Lu M

References (35)

Title : A Phenotypic Screen Identifies Potent DPP9 Inhibitors Capable of Killing HIV-1 Infected Cells - Moore_2022_ACS.Chem.Biol_17_2595
Author(s) : Moore KP , Schwaid AG , Tudor M , Park S , Beshore DC , Converso A , Shipe WD , Anand R , Lan P , Moningka R , Rothman DM , Sun W , Chi A , Cornella-Taracido I , Adam GC , Bahnck-Teets C , Carroll SS , Fay JF , Goh SL , Lusen J , Quan S , Rodriguez S , Xu M , Andrews CL , Song C , Filzen T , Li J , Hollenstein K , Klein DJ , Lammens A , Lim UM , Fang Z , McHale C , Li Y , Lu M , Diamond TL , Howell BJ , Zuck P , Balibar CJ
Ref : ACS Chemical Biology , 17 :2595 , 2022
Abstract : Although current antiretroviral therapy can control HIV-1 replication and prevent disease progression, it is not curative. Identifying mechanisms that can lead to eradication of persistent viral reservoirs in people living with HIV-1 (PLWH) remains an outstanding challenge to achieving cure. Utilizing a phenotypic screen, we identified a novel chemical class capable of killing HIV-1 infected peripheral blood mononuclear cells. Tool compounds ICeD-1 and ICeD-2 ("inducer of cell death-1 and 2"), optimized for potency and selectivity from screening hits, were used to deconvolute the mechanism of action using a combination of chemoproteomic, biochemical, pharmacological, and genetic approaches. We determined that these compounds function by modulating dipeptidyl peptidase 9 (DPP9) and activating the caspase recruitment domain family member 8 (CARD8) inflammasome. Efficacy of ICeD-1 and ICeD-2 was dependent on HIV-1 protease activity and synergistic with efavirenz, which promotes premature activation of HIV-1 protease at high concentrations in infected cells. This in vitro synergy lowers the efficacious cell kill concentration of efavirenz to a clinically relevant dose at concentrations of ICeD-1 or ICeD-2 that do not result in complete DPP9 inhibition. These results suggest engagement of the pyroptotic pathway as a potential approach to eliminate HIV-1 infected cells.
ESTHER : Moore_2022_ACS.Chem.Biol_17_2595
PubMedSearch : Moore_2022_ACS.Chem.Biol_17_2595
PubMedID: 36044633
Gene_locus related to this paper: human-DPP8 , human-DPP9

Title : Metagenomic Screening for Lipolytic Genes Reveals an Ecology-Clustered Distribution Pattern - Lu_2022_Front.Microbiol_13_851969
Author(s) : Lu M , Schneider D , Daniel R
Ref : Front Microbiol , 13 :851969 , 2022
Abstract : Lipolytic enzymes are one of the most important enzyme types for application in various industrial processes. Despite the continuously increasing demand, only a small portion of the so far encountered lipolytic enzymes exhibit adequate stability and activities for biotechnological applications. To explore novel and/or extremophilic lipolytic enzymes, microbial consortia in two composts at thermophilic stage were analyzed using function-driven and sequence-based metagenomic approaches. Analysis of community composition by amplicon-based 16S rRNA genes and transcripts, and direct metagenome sequencing revealed that the communities of the compost samples were dominated by members of the phyla Actinobacteria, Proteobacteria, Firmicutes, Bacteroidetes, and Chloroflexi. Function-driven screening of the metagenomic libraries constructed from the two samples yielded 115 unique lipolytic enzymes. The family assignment of these enzymes was conducted by analyzing the phylogenetic relationship and generation of a protein sequence similarity network according to an integrated classification system. The sequence-based screening was performed by using a newly developed database, containing a set of profile Hidden Markov models, highly sensitive and specific for detection of lipolytic enzymes. By comparing the lipolytic enzymes identified through both approaches, we demonstrated that the activity-directed complements sequence-based detection, and vice versa. The sequence-based comparative analysis of lipolytic genes regarding diversity, function and taxonomic origin derived from 175 metagenomes indicated significant differences between habitats. Analysis of the prevalent and distinct microbial groups providing the lipolytic genes revealed characteristic patterns and groups driven by ecological factors. The here presented data suggests that the diversity and distribution of lipolytic genes in metagenomes of various habitats are largely constrained by ecological factors.
ESTHER : Lu_2022_Front.Microbiol_13_851969
PubMedSearch : Lu_2022_Front.Microbiol_13_851969
PubMedID: 35756004
Gene_locus related to this paper: 9bact-estC55.154 , 9bact-a0a0n9qch2 , pseth-a0a1m6y2k1 , rhom4-d0mhw6 , thet2-q72j75 , theth-TT1662 , 9bact-estC55.42 , 9bact-estC76.136 , 9bact-estC55.118 , 9bact-estC55.62 , 9bact-estC55.268 , 9bact-estC55.52 , 9bact-estC55.3 , 9bact-estC55.235 , 9bact-estC55.90 , 9bact-estC55.102 , 9bact-estC55.145 , 9bact-estC55.105 , 9bact-estC55.151 , 9bact-estC55.71 , 9bact-estC55.88 , 9bact-estC55.156 , 9bact-estC55.169 , 9bact-estC76.202 , 9bact-estC55.165 , 9bact-estC55.241 , 9bact-estC55.78 , 9bact-estC55.8n1 , 9bact-estC55.56 , 9bact-estC55.60 , 9bact-estC55.5 , 9bact-estC55.19n1 , 9bact-estC55.253 , 9bact-estC55.95 , 9bact-estC55.13 , 9bact-estC55.77 , 9bact-estC55.229 , 9bact-estC55.167 , 9bact-estC55.234 , 9bact-estC55.25 , 9bact-estC55.76 , 9bact-estC55.19n2 , 9bact-estC55.8n2 , 9bact-estC55.20 , 9bact-estC55.96 , 9bact-estC55.2 , 9bact-estC55.4n1 , 9bact-estC55.23 , 9bact-estC55.57 , 9bact-estC55.197 , 9bact-estC76.263 , 9bact-estC55.227 , 9bact-estC55.159 , 9bact-estC55.51 , 9bact-estC55.31 , 9bact-estC55.215 , 9bact-estC55.34 , 9bact-estC55.244 , 9bact-estC55.81 , 9bact-estC55.24 , 9bact-estC55.12 , 9bact-estC55.15 , 9bact-estC55.231 , 9bact-estC55.97 , 9bact-estC76.135 , 9bact-estC76.266n2 , 9bact-estC76.28n1 , 9bact-estC76.177 , 9bact-estC76.137 , 9bact-estC76.266n1 , 9bact-estC76.248 , 9bact-estC76.221

Title : Two single mutations in carboxylesterase 001C improve fenvalerate hydrolase activity in Helicoverpa armigera - Xu_2021_Pestic.Biochem.Physiol_179_104969
Author(s) : Xu JJ , Chang YM , Lu M , Tie Y , Dong YL , Chen GY , Ma ZQ , Liu XL , Li YQ
Ref : Pestic Biochem Physiol , 179 :104969 , 2021
Abstract : Carboxylesterases (CarEs) usually play critical roles in the detoxification of toxic chemicals and therefore may be involved in insecticide resistance in agricultural pests. Previous work has shown that CarE 001C from Helicoverpa armigera was able to metabolize the isomers of cypermethrin and fenvalerate. In this study, seven mutants of CarE 001C with single amino acid substitution were produced and expressed in the Escherichia coli. Enzyme kinetic analysis indicated that all seven mutations dramatically reduced enzymatic activities toward the generic substrate alpha-naphthyl acetate, but in vitro metabolism assay showed that two of the mutations, H423I and R322L, significantly improved hydrolase activities toward fenvalerate, with their recorded specific activities being 3.5 and 5.1 nM.s(-1).mg (-1) proteins, respectively. Further, thermostability assay showed that the stability of one mutant enzyme was enhanced. This study will help us better understand the potential of CarEs in insecticide detoxification and resistance in H. armigera.
ESTHER : Xu_2021_Pestic.Biochem.Physiol_179_104969
PubMedSearch : Xu_2021_Pestic.Biochem.Physiol_179_104969
PubMedID: 34802519
Gene_locus related to this paper: helam-d5kx87

