine and globotriaosylsphingosine during deficiency of glucocerebrosidase (Gaucher disease) and α-galactosidase A (Fabry disease). Independent genetic and pharmacological evidence is presented pointing to an active role of acid ceramidase in both processes through deacylation of lysosomal glycosphingolipids. The potential pathophysiological relevance of elevated glycosphingoid bases generated through this alternative metabolism in patients suffering from lysosomal glycosidase defects is discusse

Synthesis and evaluation of dimeric lipophilic iminosugars as inhibitors of glucosylceramide metabolism

Four dimeric and four monomeric lipophilic iminosugars were synthesized and subsequently evaluated on their inhibitory potential towards mammalian glucosylceramide synthase, glucocerebrosidase, beta-glucosidase 2, sucrase and lysosomal alpha-glucosidase. Compared to their monomeric counterparts the dimeric inhibitors showed decreased inhibition of glucosylceramide synthase and generally a comparable inhibitory potency for the glycosidases. (C) 2009 Elsevier Ltd. All rights reserve

Tissue and cell-type dependent impact of secondary glucocerebrosidase abnormalities due to LIMP-2 deficiency

Sphingolipidoses comprise the most prevalent group of lysosomal storage disorders. The most frequent is Gaucher disease (GD), where it occurs the storage of the glycosphingolipid glucosylceramide (GlcCer) due to a deficiency in the enzyme glucocerebrosidase (GCase). GD is a multi-systemic disorder affecting most organs, resulting in cytopenia, hepatosplenomegaly and skeletal abnormalities. Only recently, lysosomal integral membrane protein, type 2 (LIMP-2) has been identified as the receptor involved in the intracellular sorting and trafficking of the enzyme GCase to lysosomes. Deficiency of LIMP-2 causes Action Myoclonic-Renal Failure (AMRF), which clinically differs from GD. AMRF patients present renal dysfunction and failure, myoclonic epilepsy and ataxia with progressive neurological impairment .N/

Perguntamos: qual é o diagnóstico? We ask: what is the diagnosis?

Centro de Medicina Diagnóstica FleuryUniversidade Federal de São Paulo (UNIFESP)University of British ColumbiaUNIFESPSciEL