1071-23-4Relevant articles and documents
Galstukhova et al.
, (1973)
The stereochemical course of reactions catalysed by Escherichia coli glutamic acid decarboxylase
Tilley,Akhtar,Gani
, p. 68 - 70 (1992)
-
Creation of a S1P Lyase bacterial surrogate for structure-based drug design
Argiriadi, Maria A.,Banach, David,Radziejewska, Elzbieta,Marchie, Susan,Dimauro, Jennifer,Dinges, Jurgen,Dominguez, Eric,Hutchins, Charles,Judge, Russell A.,Queeney, Kara,Wallace, Grier,Harris, Christopher M.
, p. 2293 - 2296 (2016)
S1P Lyase (SPL) has been described as a drug target in the treatment of autoimmune diseases. It plays an important role in maintaining intracellular levels of S1P thereby affecting T cell egress from lymphoid tissues. Several groups have already published approaches to inhibit S1P Lyase with small molecules, which in turn increase endogenous S1P concentrations resulting in immunosuppression. The use of structural biology has previously aided SPL inhibitor design. Novel construct design is at times necessary to provide a reagent for protein crystallography. Here we present a chimeric bacterial protein scaffold used for protein X-ray structures in the presence of early small molecule inhibitors. Mutations were introduced to the bacterial SPL from Symbiobacterium thermophilum which mimic the human enzyme. As a result, two mutant StSPL crystal structures resolved to 2.8 ? and 2.2 ? resolutions were solved and provide initial structural hypotheses for an isoxazole chemical series, whose optimization is discussed in the accompanying paper.
The sphingolipid degradation product trans-2-hexadecenal forms adducts with DNA
Upadhyaya, Pramod,Kumar, Ashok,Byun, Hoe-Sup,Bittman, Robert,Saba, Julie D.,Hecht, Stephen S.
scheme or table, p. 18 - 21 (2012/09/22)
Sphingosine 1-phosphate, a bioactive signaling molecule with diverse cellular functions, is irreversibly degraded by the endoplasmic reticulum enzyme sphingosine 1-phosphate lyase, generating trans-2-hexadecenal and phosphoethanolamine. We recently demonstrated that trans-2-hexadecenal causes cytoskeletal reorganization, detachment, and apoptosis in multiple cell types via a JNK-dependent pathway. These findings and the known chemistry of related α,β-unsaturated aldehydes raise the possibility that trans-2-hexadecenal may interact with additional cellular components. In this study, we show that it reacts readily with deoxyguanosine and DNA to produce the diastereomeric cyclic 1,. N2-deoxyguanosine adducts 3-(2-deoxy-β-d-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8. R-hydroxy-6. R-tridecylpyrimido[1,2-a]purine-10(3. H)one and 3-(2-deoxy-β-d-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8. S-hydroxy-6. S-tridecylpyrimido[1,2-a]purine-10(3. H)one. Thus, our findings suggest that trans-2-hexadecenal produced endogenously by sphingosine 1-phosphate lyase can react directly with DNA forming aldehyde-derived DNA adducts with potentially mutagenic consequences.
Understanding non-enzymatic aminophospholipid glycation and its inhibition. Polar head features affect the kinetics of Schiff base formation
Caldes, Catalina,Vilanova, Bartolome,Adrover, Miquel,Munoz, Francisco,Donoso, Josefa
experimental part, p. 4536 - 4543 (2011/09/19)
Non-enzymatic aminophospholipid glycation is an especially important process because it alters the stability of lipid bilayers and interferes with cell function and integrity as a result. However, the kinetic mechanism behind this process has scarcely been studied. As in protein glycation, the process has been suggested to involve the formation of a Schiff base as the initial, rate-determining step. In this work, we conducted a comparative kinetic study of Schiff base formation under physiological conditions in three low-molecular weight analogues of polar heads in the naturally occurring aminophospholipids O-phosphorylethanolamine (PEA), O-phospho-dl-serine (PSer) and 2-aminoethylphenethylphosphate (APP) with various glycating carbonyl compounds (glucose, arabinose and acetol) and the lipid glycation inhibitor pyridoxal 5′-phosphate (PLP). Based on the results, the presence of a phosphate group and a carboxyl group in α position respect to the amino group decrease the formation constant for the Schiff base relative to amino acids. On the other hand, esterifying the phosphate group with a non-polar substituent in APP increases the stability of its Schiff base. The observed kinetic formation constants of aminophosphates with carbonyl groups were smaller than those for PLP. Our results constitute an important contribution to understanding the competitive inhibition effect of PLP on aminophospholipid glycation.
