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Jun, Hee-jin,Hoang, Minh-Hien,Lee, Jin Woo,Yaoyao, Jia,Lee, Ji-Hae,Lee, Dong-Ho,Lee, Hak-Ju,Seo, Woo-Duck,Hwang, Bang Yeon,Lee, Sung-Joon Kluwer Academic Publishers 2012 Biotechnology letters Vol.34 No.12
<P>A novel liver X receptor (LXR) modulator, iristectorigenin B isolated from Belamcanda chinensis, stimulated the transcriptional activity of both LXR-α and LXR-β. In macrophages, iristectorigenin B suppressed cholesterol accumulation in a dose-dependent manner and induced the transcriptional activation of LXR-α/-β-responsive genes, ATP-binding cassette transporters A1 and G1. It did not induce hepatic lipid accumulation nor the expression of the lipogenesis genes sterol regulatory element-binding protein-1c, fatty acid synthase, and stearoyl-CoA desaturase-1. Iristectorigenin B thus is a dual-LXR agonist that regulates the expression of key genes in cholesterol homeostasis in macrophage cells without inducing hepatic lipid accumulation.</P>
Structure of the ArgRS–GlnRS–AIMP1 complex and its implications for mammalian translation
Fu, Yaoyao,Kim, Youngran,Jin, Kyeong Sik,Kim, Hyun Sook,Kim, Jong Hyun,Wang, DongMing,Park, Minyoung,Jo, Chang Hwa,Kwon, Nam Hoon,Kim, Doyeun,Kim, Myung Hee,Jeon, Young Ho,Hwang, Kwang Yeon,Kim, Sungh National Academy of Sciences 2014 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.111 No.42
<P><B>Significance</B></P><P>In higher eukaryotes, aminoacyl-tRNA synthetases (ARSs) are assembled to form a multisynthetase complex (MSC), which plays critical roles in translation and nontranslation functions essential for cell growth and survival of organisms. The MSC complex is comprised of nine different ARSs and three accessary proteins. The crystal structure of the arginyl-tRNA synthetase (ArgRS)–glutaminyl-tRNA synthase–aminoacyl tRNA synthetase complex-interacting multifunctional protein 1 (AIMP1) subcomplex reveals that the N-terminal domains of ArgRS and AIMP1 form an extended coiled-coil structure, which provides a central depot for the assembly of a ternary complex. The stability of the N-terminal helix of ArgRS is critical for its ARS activity and noncanonical function of the subcomplex, explaining the significance of the MSC structure in translation and cellular functions.</P><P>In higher eukaryotes, one of the two arginyl-tRNA synthetases (ArgRSs) has evolved to have an extended N-terminal domain that plays a crucial role in protein synthesis and cell growth and in integration into the multisynthetase complex (MSC). Here, we report a crystal structure of the MSC subcomplex comprising ArgRS, glutaminyl-tRNA synthetase (GlnRS), and the auxiliary factor aminoacyl tRNA synthetase complex-interacting multifunctional protein 1 (AIMP1)/p43. In this complex, the N-terminal domain of ArgRS forms a long coiled-coil structure with the N-terminal helix of AIMP1 and anchors the C-terminal core of GlnRS, thereby playing a central role in assembly of the three components. Mutation of AIMP1 destabilized the N-terminal helix of ArgRS and abrogated its catalytic activity. Mutation of the N-terminal helix of ArgRS liberated GlnRS, which is known to control cell death. This ternary complex was further anchored to AIMP2/p38 through interaction with AIMP1. These findings demonstrate the importance of interactions between the N-terminal domains of ArgRS and AIMP1 for the catalytic and noncatalytic activities of ArgRS and for the assembly of the higher-order MSC protein complex.</P>
Jun, Hee-jin,Lee, Ji Hae,Kim, Jiyoung,Jia, Yaoyao,Kim, Kyoung Heon,Hwang, Kwang Yeon,Yun, Eun Ju,Do, Kyoung-Rok,Lee, Sung-Joon American Society for Biochemistry and Molecular Bi 2014 Journal of lipid research Vol.55 No.6
<P>We investigated the hypotriglyceridemic mechanism of action of linalool, an aromatic monoterpene present in teas and fragrant herbs. Reporter gene and time-resolved fluorescence resonance energy transfer assays demonstrated that linalool is a direct ligand of PPARα. Linalool stimulation reduced cellular lipid accumulation regulating PPARα-responsive genes and significantly induced FA oxidation, and its effects were markedly attenuated by silencing PPARα expression. In mice, the oral administration of linalool for 3 weeks reduced plasma TG concentrations in Western-diet-fed C57BL/6J mice (31%, <I>P</I> < 0.05) and human apo E2 mice (50%, <I>P</I> < 0.05) and regulated hepatic PPARα target genes. However, no such effects were seen in PPARα-deficient mice. Transcriptome profiling revealed that linalool stimulation rewired global gene expression in lipid-loaded hepatocytes and that the effects of 1 mM linalool were comparable to those of 0.1 mM fenofibrate. Metabolomic analysis of the mouse plasma revealed that the global metabolite profiles were significantly distinguishable between linalool-fed mice and controls. Notably, the concentrations of saturated FAs were significantly reduced in linalool-fed mice. These findings suggest that the appropriate intake of a natural aromatic compound could exert beneficial metabolic effects by regulating a cellular nutrient sensor.</P>