Title : Protection studies of an excretory-secretory protein HcABHD against Haemonchus contortus infection - Lu_2021_Vet.Res_52_3
Author(s) : Lu M , Tian X , Zhang Y , Wang W , Tian AL , Aimulajiang K , Liu L , Li C , Yan R , Xu L , Song X , Li X
Ref : Vet Res , 52 :3 , 2021
Abstract : Unlike the successful immunization of native H. contortus antigens that contributed to the realization of the first commercial vaccine Barbervax, not many studies revealed the encouraging protective efficacies of recombinant H. contortus antigens in laboratory trials or under field conditions. In our preliminary study, H. contortus alpha/beta-hydrolase domain protein (HcABHD) was demonstrated to be an immunomodulatory excretory-secretory (ES) protein that interacts with goat T cells. We herein evaluated the protective capacities of two HcABHD preparations, recombinant HcABHD (rHcABHD) antigen and anti-rHcABHD IgG, against H. contortus challenge via active and passive immunization trials, respectively. Parasitological parameter, antibody responses, hematological pathology and cytokine profiling in unchallenged and challenged goats were monitored and determined throughout both trials. Subcutaneous administration of rHcABHD with Freund adjuvants elicited protective immune responses in challenged goats, diminishing cumulative fecal egg counts (FEC) and total worm burden by 54.0% and 74.2%, respectively, whereas passive immunization with anti-rHcABHD IgG conferred substantial protection to challenged goats by generating a 51.5% reduction of cumulative FEC and a 73.8% reduction of total worm burden. Additionally, comparable changes of mucosal IgA levels, circulating IgG levels, hemoglobin levels, and serum interleukin (IL)-4 and IL-17A levels were observed in rHcABHD protein/anti-rHcABHD IgG immunized goats in both trials. Taken together, the recombinant version of HcABHD might have further application under field conditions in protecting goats against H. contortus infection, and the integrated immunological pipeline of ES antigen identification, screening and characterization may provide new clues for further development of recombinant subunit vaccines to control H. contortus.
ESTHER : Lu_2021_Vet.Res_52_3
PubMedSearch : Lu_2021_Vet.Res_52_3
PubMedID: 33407892
Gene_locus related to this paper: haeco-CDJ88804

Title : A Novel Carboxylesterase Derived from a Compost Metagenome Exhibiting High Stability and Activity towards High Salinity - Lu_2021_Genes.(Basel)_12_E122
Author(s) : Lu M , Daniel R
Ref : Genes (Basel) , 12 : , 2021
Abstract : Halotolerant lipolytic enzymes have gained growing interest, due to potential applications under harsh conditions, such as hypersalinity and presence of organic solvents. In this study, a lipolytic gene, est56, encoding 287 amino acids was identified by functional screening of a compost metagenome. Subsequently, the gene was heterologously expressed, and the recombinant protein (Est56) was purified and characterized. Est56 is a mesophilic (T(opt) 50 degreesC) and moderate alkaliphilic (pH(opt) 8) enzyme, showing high thermostability at 30 and 40 degreesC. Strikingly, Est56 is halotolerant as it exhibited high activity and stability in the presence of up to 4 M NaCl or KCl. Est56 also displayed enhanced stability against high temperatures (50 and 60 degreesC) and urea (2, 4, and 6 M) in the presence of NaCl. In addition, the recently reported halotolerant lipolytic enzymes were summarized. Phylogenetic analysis grouped these enzymes into 13 lipolytic protein families. The majority (45%) including Est56 belonged to family IV. To explore the haloadaptation of halotolerant enzymes, the amino acid composition between halotolerant and halophilic enzymes was statistically compared. The most distinctive feature of halophilic from non-halophilic enzymes are the higher content of acidic residues (Asp and Glu), and a lower content of lysine, aliphatic hydrophobic (Leu, Met and Ile) and polar (Asn) residues. The amino acid composition and 3-D structure analysis suggested that the high content of acidic residues (Asp and Glu, 12.2%) and low content of lysine residues (0.7%), as well as the excess of surface-exposed acidic residues might be responsible for the haloadaptation of Est56.
ESTHER : Lu_2021_Genes.(Basel)_12_E122
PubMedSearch : Lu_2021_Genes.(Basel)_12_E122
PubMedID: 33478024
Gene_locus related to this paper: 9bact-a0a0n9qch2

Title : A Novel alpha\/beta Hydrolase Domain Protein Derived From Haemonchus contortus Acts at the Parasite-Host Interface - Lu_2020_Front.Immunol_11_1388
Author(s) : Lu M , Tian X , Tian AL , Li C , Yan R , Xu L , Song X , Li X
Ref : Front Immunol , 11 :1388 , 2020
Abstract : The alpha/beta-hydrolase domain (ABHD) proteins belonging to alpha/beta-hydrolase (ABH) superfamily are ubiquitously distributed throughout all the organisms, and their functional roles have been implicated in energy metabolism, cell signaling, growth and development. In our preliminary work, we identified a novel ABHD protein derived from Haemonchus contortus excretory-secretory (ES) proteins (HcESPs) that interacted with host T cells. Here, we demonstrated that H. contortus ABHD (HcABHD) protein, expressed in all life-cycle stages of H. contortus, is a mammalian ABHD17 homolog with immunodiagnostic utility and lipase activity. Given its catalytic activities and immunomodulatory potentials, we further investigated the functional diversity of HcABHD as an individual ES protein in parasite-host interactions. HcABHD protein may serve as depalmitoylase or thioesterase to suppress cell viability, inhibit cell proliferation, induce intrinsic and extrinsic T cell apoptosis, and cause cell cycle arrested at G1 phase. Moreover, recombinant HcABHD stimuli exerted critical controls on T cell cytokine production profiles, predominantly by inhibiting the secretions of interleukin (IL)-4, interferon-gamma (IFN-gama) and transforming growth factor-beta (TGF-beta) 1, and promoting IL-10 production. As the immunomodulator acting at the parasite-host interface, HcABHD protein may have potential applications for the vaccine development of therapeutic intervention. Together, these findings may help illuminate the molecular and particularly immunomodulatory aspects of ES proteins and contribute to an enhanced understanding of parasite immune evasion in H. contortus-host biology.
ESTHER : Lu_2020_Front.Immunol_11_1388
PubMedSearch : Lu_2020_Front.Immunol_11_1388
PubMedID: 32695121
Gene_locus related to this paper: haeco-CDJ88804

Title : Degradation of dibutyl phthalate (DBP) by a bacterial consortium and characterization of two novel esterases capable of hydrolyzing PAEs sequentially - Lu_2020_Ecotoxicol.Environ.Saf_195_110517
Author(s) : Lu M , Jiang W , Gao Q , Zhang M , Hong Q
Ref : Ecotoxicology & Environmental Safety , 195 :110517 , 2020
Abstract : Phthalate esters (PAEs), a class of toxic anthropogenic compounds, have been predominantly used as additives or plasticizers, and great concern and interests have been raised regarding its environmental behavior and degradation mechanism. In the present study, a bacterial consortium consisting of Microbacterium sp. PAE-1 and Pandoraea sp. PAE-2 was isolated by the enrichment method, which could degrade dibutyl phthalate (DBP) completely by biochemical cooperation. DBP was converted to phthalic acid (PA) via monobutyl phthalate (MBP) by two sequential hydrolysis steps in strain PAE-1, and then PA was further degraded by strain PAE-2. Strain PAE-1 could hydrolyze many dialkyl Phthalate esters (PAEs) including dimethyl, diethyl, dibutyl, dipentyl, benzyl butyl, dihexyl, di-(2-ethyhexyl) and their corresponding monoalkyl PAEs. Two esterase genes named dpeH and mpeH, located in the same transcription unit, were cloned from strain PAE-1 by the shotgun method and heterologously expressed in Escherichia. coli (DE3). The Km and kcat values of DpeH for DBP were 9.60 +/- 0.97 muM and (2.72 +/- 0.06) x 10(6) s(-1), while those of MpeH for MBP were 18.61 +/- 2.00 muM and (5.83 +/- 1.00) x 10(5) s(-1), respectively. DpeH could only hydrolyze dialkyl PAEs to the corresponding monoalkyl PAEs, which were then hydrolyzed to PA by MpeH. DpeH shares the highest similarity (53%) with an alpha/beta hydrolase from Microbacterium sp. MED-G48 and MpeH shows only 25% identity with a secreted lipase from Trichophyton benhamiae CBS 112371, indicating that DpeH and MpeH are two novel hydrolases against PAEs.
ESTHER : Lu_2020_Ecotoxicol.Environ.Saf_195_110517
PubMedSearch : Lu_2020_Ecotoxicol.Environ.Saf_195_110517
PubMedID: 32220793
Gene_locus related to this paper: 9mico-DpeH , 9mico-MpeH

Title : Biochemical Transformation of Bacterial Lipopolysaccharide by acyloxyacyl hydrolase reduces host injury and promotes recovery - Munford_2020_J.Biol.Chem__
Author(s) : Munford RS , Weiss JP , Lu M
Ref : Journal of Biological Chemistry , : , 2020
Abstract : Animals can sense the presence of microbes in their tissues and mobilize their own defenses by recognizing and responding to conserved microbial structures (often called Microbe-Associated Molecular Patterns or "MAMPs"). Successful host defenses may kill the invaders, yet the host animal may fail to restore homeostasis if the stimulatory microbial structures are not silenced. Although mice have many mechanisms for limiting their responses to lipopolysaccharide (LPS), a major Gram-negative bacterial MAMP, a highly conserved host lipase is required to extinguish LPS sensing in tissues and restore homeostasis. We review recent progress in understanding how this enzyme, acyloxyacyl hydrolase (AOAH), transforms LPS from stimulus to inhibitor, reduces tissue injury and death from infection, prevents prolonged post-infection immunosuppression, and keeps stimulatory LPS from entering the bloodstream. We also discuss how AOAH may increase sensitivity to pulmonary allergens. Better appreciation of how host enzymes modify LPS and other MAMPs may help prevent tissue injury and hasten recovery from infection.
ESTHER : Munford_2020_J.Biol.Chem__
PubMedSearch : Munford_2020_J.Biol.Chem__
PubMedID: 33106315

