5380-36-9Relevant articles and documents
Substrate specificity determinants of the methanogen homoaconitase enzyme: Structure and function of the small subunit
Jeyakanthan, Jeyaraman,Drevland, Randy M.,Gayathri, Dasara Raju,Velmurugan, Devadasan,Shinkai, Akeo,Kuramitsu, Seiki,Yokoyama, Shigeyuki,Graham, David E.
, p. 2687 - 2696 (2010)
The aconitase family of hydro-lyase enzymes includes three classes of proteins that catalyze the isomerization of a-hydroxy acids to β-hydroxy acids. Besides aconitase, isopropylmalate isomerase (IPMI) proteins specifically catalyze the isomerization of α,β-dicarboxylates with hydrophobic y-chain groups, and homoaconitase (HACN) proteins catalyze the isomerization of tricarboxylates with variable chain length y-carboxylate groups. These enzymes' stereospecific hydro-lyase activities make them attractive catalysts to produce diastereomers from unsaturated precursors. However, sequence similarity and convergent evolution among these proteins lead to widespread misannotation and uncertainty about gene function. To find the substrate specificity determinants of homologous IPMI and HACN proteins from Methanocaldococcus jannaschii, the small-subunit HACN protein (MJ1271 ) was crystallized for X-ray diffraction. The structural model showed characteristic residues in a flexible loop region between α2 and α3 that distinguish HACN from IPMI and aconitase proteins. Site-directed mutagenesis of MJ1271 produced loop-region variant proteins that were reconstituted with wild-type MJ1003 large-subunit protein. The heteromers formed promiscuous hydro-lyases with reduced activity but broader substrate specificity. Both R26K and R26V variants formed relatively efficient IPMI enzymes, while the T27A variant had uniformly lower specificity constants for both IPMI and HACN substrates. The R26V T27Y variant resembles the MJ1277IPMI small subunit in its flexible loop sequence but demonstrated the broad substrate specificity of the R26V variant. These mutations may reverse the evolution of HACN activity from an ancestral IPMI gene, demonstrating the evolutionary potential for promiscuity in hydro-lyase enzymes. Understanding these specificity determinants enables the functional reannotation of paralogous HACN and IPMI genes in numerous genome sequences. These structural and kinetic results will help to engineer new stereospecific hydro-lyase enzymes for chemoenzymatic syntheses.
N-HYDROXYAMIDE DERIVATIVES AND USE THEREOF
-
Page/Page column 93-94, (2008/06/13)
The present invention is related to N-hydroxyamide derivatives of Formula (I) and use thereof, in particular for the treatment and/or prophylaxis of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, cancer, respiratory diseases and fibrosis, including multiple sclerosis, arthritis, emphysema, chronic obstructive pulmonary disease, liver and pulmonary fibrosis.
Enantioselective Synthesis of (2R,3S)-3-Alkylmalic Acids, Competent Substrates for 3-Isopropylmalate Dehydrogenase
Kakinuma, Katsumi,Terasawa, Hiroaki,Li, Hui-Ying,Miyazaki, Kentaro,Oshima, Tairo
, p. 1916 - 1923 (2007/10/02)
A series of (2R,3S)-3-alkylmalic acids was enantioselectively synthesized, in conjunction with biochemical studies on the thermostable isopropylmalate dehydrogenase derived from Thermus thermophilus, by the chirality transcription approach, using a conceptually recyclable carbohydrate template.The dianion -Wittig rearrangement of alkylated allyloxyacetic acids prepared from alkylallyl tertiary-carbinols was effective in both reactivity and stereoselectivity to afford the desired diastereomers in a high yield.The derived γ,δ-unsaturated α-hydroxycarboxylic acids were oxidatively transformed into the desired (2R,3S)-3-alkylmalic acid derivatives.