Hoang, Minh-Hien,Jia, Yaoyao,Jun, Hee-jin,Lee, Ji Hae,Lee, Boo Yong,Lee, Sung-Joon American Chemical Society 2012 Journal of agricultural and food chemistry Vol.60 No.46
<P>Fucosterol, a sterol that is abundant in marine algae, has hypocholesterolemic activity, but the mechanism underlying its effect is not clearly understood. Because data suggest that fucosterol can increase plasma high-density lipoprotein concentrations, we investigated whether it could activate liver X receptors (LXRs), critical transcription factors in reverse cholesterol transport. Fucosterol dose-dependently stimulated the transcriptional activity of both LXR-α and -β in a reporter gene assay, responses that were attenuated by the LXR antagonist As<SUB>2</SUB>O<SUB>3</SUB>. Fucosterol also activated co-activator recruitment in cell-free time-resolved fluorescence resonance energy transfer analysis. In THP-1-derived macrophages, it induced the transcriptional activation of ABCA1, ABCG1, and ApoE, key genes in reverse cholesterol transport, and thereby significantly increased the efflux of cholesterol. Fucosterol also regulated intestinal NPC1L1 and ABCA1 in Caco-2 cells. Notably, fucosterol did not induce cellular triglyceride accumulation in HepG2 cells, primarily because of its upregulation of Insig-2a, which delays nuclear translocation of SREBP-1c, a key hepatic lipogenic transcription factor. These results suggest that fucosterol is a dual-LXR agonist that regulates the expression of key genes in cholesterol homeostasis in multiple cell lines without inducing hepatic triglyceride accumulation.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jafcau/2012/jafcau.2012.60.issue-46/jf3019084/production/images/medium/jf-2012-019084_0006.gif'></P>
Cho, Sung-Yun,Jun, Hee-jin,Lee, Ji Hae,Jia, Yaoyao,Kim, Kyoung Heon,Lee, Sung-Joon Elsevier 2011 FEBS letters Vol.585 No.20
<P><B>Highlights</B></P><P>► Linalool is an aromatic monoterpene abundant in teas and essential oils. ► Linalool feeding significantly lowered LDL cholesterol concentrations in mice. ► Linalool reduced the expression of HMG-CoA reductase by SREBP-2-dependent mechanism. ► Linalool also induced ubiquitin-dependent proteolysis of the HMG-CoA reductase. ► These suggest food compounds with a pleasant scent exert beneficial metabolic effects.</P> <P><B>Abstract</B></P><P>We investigated hypocholesterolemic mechanisms of linalool, an aromatic anti-oxidative monoterpene, which is abundant in teas and essential oils. Oral administration of linalool to mice for 6weeks significantly lowered total and low-density lipoprotein cholesterol concentrations, and HMG-CoA reductase protein expression (−46%; <I>P</I><0.05) by both transcriptional and posttranscriptional mechanisms. Linalool suppressed the gene expression of HMG-CoA reductase by reducing the binding of SREBP-2 to its promoter, as assessed by qPCR and chromatin immunoprecipitation, and by inducing ubiquitin-dependent proteolysis of the HMG-CoA reductase. These findings suggest that food molecules with a pleasant scent could exert beneficial metabolic effects through multiple mechanisms.</P>
Lee, Ji Hae,Jun, Hee-jin,Jia, Yaoyao,Kim, Wook,Choi, Sung-Gil,Lee, Sung-Joon American Chemical Society 2011 Journal of agricultural and food chemistry Vol.59 No.21
<P>The consumption of soy protein and fiber reduces body fat accumulation; however, the mechanism of this effect has not been clearly understood. We investigated the antiobesogenic effect of soy protein and fiber in two different mouse models. Normolipidemic nonobese C57BL/6J and hyperlipidemic obese human apolipoprotein E2 transgenic mice were fed either delipidated soybean (DLSB) containing soy protein and fiber or a control diet. The DLSB-fed mice showed a significant reduction in body weight gain and adiposity compared with controls, in both C57BL/6J and apoE2 mice. All metabolic parameters were significantly improved in the DLSB group compared with controls: total cholesterol, low-density lipoprotein cholesterol, insulin, and leptin levels were significantly reduced. Adiponectin concentrations were significantly elevated, and glucose tolerance was improved. In both types of DLSB-fed mice, the specific induction of PPAR-δ protein expression was evident in muscle and adipose tissues. The expression of PPAR-δ target genes in the DLSB-fed mice was also significantly altered. Acetyl-CoA carboxylase-1 and fatty acid synthase levels in adipose tissue were downregulated, and uncoupling protein-2 in muscle was upregulated. Intestinal expression of fatty acid transport protein-4, cluster of differentiation-36, and acyl-CoA synthetase were significantly downregulated. We propose that marked activation of PPAR-δ is the primary mechanism mediating the antiobesogenic effect of soybean and that PPAR-δ has multiple actions: induction of thermogenesis in muscle, reduction of fatty acid synthesis in adipose tissue, and reduction of fatty acid uptake in intestinal tissue.</P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jf202910u'>ACS Electronic Supporting Info</A></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jf202910u'>ACS Electronic Supporting Info</A></P>