Title : Biochemical profiles of two thermostable and organic solvent-tolerant esterases derived from a compost metagenome - Lu_2019_Appl.Microbiol.Biotechnol_103_3421
Author(s) : Lu M , Dukunde A , Daniel R
Ref : Applied Microbiology & Biotechnology , 103 :3421 , 2019
Abstract : Owing to the functional versatility and potential applications in industry, interest in lipolytic enzymes tolerant to organic solvents is increasing. In this study, functional screening of a compost soil metagenome resulted in identification of two lipolytic genes, est1 and est2, encoding 270 and 389 amino acids, respectively. The two genes were heterologously expressed and characterized. Est1 and Est2 are thermostable enzymes with optimal enzyme activities at 80 and 70 degrees C, respectively. A second-order rotatable design, which allows establishing the relationship between multiple variables with the obtained responses, was used to explore the combined effects of temperature and pH on esterase stability. The response curve indicated that Est1, and particularly Est2, retained high stability within a broad range of temperature and pH values. Furthermore, the effects of organic solvents on Est1 and Est2 activities and stabilities were assessed. Notably, Est2 activity was significantly enhanced (two- to tenfold) in the presence of ethanol, methanol, isopropanol, and 1-propanol over a concentration range between 6 and 30% (v/v). For the short-term stability (2 h of incubation), Est2 exhibited high tolerance against 60% (v/v) of ethanol, methanol, isopropanol, DMSO, and acetone, while Est1 activity resisted these solvents only at lower concentrations (below 30%, v/v). Est2 also displayed high stability towards some water-immiscible organic solvents, such as ethyl acetate, diethyl ether, and toluene. With respect to long-term stability, Est2 retained most of its activity after 26 days of incubation in the presence of 30% (v/v) ethanol, methanol, isopropanol, DMSO, or acetone. All of these features indicate that Est1 and Est2 possess application potential.
ESTHER : Lu_2019_Appl.Microbiol.Biotechnol_103_3421
PubMedSearch : Lu_2019_Appl.Microbiol.Biotechnol_103_3421
PubMedID: 30809711
Gene_locus related to this paper: 9bact-a0a0n9qma1

Title : A sensitive fluorescence assay of organophosphorus pesticides using acetylcholinesterase and copper-catalyzed click chemistry - Huang_2019_Analyst_144_3436
Author(s) : Huang N , Qin Y , Li M , Chen T , Lu M , Zhao J
Ref : Analyst , 144 :3436 , 2019
Abstract : Organophosphorus pesticides (OPs) are widely used in agricultural fields, but exhibit high toxicity to human beings. A sensitive fluorescence assay for organophosphorus pesticides was developed using the inhibition of acetylcholinesterase (AChE) activity and the copper-catalyzed click chemical reaction. In the click reaction, two hybridized DNA probes can be ligated with copper ions, inducing a fluorescence quenching during the strand displacement reaction. AChE can hydrolyze acetylthiocholine (ATCh) to form thiocholine (TCh) which contains a thiol group. TCh will react with copper ions, blocking the click reaction and a high fluorescence signal is observed. But in the presence of OPs, the activity of AChE is inhibited, releasing a high concentration of copper ions that catalyze the click chemical reaction and resulting in decreased fluorescence signals. Taking advantage of the copper-mediated signal amplification effect, the sensitivity was improved. This assay has also been applied to detect OPs in river water samples with satisfactory results, which demonstrates that the method has great potential for practical applications in environmental protection and food safety fields.
ESTHER : Huang_2019_Analyst_144_3436
PubMedSearch : Huang_2019_Analyst_144_3436
PubMedID: 31020297

Title : Characterization, in vitro binding properties, and inhibitory activity on pancreatic lipase of beta-glucans from different Qingke (Tibetan hulless barley) cultivars - Guo_2018_Int.J.Biol.Macromol_120_2517
Author(s) : Guo H , Lin S , Lu M , Gong JDB , Wang L , Zhang Q , Lin DR , Qin W , Wu DT
Ref : Int J Biol Macromol , 120 :2517 , 2018
Abstract : In order to explore Qingke beta-glucans as functional food ingredients for prevention of obesity, the physicochemical structures, in vitro binding properties, and inhibitory activities on pancreatic lipase of beta-glucans from three different Qingke cultivars, including Ganyucang (black), Dingqing (blue), and Zangqing 320 (white), were investigated and compared. Results showed that molecular weights, particle sizes, and intrinsic viscosities of beta-glucans from colored (black and blue) Qingke cultivars were much higher than those of white Qingke beta-glucans, respectively. In addition, the constituent monosaccharides of beta-glucans from colored Qingke cultivars were determined as arabinose, xylose, glucose, and galactose, and glucose was the dominant monosaccharide. Furthermore, colored Qingke beta-glucans exerted strong fat binding, cholesterol binding, and bile-acid binding capacities, as well as inhibitory activities on pancreatic lipase, which were much higher than those of white Qingke beta-glucans. Indeed, the fat binding, cholesterol binding, and bile-acid binding capacities, as well as the inhibitory activities on pancreatic lipase of Qingke beta-glucans were positively associated with their molecular weights and intrinsic viscosities. Results are beneficial for better understanding of the structure-function relationship of Qingke beta-glucans, and beta-glucans from colored Qingke cultivars (Ganyucang and Dingqing) could be further explored as functional food ingredients for prevention of obesity.
ESTHER : Guo_2018_Int.J.Biol.Macromol_120_2517
PubMedSearch : Guo_2018_Int.J.Biol.Macromol_120_2517
PubMedID: 30195000

Title : NDRG3 facilitates colorectal cancer metastasis through activating Src phosphorylation - Li_2018_Onco.Targets.Ther_11_2843
Author(s) : Li T , Sun R , Lu M , Chang J , Meng X , Wu H
Ref : Onco Targets Ther , 11 :2843 , 2018
Abstract : Background: NDRG3 is an N-myc downregulated gene (NDRG). The aim of this article was to identify the role of NDRG3 in colorectal cancer (CRC) and to determine the mechanism underlying its function. Methods: Using immunohistochemical staining, expression and clinicopathological variables of NDRG3 were analyzed in 170 CRC samples. Overexpression of NDRG3 was employed in SW1116 cells, downregulation of NDRG3 was achieved in RKO cells, then migration and invasion assays were performed in vitro, and a mouse model was constructed in vivo. Results: Increased expression of NDRG3 was observed in primary CRC tissues, and this expression was correlated with distant metastasis. Consistently, ectopic expression of NDRG3 in SW1116 cells enhanced cell migration and invasion, while knockdown of NDRG3 in RKO cells significantly suppressed CRC cell metastasis. The portal vein injection models suggested that NDRG3 overexpression facilitates liver metastasis. These events were associated with the phosphorylation of Src (c-Src) at Tyr 419 site. Conclusion: Our results showed that NDRG3 facilitates CRC migration and invasion by activating Src phosphorylation, suggesting the role of NDRG3 as a candidate oncogene.
ESTHER : Li_2018_Onco.Targets.Ther_11_2843
PubMedSearch : Li_2018_Onco.Targets.Ther_11_2843
PubMedID: 29844682

Title : Effectiveness of Florbetapir PET Imaging in Changing Patient Management - Pontecorvo_2017_Dement.Geriatr.Cogn.Disord_44_129
Author(s) : Pontecorvo MJ , Siderowf A , Dubois B , Doraiswamy PM , Frisoni GB , Grundman M , Nobili F , Sadowsky CH , Salloway S , Arora AK , Chevrette A , Deberdt W , Dell'Agnello G , Flitter M , Galante N , Lowrey MJ , Lu M , McGeehan A , Devous MD, Sr. , Mintun MA
Ref : Dementia & Geriatric Cognitive Disorders , 44 :129 , 2017
Abstract : AIMS: To evaluate the impact of amyloid PET imaging on diagnosis and patient management in a multicenter, randomized, controlled study.
METHODS: Physicians identified patients seeking a diagnosis for mild cognitive impairment or dementia, possibly due to Alzheimer disease (AD), and recorded a working diagnosis and a management plan. The patients underwent florbetapir PET scanning and were randomized to either immediate or delayed (1-year) feedback regarding amyloid status. At the 3-month visit, the physician updated the diagnosis and recorded a summary of the actual patient management since the post-scan visit. The study examined the impact of immediate versus delayed feedback on patient diagnosis/management at 3 and 12 months.
RESULTS: A total of 618 subjects were randomized (1:1) to immediate or delayed feedback arms, and 602 subjects completed the 3-month primary endpoint visit. A higher proportion of patients in the immediate feedback arm showed a change in diagnosis compared to the controls (32.6 vs. 6.4%; p = 0.0001). Similarly, a higher proportion of patients receiving immediate feedback had a change in management plan (68 vs. 55.5%; p < 0.002), mainly driven by changes in AD medication. Specifically, acetylcholinesterase inhibitors were prescribed to 67% of the amyloid-positive and 27% of the amyloid-negative subjects in the information group compared with 56 and 43%, respectively, in the control group (p < 0.0001). These between-group differences persisted until the 12-month visit. CONCLUSION: Knowledge of the amyloid status affects the diagnosis and alters patient management.
ESTHER : Pontecorvo_2017_Dement.Geriatr.Cogn.Disord_44_129
PubMedSearch : Pontecorvo_2017_Dement.Geriatr.Cogn.Disord_44_129
PubMedID: 28787712

