Park JS

References (10)

Title : The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism - Oh_2023_Nat.Commun_14_5728
Author(s) : Oh M , Jang SY , Lee JY , Kim JW , Jung Y , Kim J , Seo J , Han TS , Jang E , Son HY , Kim D , Kim MW , Park JS , Song KH , Oh KJ , Kim WK , Bae KH , Huh YM , Kim SH , Han BS , Lee SC , Hwang GS , Lee EW
Ref : Nat Commun , 14 :5728 , 2023
Abstract : Arachidonic and adrenic acids in the membrane play key roles in ferroptosis. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen reveals that darapladib, an inhibitor of Lp-PLA2, synergistically induces ferroptosis in the presence of GPX4 inhibitors. We show that darapladib is able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, we find that Lp-PLA2 is located in the membrane and cytoplasm and suppresses ferroptosis, suggesting a critical role for intracellular Lp-PLA2. Lipidomic analyses show that darapladib treatment or deletion of PLA2G7, which encodes Lp-PLA2, generally enriches phosphatidylethanolamine species and reduces lysophosphatidylethanolamine species. Moreover, combination treatment of darapladib with the GPX4 inhibitor PACMA31 efficiently inhibits tumour growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment.
ESTHER : Oh_2023_Nat.Commun_14_5728
PubMedSearch : Oh_2023_Nat.Commun_14_5728
PubMedID: 37714840

Title : Inhibition of soluble epoxide hydrolase by phytochemical constituents of the root bark of Ulmus davidiana var. japonica - Kim_2021_J.Enzyme.Inhib.Med.Chem_36_1049
Author(s) : Kim JH , Park JS , Lee YJ , Choi S , Kim YH , Yang SY
Ref : J Enzyme Inhib Med Chem , 36 :1049 , 2021
Abstract : A novel compound 1 and nine known compounds (2-10) were isolated by open column chromatography analysis of the root bark of Ulmus davidiana. Pure compounds (1-10) were tested in vitro to determine the inhibitory activity of the catalytic reaction of soluble epoxide hydrolase (sEH). Compounds 1, 2, 4, 6-8, and 10 had IC(50) values ranging from 11.4 +/- 2.3 to 36.9 +/- 2.6 microM. We used molecular docking to simulate inhibitor binding of each compound and estimated the binding pose of the catalytic site of sEH. From this analysis, the compound 2 was revealed to be a potential inhibitor of sEH in vitro and in silico. Additionally, molecular dynamics (MD) study was performed to find detailed interaction signals of inhibitor 2 with enzyme. Finally, compound 2 is promising candidates for the development of a new sEH inhibitor from natural plants.
ESTHER : Kim_2021_J.Enzyme.Inhib.Med.Chem_36_1049
PubMedSearch : Kim_2021_J.Enzyme.Inhib.Med.Chem_36_1049
PubMedID: 34000951

Title : Differential expression and hypoxia-mediated regulation of the N-myc downstream regulated gene family - Le_2021_FASEB.J_35_e21961
Author(s) : Le N , Hufford TM , Park JS , Brewster RM
Ref : FASEB Journal , 35 :e21961 , 2021
Abstract : Many organisms rely on oxygen to generate cellular energy (adenosine triphosphate or ATP). During severe hypoxia, the production of ATP decreases, leading to cell damage or death. Conversely, excessive oxygen causes oxidative stress that is equally damaging to cells. To mitigate pathological outcomes, organisms have evolved mechanisms to adapt to fluctuations in oxygen levels. Zebrafish embryos are remarkably hypoxia-tolerant, surviving anoxia (zero oxygen) for hours in a hypometabolic, energy-conserving state. To begin to unravel underlying mechanisms, we analyze here the distribution of the N-myc Downstream Regulated Gene (ndrg) family, ndrg1-4, and their transcriptional response to hypoxia. These genes have been primarily studied in cancer cells and hence little is understood about their normal function and regulation. We show here using in situ hybridization that ndrgs are expressed in metabolically demanding organs of the zebrafish embryo, such as the brain, kidney, and heart. To investigate whether ndrgs are hypoxia-responsive, we exposed embryos to different durations and severity of hypoxia and analyzed transcript levels. We observed that ndrgs are differentially regulated by hypoxia and that ndrg1a has the most robust response, with a ninefold increase following prolonged anoxia. We further show that this treatment resulted in de novo expression of ndrg1a in tissues where the transcript is not observed under normoxic conditions and changes in Ndrg1a protein expression post-reoxygenation. These findings provide an entry point into understanding the role of this conserved gene family in the adaptation of normal cells to hypoxia and reoxygenation.
ESTHER : Le_2021_FASEB.J_35_e21961
PubMedSearch : Le_2021_FASEB.J_35_e21961
PubMedID: 34665878