Han, Gui Hwan,Seong, Wonjae,Fu, Yaoyao,Yoon, Paul K.,Kim, Seong Keun,Yeom, Soo-Jin,Lee, Dae-Hee,Lee, Seung-Goo Academic Press 2017 Metabolic engineering Vol.40 No.-
<P><B>Abstract</B></P> <P>Metabolons in nature have evolved to facilitate more efficient catalysis of multistep reactions through the co-localization of functionally related enzymes to cellular organelles or membrane structures. To mimic the natural metabolon architecture, we present a novel artificial metabolon that was created by targeting multi-enzyme cascade reactions onto inclusion body (IB) in <I>Escherichia coli</I>. The utility of this system was examined by co-localizing four heterologous enzymes of the 1-butanol pathway onto an IB that was formed in <I>E. coli</I> through overexpression of the cellulose binding domain (CBD) of <I>Cellulomonas fimi</I> exoglucanase. To target the 1-butanol pathway enzymes to the CBD IB, we utilized a peptide-peptide interaction between leucine zipper (LZ) peptides. We genetically fused the LZ peptide to the N-termini of four heterologous genes involved in the synthetic 1-butanol pathway, whereas an antiparallel LZ peptide was fused to the CBD gene. The <I>in vivo</I> activity of the CBD IB-based metabolon was examined through the determination of 1-butanol synthesis using <I>E. coli</I> transformed with two plasmids containing the LZ-fused CBD and LZ-fused 1-butanol pathway genes, respectively. <I>In vivo</I> synthesis of 1-butanol using the engineered <I>E. coli</I> yielded 1.98g/L of 1-butanol from glucose, representing a 1.5-fold increase over that obtained from <I>E. coli</I> expressing the LZ-fused 1-butanol pathway genes alone. In an attempt to examine the <I>in vitro</I> 1-butanol productivity, we reconstituted CBD IB-based metabolon using CBD IB and individual enzymes of 1-butanol pathway. The 1-butanol productivity of <I>in vitro</I> reconstituted CBD IB-based metabolon using acetoacetyl-CoA as the starting material was 2.29mg/L/h, 7.9-fold higher than that obtained from metabolon-free enzymes of 1-butanol pathway. Therefore, this novel CBD-based artificial metabolon may prove useful in metabolic engineering both <I>in vivo</I> and <I>in vitro</I> for the efficient production of desired products.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Enzyme cascades via heterologous metabolons facilitate host cell product production </LI> <LI> We used leucine zipper (LZ) tags to target metabolon reactions onto inclusion body </LI> <LI> Enhanced production of 1-butanol occurred both <I>in vitro</I> and <I>in vivo</I> </LI> <LI> Enzyme localization via LZ binding gave 7.9-fold increase in 1-butanol productivity </LI> <LI> This strategy may be useful in metabolic engineering for multiple target production </LI> </UL> </P>
Crystal structures of the structure-selective nuclease Mus81-Eme1 bound to flap DNA substrates.
Gwon, Gwang Hyeon,Jo, Aera,Baek, Kyuwon,Jin, Kyeong Sik,Fu, Yaoyao,Lee, Jong-Bong,Kim, Youngchang,Cho, Yunje Published for the European Molecular Biology Organ 2014 The EMBO journal Vol.33 No.9
<P>The Mus81-Eme1 complex is a structure-selective endonuclease with a critical role in the resolution of recombination intermediates during DNA repair after interstrand cross-links, replication fork collapse, or double-strand breaks. To explain the molecular basis of 3' flap substrate recognition and cleavage mechanism by Mus81-Eme1, we determined crystal structures of human Mus81-Eme1 bound to various flap DNA substrates. Mus81-Eme1 undergoes gross substrate-induced conformational changes that reveal two key features: (i) a hydrophobic wedge of Mus81 that separates pre- and post-nick duplex DNA and (ii) a '5' end binding pocket' that hosts the 5' nicked end of post-nick DNA. These features are crucial for comprehensive protein-DNA interaction, sharp bending of the 3' flap DNA substrate, and incision strand placement at the active site. While Mus81-Eme1 unexpectedly shares several common features with members of the 5' flap nuclease family, the combined structural, biochemical, and biophysical analyses explain why Mus81-Eme1 preferentially cleaves 3' flap DNA substrates with 5' nicked ends.</P>