Title : A novel, versatile family IV carboxylesterase exhibits high stability and activity in a broad pH spectrum - Dukunde_2017_Biotechnol.Lett_39_577
Author(s) : Dukunde A , Schneider D , Lu M , Brady S , Daniel R
Ref : Biotechnol Lett , 39 :577 , 2017
Abstract : OBJECTIVES: To investigate the properties of a novel metagenome-derived member of the hormone-sensitive lipase family of lipolytic enzymes.
RESULTS: A forest soil metagenome-derived gene encoding an esterase (Est06) belonging to the hormone-sensitive lipase family of lipolytic enzymes was subcloned, heterologously expressed and characterized. Est06 is a polypeptide of 295 amino acids with a molecular mass of 31 kDa. The deduced protein sequence shares 61% similarity with a hypothetical protein from the marine symbiont Candidatus Entotheonella sp. TSY1. Purified Est06 exhibited high affinity for acyl esters with short-chain fatty acids, and showed optimum activity with p-nitrophenyl valerate (C5). Maximum enzymatic activity was at 50 degrees C and pH 7. Est06 exhibited high stability at moderate temperatures by retaining all of its catalytic activity below 30 degrees C over 13 days. Additionally, Est06 displayed high stability between pH 5 and 9. Esterase activity was not inhibited by metal ions or detergents, although organic solvents decreased activity.
CONCLUSIONS: The combination of Est06 properties place it among novel biocatalysts that have potential for industrial use including low temperature applications.
ESTHER : Dukunde_2017_Biotechnol.Lett_39_577
PubMedSearch : Dukunde_2017_Biotechnol.Lett_39_577
PubMedID: 28044227
Gene_locus related to this paper: 9zzzz-g3crd1

Title : Agonistic Human Antibodies Binding to Lecithin-Cholesterol Acyltransferase Modulate High Density Lipoprotein Metabolism - Gunawardane_2016_J.Biol.Chem_291_2799
Author(s) : Gunawardane RN , Fordstrom P , Piper DE , Masterman S , Siu S , Liu D , Brown M , Lu M , Tang J , Zhang R , Cheng J , Gates A , Meininger D , Chan J , Carlson T , Walker N , Schwarz M , Delaney J , Zhou M
Ref : Journal of Biological Chemistry , 291 :2799 , 2016
Abstract : Drug discovery opportunities where loss-of-function alleles of a target gene link to a disease-relevant phenotype often require an agonism approach to up-regulate or re-establish the activity of the target gene. Antibody therapy is increasingly recognized as a favored drug modality due to multiple desirable pharmacological properties. However, agonistic antibodies that enhance the activities of the target enzymes are rarely developed because the discovery of agonistic antibodies remains elusive. Here we report an innovative scheme of discovery and characterization of human antibodies capable of binding to and agonizing a circulating enzyme lecithin cholesterol acyltransferase (LCAT). Utilizing a modified human LCAT protein with enhanced enzymatic activity as an immunogen, we generated fully human monoclonal antibodies using the XenoMouse(TM) platform. One of the resultant agonistic antibodies, 27C3, binds to and substantially enhances the activity of LCAT from humans and cynomolgus macaques. X-ray crystallographic analysis of the 2.45 A LCAT-27C3 complex shows that 27C3 binding does not induce notable structural changes in LCAT. A single administration of 27C3 to cynomolgus monkeys led to a rapid increase of plasma LCAT enzymatic activity and a 35% increase of the high density lipoprotein cholesterol that was observed up to 32 days after 27C3 administration. Thus, this novel scheme of immunization in conjunction with high throughput screening may represent an effective strategy for discovering agonistic antibodies against other enzyme targets. 27C3 and other agonistic human anti-human LCAT monoclonal antibodies described herein hold potential for therapeutic development for the treatment of dyslipidemia and cardiovascular disease.
ESTHER : Gunawardane_2016_J.Biol.Chem_291_2799
PubMedSearch : Gunawardane_2016_J.Biol.Chem_291_2799
PubMedID: 26644477
Gene_locus related to this paper: human-LCAT

Title : Bacterial Expression and Kinetic Analysis of Carboxylesterase 001D from Helicoverpa armigera - Li_2016_Int.J.Mol.Sci_17_
Author(s) : Li Y , Liu J , Lu M , Ma Z , Cai C , Wang Y , Zhang X
Ref : Int J Mol Sci , 17 : , 2016
Abstract : Carboxylesterasesare an important class of detoxification enzymes involved in insecticide resistance in insects. A subgroup of Helicoverpa armigera esterases, known as Clade 001, was implicated in organophosphate and pyrethroid insecticide resistance due to their overabundance in resistant strains. In this work, a novel carboxylesterasegene 001D of H. armigera from China was cloned, which has an open reading frame of 1665 nucleotides encoding 554 amino acid residues. We used a series of fusion proteins to successfully express carboxylesterase 001D in Escherichia coli. Three different fusion proteins were generated and tested. The enzyme kinetic assay towards 1-naphthyl acetate showed all three purified fusion proteins are active with a Kcat between 0.35 and 2.29 s(-1), and a Km between 7.61 and 19.72 muM. The HPLC assay showed all three purified fusion proteins had low but measurable hydrolase activity towards beta-cypermethrin and fenvalerate insecticides (specific activities ranging from 0.13 to 0.67 muM.min(-1).(muM(-1).protein)). The enzyme was stable up to 40 degrees C and at pH 6.0-11.0. The results imply that carboxylesterase 001D is involved in detoxification, and this moderate insecticide hydrolysis may suggest that overexpression of the gene to enhance insecticide sequestration is necessary to allow carboxylesterases to confer resistance to these insecticides in H. armigera.
ESTHER : Li_2016_Int.J.Mol.Sci_17_
PubMedSearch : Li_2016_Int.J.Mol.Sci_17_
PubMedID: 27049381
Gene_locus related to this paper: helam-d5kxa9

Title : The organophosphate insecticide chlorpyrifos confers its genotoxic effects by inducing DNA damage and cell apoptosis - Li_2015_Chemosphere_135_387
Author(s) : Li D , Huang Q , Lu M , Zhang L , Yang Z , Zong M , Tao L
Ref : Chemosphere , 135 :387 , 2015
Abstract : The organophosphate insecticide chlorpyrifos (CPF) is known to induce neurological effects, malformation and micronucleus formation, persistent developmental disorders, and maternal toxicity in rats and mice. The binding of chlorpyrifos with DNA to produce DNA adducts leads to an increasing social concern about the genotoxic risk of CPF in human, but CPF-induced cytotoxicity through DNA damage and cell apoptosis is not well understood. Here, we quantified the cytotoxicity and potential genotoxicity of CPF using the alkaline comet assay, gammaH2AX foci formation, and the DNA laddering assay in order to detect DNA damage and apoptosis in human HeLa and HEK293 cells in vitro. Drosophila S2 cells were used as a positive control. The alkaline comet assay showed that sublethal concentrations of CPF induced significant concentration-dependent increases in single-strand DNA breaks in the treated cells compared with the control. The percentage of gammaH2AX-positive HeLa cells revealed that CPF also causes DNA double-strand breaks in a time-dependent manner. Moreover, DNA fragmentation analysis demonstrated that exposure to CPF induced a significant concentration- and time-dependent increase in cell apoptosis. We conclude that CPF is a strongly genotoxic agent that induces DNA damage and cell apoptosis.
ESTHER : Li_2015_Chemosphere_135_387
PubMedSearch : Li_2015_Chemosphere_135_387
PubMedID: 26002045