Title : Structural and Biophysical Analyses of Human N-Myc Downstream-Regulated Gene 3 (NDRG3) Protein - Kim_2020_Biomolecules_10_
Author(s) : Kim KR , Kim KA , Park JS , Jang JY , Choi Y , Lee HH , Lee DC , Park KC , Yeom YI , Kim HJ , Han BW
Ref : Biomolecules , 10 : , 2020
Abstract : The N-Myc downstream-regulated gene (NDRG) family belongs to the alpha/beta-hydrolase fold and is known to exert various physiologic functions in cell proliferation, dierentiation, and hypoxia-induced cancer metabolism. In particular, NDRG3 is closely related to proliferation and migration of prostate cancer cells, and recent studies reported its implication in lactate-triggered hypoxia responses or tumorigenesis. However, the underlying mechanism for the functions of NDRG3 remains unclear. Here, we report the crystal structure of human NDRG3 at 2.2 resolution, with six molecules in an asymmetric unit. While NDRG3 adopts the alpha/beta-hydrolase fold, complete substitution of the canonical catalytic triad residues to non-reactive residues and steric hindrance around the pseudo-active site seem to disable the alpha/beta-hydrolase activity. While NDRG3 shares a high similarity to NDRG2 in terms of amino acid sequence and structure, NDRG3 exhibited remarkable structural differences in a flexible loop corresponding to helix alpha6 of NDRG2 that is responsible for tumor suppression. Thus, this flexible loop region seems to play a distinct role in oncogenic progression induced by NDRG3. Collectively, our studies could provide structural and biophysical insights into the molecular characteristics of NDRG3.
ESTHER : Kim_2020_Biomolecules_10_
PubMedSearch : Kim_2020_Biomolecules_10_
PubMedID: 31935861
Gene_locus related to this paper: human-NDRG3

Title : Metabolic engineering of Corynebacterium glutamicum for L-arginine production - Park_2014_Nat.Commun_5_4618
Author(s) : Park SH , Kim HU , Kim TY , Park JS , Kim SS , Lee SY
Ref : Nat Commun , 5 :4618 , 2014
Abstract : L-arginine is an important amino acid for diverse industrial and health product applications. Here we report the development of metabolically engineered Corynebacterium glutamicum ATCC 21831 for the production of L-arginine. Random mutagenesis is first performed to increase the tolerance of C. glutamicum to L-arginine analogues, followed by systems metabolic engineering for further strain improvement, involving removal of regulatory repressors of arginine operon, optimization of NADPH level, disruption of L-glutamate exporter to increase L-arginine precursor and flux optimization of rate-limiting L-arginine biosynthetic reactions. Fed-batch fermentation of the final strain in 5 l and large-scale 1,500 l bioreactors allows production of 92.5 and 81.2 g l(-1) of L-arginine with the yields of 0.40 and 0.35 g L-arginine per gram carbon source (glucose plus sucrose), respectively. The systems metabolic engineering strategy described here will be useful for engineering Corynebacteria strains for the industrial production of L-arginine and related products.
ESTHER : Park_2014_Nat.Commun_5_4618
PubMedSearch : Park_2014_Nat.Commun_5_4618
PubMedID: 25091334
Gene_locus related to this paper: corgl-Cgl1133 , corgl-Cgl2249 , corgl-CGL2393

Title : Multiple Cytochrome P450 Isoforms Are Involved in the Generation of a Pharmacologically Active Thiol Metabolite, whereas Paraoxonase 1 and Carboxylesterase 1 Catalyze the Formation of a Thiol Metabolite Isomer from Ticlopidine - Kim_2014_Drug.Metab.Dispos_42_141
Author(s) : Kim MJ , Jeong ES , Park JS , Lee SJ , Ghim JL , Choi CS , Shin JG , Kim DH
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 42 :141 , 2014
Abstract : Ticlopidine is a first-generation thienopyridine antiplatelet drug that prevents adenosine 5'-diphosphate (ADP)-induced platelet aggregation. We identified the enzymes responsible for the two-step metabolic bioactivation of ticlopidine in human liver microsomes and plasma. Formation of 2-oxo-ticlopidine, an intermediate metabolite, was NADPH dependent and cytochrome P450 (CYP) 1A2, 2B6, 2C19, and 2D6 were involved in this reaction. Conversion of 2-oxo-ticlopidine to thiol metabolites was observed in both microsomes (M1 and M2) and plasma (M1). These two metabolites were considered as isomers, and mass spectral analysis suggested that M2 was a thiol metabolite bearing an exocyclic double bond, whereas M1 was an isomer in which the double bond was migrated to an endocyclic position in the piperidine ring. The conversion of 2-oxo-ticlopidine to M1 in plasma was significantly increased by the addition of 1 mM CaCl2. In contrast, the activity in microsomes was not changed in the presence of CaCl2. M1 formation in plasma was inhibited by EDTA but not by other esterase inhibitors, whereas this activity in microsomes was substantially inhibited by carboxylesterase (CES) inhibitors such as bis-(p-nitrophenyl)phosphate (BNPP), diisopropylphosphorofluoride (DFP), and clopidogrel. The conversion of 2-oxo-ticlopidine to M1 was further confirmed with recombinant paraoxonase 1 (PON1) and CES1. However, M2 was detected only in NADPH-dependent microsomal incubation, and multiple CYP isoforms were involved in M2 formation with highest contribution of CYP2B6. In vitro platelet aggregation assay demonstrated that M2 was pharmacologically active. These results collectively indicated that the formation of M2 was mediated by CYP isoforms whereas M1, an isomer of M2, was generated either by human PON1 in plasma or by CES1 in the human liver.
ESTHER : Kim_2014_Drug.Metab.Dispos_42_141
PubMedSearch : Kim_2014_Drug.Metab.Dispos_42_141
PubMedID: 24170778
Gene_locus related to this paper: human-CES1