Title : Potential impact of amyloid imaging on diagnosis and intended management in patients with progressive cognitive decline - Grundman_2013_Alzheimer.Dis.Assoc.Disord_27_4
Author(s) : Grundman M , Pontecorvo MJ , Salloway SP , Doraiswamy PM , Fleisher AS , Sadowsky CH , Nair AK , Siderowf A , Lu M , Arora AK , Agbulos A , Flitter ML , Krautkramer MJ , Sarsour K , Skovronsky DM , Mintun MA
Ref : Alzheimer Disease & Associated Disorders , 27 :4 , 2013
Abstract : Florbetapir F18 has been approved by the Food and Drug Administration for in vivo assessment of amyloid pathology in patients undergoing evaluation for Alzheimer disease (AD). The aim of this study was to determine the impact of amyloid imaging on the diagnoses and management of patients undergoing evaluation for cognitive decline. Patients were recruited to participate at 19 clinical sites. The site physician provided a provisional diagnosis, an estimate of their diagnostic confidence, and their plan for diagnostic evaluation and management both before and after receiving the results from amyloid imaging with florbetapir F18. Analyses compared the frequency of AD and non-AD diagnoses, plans for ancillary testing, and intended patient management before and after florbetapir imaging. A total of 229 patients participated in the trial (113 amyloid positive, 116 amyloid negative). After receiving the results of the florbetapir scan, diagnosis changed in 125/229, or 54.6% [95% confidence intervals (CI), 48.1%-60.9%], of cases, and diagnostic confidence increased by an average of 21.6% (95% CI, 18.3%-24.8%). A total of 199/229 or 86.9% (95% CI, 81.9%-90.7%) of cases had at least 1 change in their management plan. Intended cholinesterase inhibitor or memantine treatment increased by 17.7% (95% CI, 11.8%-25.8%) of all cases with positive scans and decreased by 23.3% (95% CI, 16.5%-31.8%) of all those with negative scans. Among subjects who had not yet undergone a completed work up, planned brain structural imaging (computed tomographic/magnetic resonance imaging) decreased by 24.4% (95% CI, 17.5%-32.8%) and planned neuropsychological testing decreased by 32.8% (95% CI, 25.0%-41.6%). In summary, amyloid imaging results altered physician's diagnostic thinking, intended testing, and management of patients undergoing evaluation for cognitive decline.
ESTHER : Grundman_2013_Alzheimer.Dis.Assoc.Disord_27_4
PubMedSearch : Grundman_2013_Alzheimer.Dis.Assoc.Disord_27_4
PubMedID: 23203162

Title : An Inhibitory Antibody against Dipeptidyl Peptidase IV Improves Glucose Tolerance in Vivo - Tang_2013_J.Biol.Chem_288_1307
Author(s) : Tang J , Majeti J , Sudom A , Xiong Y , Lu M , Liu Q , Higbee J , Zhang Y , Wang Y , Wang W , Cao P , Xia Z , Johnstone S , Min X , Yang X , Shao H , Yu T , Sharkov N , Walker N , Tu H , Shen W , Wang Z
Ref : Journal of Biological Chemistry , 288 :1307 , 2013
Abstract : Dipeptidyl peptidase IV (DPP-IV) degrades the incretin hormone glucagon-like peptide 1 (GLP-1). Small molecule DPP-IV inhibitors have been used as treatments for type 2 diabetes to improve glucose tolerance. However, each of the marketed small molecule drugs has its own limitation in terms of efficacy and side effects. To search for an alternative strategy of inhibiting DPP-IV activity, we generated a panel of tight binding inhibitory mouse monoclonal antibodies (mAbs) against rat DPP-IV. When tested in vitro, these mAbs partially inhibited the GLP-1 cleavage activity of purified enzyme and rat plasma. To understand the partial inhibition, we solved the co-crystal structure of one of the mAb Fabs (Ab1) in complex with rat DPP-IV. Although Ab1 does not bind at the active site, it partially blocks the side opening, which prevents the large substrates such as GLP-1 from accessing the active site, but not small molecules such as sitagliptin. When Ab1 was tested in vivo, it reduced plasma glucose and increased plasma GLP-1 concentration during an oral glucose tolerance test in rats. Together, we demonstrated the feasibility of using mAbs to inhibit DPP-IV activity and to improve glucose tolerance in a diabetic rat model.
ESTHER : Tang_2013_J.Biol.Chem_288_1307
PubMedSearch : Tang_2013_J.Biol.Chem_288_1307
PubMedID: 23184939
Gene_locus related to this paper: ratno-dpp4

Title : Genome sequence of the thermophilic fresh-water bacterium Spirochaeta caldaria type strain (H1(T)), reclassification of Spirochaeta caldaria, Spirochaeta stenostrepta, and Spirochaeta zuelzerae in the genus Treponema as Treponema caldaria comb. nov., Treponema stenostrepta comb. nov., and Treponema zuelzerae comb. nov., and emendation of the genus Treponema - Abt_2013_Stand.Genomic.Sci_8_88
Author(s) : Abt B , Goker M , Scheuner C , Han C , Lu M , Misra M , Lapidus A , Nolan M , Lucas S , Hammon N , Deshpande S , Cheng JF , Tapia R , Goodwin LA , Pitluck S , Liolios K , Pagani I , Ivanova N , Mavromatis K , Mikhailova N , Huntemann M , Pati A , Chen A , Palaniappan K , Land M , Hauser L , Jeffries CD , Rohde M , Spring S , Gronow S , Detter JC , Bristow J , Eisen JA , Markowitz V , Hugenholtz P , Kyrpides NC , Woyke T , Klenk HP
Ref : Stand Genomic Sci , 8 :88 , 2013
Abstract : Spirochaeta caldaria Pohlschroeder et al. 1995 is an obligately anaerobic, spiral-shaped bacterium that is motile via periplasmic flagella. The type strain, H1(T), was isolated in 1990 from cyanobacterial mat samples collected at a freshwater hot spring in Oregon, USA, and is of interest because it enhances the degradation of cellulose when grown in co-culture with Clostridium thermocellum. Here we provide a taxonomic re-evaluation for S. caldaria based on phylogenetic analyses of 16S rRNA sequences and whole genomes, and propose the reclassification of S. caldaria and two other Spirochaeta species as members of the emended genus Treponema. Whereas genera such as Borrelia and Sphaerochaeta possess well-distinguished genomic features related to their divergent lifestyles, the physiological and functional genomic characteristics of Spirochaeta and Treponema appear to be intermixed and are of little taxonomic value. The 3,239,340 bp long genome of strain H1(T) with its 2,869 protein-coding and 59 RNA genes is a part of the G enomic E ncyclopedia of Bacteria and Archaea project.
ESTHER : Abt_2013_Stand.Genomic.Sci_8_88
PubMedSearch : Abt_2013_Stand.Genomic.Sci_8_88
PubMedID: 23961314
Gene_locus related to this paper: trech-f8f1l1

Title : Genome sequence of the ocean sediment bacterium Saccharomonospora marina type strain (XMU15(T)) - Klenk_2012_Stand.Genomic.Sci_6_265
Author(s) : Klenk HP , Lu M , Lucas S , Lapidus A , Copeland A , Pitluck S , Goodwin LA , Han C , Tapia R , Brambilla EM , Potter G , Land M , Ivanova N , Rohde M , Goker M , Detter JC , Li WJ , Kyrpides NC , Woyke T
Ref : Stand Genomic Sci , 6 :265 , 2012
Abstract : Saccharomonospora marina Liu et al. 2010 is a member of the genus Saccharomonospora, in the family Pseudonocardiaceae that is poorly characterized at the genome level thus far. Members of the genus Saccharomonospora are of interest because they originate from diverse habitats, such as leaf litter, manure, compost, surface of peat, moist, over-heated grain, and ocean sediment, where they might play a role in the primary degradation of plant material by attacking hemicellulose. Organisms belonging to the genus are usually Gram-positive staining, non-acid fast, and classify among the actinomycetes. Here we describe the features of this organism, together with the complete genome sequence (permanent draft status), and annotation. The 5,965,593 bp long chromosome with its 5,727 protein-coding and 57 RNA genes was sequenced as part of the DOE funded Community Sequencing Program (CSP) 2010 at the Joint Genome Institute (JGI).
ESTHER : Klenk_2012_Stand.Genomic.Sci_6_265
PubMedSearch : Klenk_2012_Stand.Genomic.Sci_6_265
PubMedID: 22768369
Gene_locus related to this paper: 9pseu-h5x8w4 , 9pseu-h5x5e2 , 9pseu-h5xbd6 , 9pseu-h5x783

Title : Complete genome sequence of Marinomonas posidonica type strain (IVIA-Po-181(T)) - Lucas-Elio_2012_Stand.Genomic.Sci_7_31
Author(s) : Lucas-Elio P , Goodwin L , Woyke T , Pitluck S , Nolan M , Kyrpides NC , Detter JC , Copeland A , Lu M , Bruce D , Detter C , Tapia R , Han S , Land ML , Ivanova N , Mikhailova N , Johnston AW , Sanchez-Amat A
Ref : Stand Genomic Sci , 7 :31 , 2012
Abstract : Marinomonas posidonica IVIA-Po-181(T) Lucas-Elio et al. 2011 belongs to the family Oceanospirillaceae within the phylum Proteobacteria. Different species of the genus Marinomonas can be readily isolated from the seagrass Posidonia oceanica. M. posidonica is among the most abundant species of the genus detected in the cultured microbiota of P. oceanica, suggesting a close relationship with this plant, which has a great ecological value in the Mediterranean Sea, covering an estimated surface of 38,000 Km(2). Here we describe the genomic features of M. posidonica. The 3,899,940 bp long genome harbors 3,544 protein-coding genes and 107 RNA genes and is a part of the GenomicEncyclopedia ofBacteriaandArchaea project.
ESTHER : Lucas-Elio_2012_Stand.Genomic.Sci_7_31
PubMedSearch : Lucas-Elio_2012_Stand.Genomic.Sci_7_31
PubMedID: 23458837
Gene_locus related to this paper: halh1-f4l1a0 , marpp-f6d018 , marpp-f6czj1

Title : Complete genome sequence of the rapeseed plant-growth promoting Serratia plymuthica strain AS9 - Neupane_2012_Stand.Genomic.Sci_6_54
Author(s) : Neupane S , Hogberg N , Alstrom S , Lucas S , Han J , Lapidus A , Cheng JF , Bruce D , Goodwin L , Pitluck S , Peters L , Ovchinnikova G , Lu M , Han C , Detter JC , Tapia R , Fiebig A , Land M , Hauser L , Kyrpides NC , Ivanova N , Pagani I , Klenk HP , Woyke T , Finlay RD
Ref : Stand Genomic Sci , 6 :54 , 2012
Abstract : Serratia plymuthica are plant-associated, plant beneficial species belonging to the family Enterobacteriaceae. The members of the genus Serratia are ubiquitous in nature and their life style varies from endophytic to free-living. S. plymuthica AS9 is of special interest for its ability to inhibit fungal pathogens of rapeseed and to promote plant growth. The genome of S. plymuthica AS9 comprises a 5,442,880 bp long circular chromosome that consists of 4,952 protein-coding genes, 87 tRNA genes and 7 rRNA operons. This genome is part of the project entitled "Genomics of four rapeseed plant growth promoting bacteria with antagonistic effect on plant pathogens" awarded through the 2010 DOE-JGI Community Sequencing Program (CSP2010).
ESTHER : Neupane_2012_Stand.Genomic.Sci_6_54
PubMedSearch : Neupane_2012_Stand.Genomic.Sci_6_54
PubMedID: 22675598
Gene_locus related to this paper: serpl-s0ae95 , serpl-s0aiv6 , sersa-g0bfi6 , serp5-a8gjr8 , serpl-s4yi15

Title : Complete genome sequence of Cellulophaga algicola type strain (IC166) - Abt_2011_Stand.Genomic.Sci_4_72
Author(s) : Abt B , Lu M , Misra M , Han C , Nolan M , Lucas S , Hammon N , Deshpande S , Cheng JF , Tapia R , Goodwin L , Pitluck S , Liolios K , Pagani I , Ivanova N , Mavromatis K , Ovchinikova G , Pati A , Chen A , Palaniappan K , Land M , Hauser L , Chang YJ , Jeffries CD , Detter JC , Brambilla E , Rohde M , Tindall BJ , Goker M , Woyke T , Bristow J , Eisen JA , Markowitz V , Hugenholtz P , Kyrpides NC , Klenk HP , Lapidus A
Ref : Stand Genomic Sci , 4 :72 , 2011
Abstract : Cellulophaga algicola Bowman 2000 belongs to the family Flavobacteriaceae within the phylum 'Bacteroidetes' and was isolated from Melosira collected from the Eastern Antarctic coastal zone. The species is of interest because its members produce a wide range of extracellular enzymes capable of degrading proteins and polysaccharides with temperature optima of 20-30 degrees C. This is the first completed genome sequence of a member of the genus Cellulophaga. The 4,888,353 bp long genome with its 4,285 protein-coding and 62 RNA genes consists of one circular chromosome and is a part of the Genomic Encyclopedia of Bacteria and Archaea project.
ESTHER : Abt_2011_Stand.Genomic.Sci_4_72
PubMedSearch : Abt_2011_Stand.Genomic.Sci_4_72
PubMedID: 21475589
Gene_locus related to this paper: celad-e6x4e5 , celad-e6x420 , celad-e6x777 , celad-e6xbe7

Title : Complete genome sequence of 'Thermobaculum terrenum' type strain (YNP1) - Kiss_2010_Stand.Genomic.Sci_3_153
Author(s) : Kiss H , Cleland D , Lapidus A , Lucas S , Del Rio TG , Nolan M , Tice H , Han C , Goodwin L , Pitluck S , Liolios K , Ivanova N , Mavromatis K , Ovchinnikova G , Pati A , Chen A , Palaniappan K , Land M , Hauser L , Chang YJ , Jeffries CD , Lu M , Brettin T , Detter JC , Goker M , Tindall BJ , Beck B , McDermott TR , Woyke T , Bristow J , Eisen JA , Markowitz V , Hugenholtz P , Kyrpides NC , Klenk HP , Cheng JF
Ref : Stand Genomic Sci , 3 :153 , 2010
Abstract : 'Thermobaculum terrenum' Botero et al. 2004 is the sole species within the proposed genus 'Thermobaculum'. Strain YNP1(T) is the only cultivated member of an acid tolerant, extremely thermophilic species belonging to a phylogenetically isolated environmental clone group within the phylum Chloroflexi. At present, the name 'Thermobaculum terrenum' is not yet validly published as it contravenes Rule 30 (3a) of the Bacteriological Code. The bacterium was isolated from a slightly acidic extreme thermal soil in Yellowstone National Park, Wyoming (USA). Depending on its final taxonomic allocation, this is likely to be the third completed genome sequence of a member of the class Thermomicrobia and the seventh type strain genome from the phylum Chloroflexi. The 3,101,581 bp long genome with its 2,872 protein-coding and 58 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project.
ESTHER : Kiss_2010_Stand.Genomic.Sci_3_153
PubMedSearch : Kiss_2010_Stand.Genomic.Sci_3_153
PubMedID: 21304745
Gene_locus related to this paper: thet1-d1cbe2 , thet1-d1cbh1 , thet1-d1cbh5 , thet1-d1cdw7 , thet1-d1cej0 , thet1-d1cfr4 , thet1-d1chv7 , thet1-d1cih9

Title : Bis-(-)-nor-meptazinols as novel nanomolar cholinesterase inhibitors with high inhibitory potency on amyloid-beta aggregation - Xie_2008_J.Med.Chem_51_2027
Author(s) : Xie Q , Wang H , Xia Z , Lu M , Zhang W , Wang X , Fu W , Tang Y , Sheng W , Li W , Zhou W , Zhu X , Qiu Z , Chen H
Ref : Journal of Medicinal Chemistry , 51 :2027 , 2008
Abstract : Bis-(-)-nor-meptazinols (bis-(-)-nor-MEPs) 5 were designed and synthesized by connecting two (-)-nor-MEP monomers with alkylene linkers of different lengths via the secondary amino groups. Their acetylcholinesterase (AChE) inhibitory activities were more greatly influenced by the length of the alkylene chain than butyrylcholinesterase (BChE) inhibition. The most potent nonamethylene-tethered dimer 5h exhibited low-nanomolar IC 50 values for both ChEs, having a 10 000-fold and 1500-fold increase in inhibition of AChE and BChE compared with (-)-MEP. Molecular docking elucidated that 5h simultaneously bound to the catalytic and peripheral sites in AChE via hydrophobic interactions with Trp86 and Trp286. In comparison, it folded in the large aliphatic cavity of BChE because of the absence of peripheral site and the enlargement of the active site. Furthermore, 5h and 5i markedly prevented the AChE-induced Abeta aggregation with IC 50 values of 16.6 and 5.8 microM, similar to that of propidium (IC 50 = 12.8 microM), which suggests promising disease-modifying agents for the treatment of AD patients.
ESTHER : Xie_2008_J.Med.Chem_51_2027
PubMedSearch : Xie_2008_J.Med.Chem_51_2027
PubMedID: 18333606

Title : Host inactivation of bacterial lipopolysaccharide prevents prolonged tolerance following gram-negative bacterial infection - Lu_2008_Cell.Host.Microbe_4_293
Author(s) : Lu M , Varley AW , Ohta S , Hardwick J , Munford RS
Ref : Cell Host Microbe , 4 :293 , 2008
Abstract : A transient state of tolerance to microbial molecules accompanies many infectious diseases. Such tolerance is thought to minimize inflammation-induced injury, but it may also alter host defenses. Here we report that recovery from the tolerant state induced by Gram-negative bacteria is greatly delayed in mice that lack acyloxyacyl hydrolase (AOAH), a lipase that partially deacylates the bacterial cell-wall lipopolysaccharide (LPS). Whereas wild-type mice regained normal responsiveness within 14 days after they received an intraperitoneal injection of LPS or Gram-negative bacteria, AOAH-deficient mice had greatly reduced proinflammatory responses to a second LPS injection for at least 3 weeks. In contrast, LPS-primed Aoah- knockout mice maintained an anti-inflammatory response, evident from their plasma levels of interleukin-10 (IL-10). LPS-primed Aoah-knockout mice experiencing prolonged tolerance were highly susceptible to virulent E. coli challenge. Inactivating LPS, an immunostimulatory microbial molecule, is thus important for restoring effective host defenses following Gram-negative bacterial infection in animals.
ESTHER : Lu_2008_Cell.Host.Microbe_4_293
PubMedSearch : Lu_2008_Cell.Host.Microbe_4_293
PubMedID: 18779055

Title : A host lipase detoxifies bacterial lipopolysaccharides in the liver and spleen - Shao_2007_J.Biol.Chem_282_13726
Author(s) : Shao B , Lu M , Katz SC , Varley AW , Hardwick J , Rogers TE , Ojogun N , Rockey DC , Dematteo RP , Munford RS
Ref : Journal of Biological Chemistry , 282 :13726 , 2007
Abstract : Much of the inflammatory response of the body to bloodborne Gram-negative bacteria occurs in the liver and spleen, the major organs that remove these bacteria and their lipopolysaccharide (LPS, endotoxin) from the bloodstream. We show here that LPS undergoes deacylation in the liver and spleen by acyloxyacyl hydrolase (AOAH), an endogenous lipase that selectively removes the secondary fatty acyl chains that are required for LPS recognition by its mammalian signaling receptor, MD-2-TLR4. We further show that Kupffer cells produce AOAH and are required for hepatic LPS deacylation in vivo. AOAH-deficient mice did not deacylate LPS and, whereas their inflammatory responses to low doses of LPS were similar to those of wild type mice for approximately 3 days after LPS challenge, they subsequently developed pronounced hepatosplenomegaly. Providing recombinant AOAH restored LPS deacylating ability to Aoah(-/-) mice and prevented LPS-induced hepatomegaly. AOAH-mediated deacylation is a previously unappreciated mechanism that prevents prolonged inflammatory reactions to Gram-negative bacteria and LPS in the liver and spleen.
ESTHER : Shao_2007_J.Biol.Chem_282_13726
PubMedSearch : Shao_2007_J.Biol.Chem_282_13726
PubMedID: 17322564

Title : The genome of the social amoeba Dictyostelium discoideum - Eichinger_2005_Nature_435_43
Author(s) : Eichinger L , Pachebat JA , Glockner G , Rajandream MA , Sucgang R , Berriman M , Song J , Olsen R , Szafranski K , Xu Q , Tunggal B , Kummerfeld S , Madera M , Konfortov BA , Rivero F , Bankier AT , Lehmann R , Hamlin N , Davies R , Gaudet P , Fey P , Pilcher K , Chen G , Saunders D , Sodergren E , Davis P , Kerhornou A , Nie X , Hall N , Anjard C , Hemphill L , Bason N , Farbrother P , Desany B , Just E , Morio T , Rost R , Churcher C , Cooper J , Haydock S , van Driessche N , Cronin A , Goodhead I , Muzny D , Mourier T , Pain A , Lu M , Harper D , Lindsay R , Hauser H , James K , Quiles M , Madan Babu M , Saito T , Buchrieser C , Wardroper A , Felder M , Thangavelu M , Johnson D , Knights A , Loulseged H , Mungall K , Oliver K , Price C , Quail MA , Urushihara H , Hernandez J , Rabbinowitsch E , Steffen D , Sanders M , Ma J , Kohara Y , Sharp S , Simmonds M , Spiegler S , Tivey A , Sugano S , White B , Walker D , Woodward J , Winckler T , Tanaka Y , Shaulsky G , Schleicher M , Weinstock G , Rosenthal A , Cox EC , Chisholm RL , Gibbs R , Loomis WF , Platzer M , Kay RR , Williams J , Dear PH , Noegel AA , Barrell B , Kuspa A
Ref : Nature , 435 :43 , 2005
Abstract : The social amoebae are exceptional in their ability to alternate between unicellular and multicellular forms. Here we describe the genome of the best-studied member of this group, Dictyostelium discoideum. The gene-dense chromosomes of this organism encode approximately 12,500 predicted proteins, a high proportion of which have long, repetitive amino acid tracts. There are many genes for polyketide synthases and ABC transporters, suggesting an extensive secondary metabolism for producing and exporting small molecules. The genome is rich in complex repeats, one class of which is clustered and may serve as centromeres. Partial copies of the extrachromosomal ribosomal DNA (rDNA) element are found at the ends of each chromosome, suggesting a novel telomere structure and the use of a common mechanism to maintain both the rDNA and chromosomal termini. A proteome-based phylogeny shows that the amoebozoa diverged from the animal-fungal lineage after the plant-animal split, but Dictyostelium seems to have retained more of the diversity of the ancestral genome than have plants, animals or fungi.
ESTHER : Eichinger_2005_Nature_435_43
PubMedSearch : Eichinger_2005_Nature_435_43
PubMedID: 15875012
Gene_locus related to this paper: dicdi-abhd , dicdi-ACHE , dicdi-apra , dicdi-cinbp , dicdi-CMBL , dicdi-crysp , dicdi-DPOA , dicdi-P90528 , dicdi-ppme1 , dicdi-Q8MYE7 , dicdi-q54cf7 , dicdi-q54cl7 , dicdi-q54cm0 , dicdi-q54ct5 , dicdi-q54cu1 , dicdi-q54d54 , dicdi-q54d66 , dicdi-q54dj5 , dicdi-q54dy7 , dicdi-q54ek1 , dicdi-q54eq6 , dicdi-q54et1 , dicdi-q54et7 , dicdi-q54f01 , dicdi-q54g24 , dicdi-q54g47 , dicdi-q54gi7 , dicdi-q54gw5 , dicdi-q54gx3 , dicdi-q54h23 , dicdi-q54h73 , dicdi-q54i38 , dicdi-q54ie5 , dicdi-q54in4 , dicdi-q54kz1 , dicdi-q54l36 , dicdi-q54li1 , dicdi-q54m29 , dicdi-q54n21 , dicdi-q54n35 , dicdi-q54n85 , dicdi-q54qe7 , dicdi-q54qi3 , dicdi-q54qk2 , dicdi-q54rl3 , dicdi-q54rl8 , dicdi-q54sy6 , dicdi-q54sz3 , dicdi-q54t49 , dicdi-q54t91 , dicdi-q54th2 , dicdi-q54u01 , dicdi-q54vc2 , dicdi-q54vw1 , dicdi-q54xe3 , dicdi-q54xl3 , dicdi-q54xu1 , dicdi-q54xu2 , dicdi-q54y48 , dicdi-q54yd0 , dicdi-q54ye0 , dicdi-q54yl1 , dicdi-q54yr8 , dicdi-q54z90 , dicdi-q55bx3 , dicdi-q55d01 , dicdi-q55d81 , dicdi-q55du6 , dicdi-q55eu1 , dicdi-q55eu8 , dicdi-q55fk4 , dicdi-q55gk7 , dicdi-Q54ZA6 , dicdi-q86h82 , dicdi-Q86HC9 , dicdi-Q86HM5 , dicdi-Q86HM6 , dicdi-q86iz7 , dicdi-q86jb6 , dicdi-Q86KU7 , dicdi-q550s3 , dicdi-q552c0 , dicdi-q553t5 , dicdi-q555e5 , dicdi-q555h0 , dicdi-q555h1 , dicdi-q557k5 , dicdi-q558u2 , dicdi-Q869Q8 , dicdi-u554 , dicdi-y9086 , dicdi-q54r44 , dicdi-f172a

Title : Identification of acyloxyacyl hydrolase, a lipopolysaccharide-detoxifying enzyme, in the murine urinary tract - Feulner_2004_Infect.Immun_72_3171
Author(s) : Feulner JA , Lu M , Shelton JM , Zhang M , Richardson JA , Munford RS
Ref : Infect Immun , 72 :3171 , 2004
Abstract : Acyloxyacyl hydrolase (AOAH) is an unusual but highly conserved lipase, previously described only in myeloid cells, that removes secondary fatty acyl chains from bacterial lipopolysaccharides (LPS) and may also act on various glycero(phospho)lipids. Deacylation by AOAH greatly reduces the ability of LPS to stimulate cells via CD14-MD-2-Toll-like receptor 4. We report here that renal cortical tubule cells produce AOAH and secrete it into urine, where it can deacylate LPS. In vitro studies revealed that proximal tubule cells secrete pro-AOAH, which can be taken up by bladder cells and processed to the heterodimeric, more enzymatically active, mature form of AOAH. AOAH can then be used by the recipient cells to deacylate LPS. The enzyme produced by proximal tubule epithelium may thus be shared with downstream cells. In addition, mature AOAH is found in the urine. We suggest that cortical tubule cells may produce and secrete AOAH to limit inflammatory responses to gram-negative bacteria throughout the urinary tract.
ESTHER : Feulner_2004_Infect.Immun_72_3171
PubMedSearch : Feulner_2004_Infect.Immun_72_3171
PubMedID: 15155618

Title : Specificity of the rat vesicular acetylcholine transporter - Kim_2003_Neurochem.Res_28_473
Author(s) : Kim MH , Lu M , Rogers GA , Parsons SM , Hersh LB
Ref : Neurochem Res , 28 :473 , 2003
Abstract : The protein kinase A-deficient PC12 cell line PC12A123.7 lacks both choline acetyltransferase and the vesicular acetylcholine transporter. This cell line has been used to establish a stably transfected cell line expressing recombinant rat vesicular acetylcholine transporter that is appropriately trafficked to small synaptic vesicles. Acetylcholine is transported by the rat vesicular acetylcholine transporter at a maximal rate of 1.45 nmol acetylcholine/min/mg protein and exhibits a Km for transport of 2.5 mM. The transporter binds vesamicol with a Kd of 7.5 nM. The ability of structural analogs of acetylcholine to inhibit both acetylcholine uptake and vesamicol binding was measured. The results demonstrate that like Torpedo vesicular acetylcholine transporter, the mammalian transporter can bind a diverse group of acetylcholine analogs.
ESTHER : Kim_2003_Neurochem.Res_28_473
PubMedSearch : Kim_2003_Neurochem.Res_28_473
PubMedID: 12675133

Title : Collection, mapping, and annotation of over 28,000 cDNA clones from japonica rice - Kikuchi_2003_Science_301_376
Author(s) : Kikuchi S , Satoh K , Nagata T , Kawagashira N , Doi K , Kishimoto N , Yazaki J , Ishikawa M , Yamada H , Ooka H , Hotta I , Kojima K , Namiki T , Ohneda E , Yahagi W , Suzuki K , Li CJ , Ohtsuki K , Shishiki T , Otomo Y , Murakami K , Iida Y , Sugano S , Fujimura T , Suzuki Y , Tsunoda Y , Kurosaki T , Kodama T , Masuda H , Kobayashi M , Xie Q , Lu M , Narikawa R , Sugiyama A , Mizuno K , Yokomizo S , Niikura J , Ikeda R , Ishibiki J , Kawamata M , Yoshimura A , Miura J , Kusumegi T , Oka M , Ryu R , Ueda M , Matsubara K , Kawai J , Carninci P , Adachi J , Aizawa K , Arakawa T , Fukuda S , Hara A , Hashizume W , Hayatsu N , Imotani K , Ishii Y , Itoh M , Kagawa I , Kondo S , Konno H , Miyazaki A , Osato N , Ota Y , Saito R , Sasaki D , Sato K , Shibata K , Shinagawa A , Shiraki T , Yoshino M , Hayashizaki Y , Yasunishi A
Ref : Science , 301 :376 , 2003
Abstract : We collected and completely sequenced 28,469 full-length complementary DNA clones from Oryza sativa L. ssp. japonica cv. Nipponbare. Through homology searches of publicly available sequence data, we assigned tentative protein functions to 21,596 clones (75.86%). Mapping of the cDNA clones to genomic DNA revealed that there are 19,000 to 20,500 transcription units in the rice genome. Protein informatics analysis against the InterPro database revealed the existence of proteins presented in rice but not in Arabidopsis. Sixty-four percent of our cDNAs are homologous to Arabidopsis proteins.
ESTHER : Kikuchi_2003_Science_301_376
PubMedSearch : Kikuchi_2003_Science_301_376
PubMedID: 12869764
Gene_locus related to this paper: orysa-Q852M6 , orysa-Q8GSE8 , orysa-Q9FYP7 , orysa-Q5JLP6 , orysa-Q8H5P5 , orysa-Q7F1Y5 , orysa-cbp3 , orysa-Q6YSZ8 , orysa-Q8S5X5 , orysa-Q8LIG3 , orysa-Q7F1B1 , orysa-Q9FW17 , orysa-Q337C3 , orysa-Q84QZ6 , orysa-Q84QY7 , orysa-Q6ZDG5 , orysa-Q658B2 , orysa-Q8H3R3 , orysa-Q5SNH3 , orysa-q2qnj4 , orysa-q2qyi1 , orysa-Q4VWY7 , orysa-q5smv5 , orysa-q5z901 , orysa-Q5ZBI5 , orysa-q6atz0 , orysa-q6i5q3 , orysj-q6yse8 , orysa-q6z8b1 , orysa-q6z995 , orysa-q7x7y5 , orysa-q7xkj9 , orysa-q7xr63 , orysa-q7xsq2 , orysa-q7xts6 , orysa-Q8LQS5 , orysa-Q8W3C6 , orysa-q53m20 , orysa-q67iz3 , orysa-q67j02 , orysa-q67j05 , orysa-q67j09 , orysa-q67j10 , orysa-q67tv0 , orysa-q67uz1 , orysa-q69xr2 , orysa-q69y21 , orysa-q75hy2 , orysa-q75i01 , orysa-q688m8 , orysa-q688m9 , orysa-Q6H8G1 , orysi-b8a7e7 , orysi-b8bfe5 , orysj-cgep , orysj-q0djj0 , orysj-q0jaf0 , orysj-q5jl22 , orysj-q6h7q9 , orysj-q6yvk6 , orysj-q7f8x1 , orysj-q10j20 , orysj-q10ss2 , orysj-q69uw6

Title : Mutational analysis of basic residues in the rat vesicular acetylcholine transporter. Identification of a transmembrane ion pair and evidence that histidine is not involved in proton translocation - Kim_2000_J.Biol.Chem_275_6175
Author(s) : Kim MH , Lu M , Kelly M , Hersh LB
Ref : Journal of Biological Chemistry , 275 :6175 , 2000
Abstract : The function of positively charged residues and the interaction of positively and negatively charged residues of the rat vesicular acetylcholine transporter (rVAChT) were studied. Changing Lys-131 in transmembrane domain helix 2 (TM2) to Ala or Leu eliminated transport activity, with no effect on vesamicol binding. However, replacement by His or Arg retained transport activity, suggesting a positive charge in this position is critical. Mutation of His-444 in TM12 or His-413 in the cytoplasmic loop between TM10 and TM11 was without effect on ACh transport, but vesamicol binding was reduced with His-413 mutants. Changing His-338 in TM8 to Ala or Lys did not effect ACh transport, however replacement with Cys or Arg abolished activity. Mutation of both of the transmembrane histidines or all three of the luminal loop histidines showed no change in acetylcholine transport. The mutant H338A/D398N between oppositely charged residues in transmembrane domains showed no vesamicol binding, however the charge reversal mutant H338D/D398H restored binding. This suggests that His-338 forms an ion pair with Asp-398. The charge neutralizing mutant K131A/D425N or the charge exchanged mutant K131D/D425K did not restore ACh transport. Taken together these results provide new insights into the tertiary structure in VAChT.
ESTHER : Kim_2000_J.Biol.Chem_275_6175
PubMedSearch : Kim_2000_J.Biol.Chem_275_6175
PubMedID: 10692409

Title : Mutational analysis of aspartate residues in the transmembrane regions and cytoplasmic loops of rat vesicular acetylcholine transporter - Kim_1999_J.Biol.Chem_274_673
Author(s) : Kim MH , Lu M , Lim EJ , Chai YG , Hersh LB
Ref : Journal of Biological Chemistry , 274 :673 , 1999
Abstract : The vesicular acetylcholine transporter (VAChT) is responsible for the transport of the neurotransmitter acetylcholine (ACh) into synaptic vesicles using an electrochemical gradient to drive transport. Rat VAChT has a number of aspartate residues within its predicted transmembrane domains (TM) and cytoplasmic loops, which may play important structural or functional roles in acetylcholine transport. In order to identify functional charged residues, site-directed mutagenesis of rVAChT was undertaken. No effect on ACh transport was observed when any of the five aspartate residues in the cytoplasmic loop were converted to asparagine. Similarly, changing Asp-46 (D46N) in TM1 or Asp-255 (D255N) in TM6 had no effect on ACh transport or vesamicol binding. However, replacement of Asp-398 in TM10 with Asn completely eliminated both ACh transport and vesamicol binding. The conservative mutant D398E retained transport activity, but not vesamicol binding, suggesting this residue is critical for transport. Mutation of Asp-193 in TM4 did not affect ACh transport activity; however, vesamicol binding was dramatically reduced. With mutant D425N of TM11 transport activity for ACh was completely blocked, without an effect on vesamicol binding. Activity was not restored in the conservative mutant D425E, suggesting the side chain as well as the negative charge of Asp-425 is important for substrate binding. These mutants, as well as mutant D193N, clearly dissociated ACh binding and transport from vesamicol binding. These data suggest that Asp-398 in TM10 and Asp-425 in TM11 are important for ACh binding and transport, while Asp-193 and Asp-398 in TM4 and TM10, respectively, are involved in vesamicol binding.
ESTHER : Kim_1999_J.Biol.Chem_274_673
PubMedSearch : Kim_1999_J.Biol.Chem_274_673
PubMedID: 9873001

Title : The role of charged transmembrane residues of rVAChT on ACh transport and vesamicol binding -
Author(s) : Kim MH , Lu M , Lim EJ , Chai YG , Hersh LB
Ref : Journal de Physiologie (Paris) , 92 :448 , 1998