Title : Antidiabetic complications and anti-Alzheimer activities of sophoflavescenol, a prenylated flavonol from Sophora flavescens, and its structure-activity relationship - Jung_2011_Phytother.Res_25_709
Author(s) : Jung HA , Jin SE , Park JS , Choi JS
Ref : Phytother Res , 25 :709 , 2011
Abstract : It was previously reported that prenylated flavonols from Sophora flavescens are inhibitors of rat lens aldose reductase (RLAR), human recombinant aldose reductase (HRAR), advanced glycation endproducts (AGE), beta-secretase (BACE1) and cholinesterases (ChE). Based upon structure-activity relationships, 3,4'-dihydroxy flavonols with a prenyl or lavandulyl group substitution at the C-8 position, and a hydroxy group at the C-5, are important for such inhibition. In our ongoing study to isolate active principles from S. flavescens by an activity-guided isolation procedure, further detailed phytochemical investigations of the CH(2)Cl(2) fraction were conducted via repeated chromatography over silica gel and Sephadex LH-20 columns. This ultimately resulted in the isolation of a promising active sophoflavescenol with higher inhibitory activities among the current prenylated flavonols isolated from S. flavescens against RLAR, HRAR, AGE, BACE1 and ChEs. The results further support that 3,4'-dihydroxy flavonols with a prenyl or lavandulyl substitution at the C-8 position and a methoxy group at C-5 represent a new class of RLAR, HRAR and AGE inhibitors. Nevertheless, the C-5 hydroxyl group of prenylated flavonoids is important for inhibition of BACE1 and ChEs, indicating that the hydroxyl group at C-5 might be the main contributor to the augmentation and/or modification of prenylated flavonol activity.
ESTHER : Jung_2011_Phytother.Res_25_709
PubMedSearch : Jung_2011_Phytother.Res_25_709
PubMedID: 21077260

Title : Functional fusion mutant of Candida antarctica lipase B (CalB) expressed in Escherichia coli - Seo_2009_Biochim.Biophys.Acta_1794_519
Author(s) : Seo HS , Kim SE , Han KY , Park JS , Kim YH , Sim SJ , Lee J
Ref : Biochimica & Biophysica Acta , 1794 :519 , 2009
Abstract : Candida antarctica lipase B (CalB) was functionally expressed in the cytoplasm of Escherichia coli Origami(DE3) with the N-terminus fusion of E. coli endogenous proteins. The previously-identified stress responsive proteins through comparative proteome analyses such as malate dehydrogenase (Mdh), spermidine/putrescine-binding periplasmic protein (PotD), and FKBP-type peptidyl-prolyl cis-trans isomerase (PPIases) (SlyD) dramatically increased the solubility of CalB in E. coli cytoplasm when used as N-terminus fusion partners. We demonstrated that Mdh, PotD, and SlyD were powerful solubility enhancers that presumably facilitated the protein folding of CalB. Moreover, among the various fusion mutants, Mdh-CalB showed the highest hydrolytic activity and was as biologically active as standard CalB. Similarly to the previous report, the electrophoretic properties of CalB indicate that CalB seems to form dimer-based oligomer structures. We evaluated the structural compatibility between the fusion partner protein and CalB, which seems to be of crucial importance upon the bioactive dimer formation of CalB and might affect the substrate accessibility to the enzyme active site, thereby determining the biological activities of the fusion mutants.
ESTHER : Seo_2009_Biochim.Biophys.Acta_1794_519
PubMedSearch : Seo_2009_Biochim.Biophys.Acta_1794_519
PubMedID: 19159700

Title : Chitooligosaccharides suppress the level of protein expression and acetylcholinesterase activity induced by Abeta25-35 in PC12 cells - Lee_2009_Bioorg.Med.Chem.Lett_19_860
Author(s) : Lee SH , Park JS , Kim SK , Ahn CB , Je JY
Ref : Bioorganic & Medicinal Chemistry Lett , 19 :860 , 2009
Abstract : Clinical applications of acetylcholinesterase (AChE) inhibitors are widespread in Alzheimer's sufferers in order to activate central cholinergic system and alleviate cognitive deficits by inhibiting the hydrolysis of acetylcholine. In this study, six kinds of chitooligosaccharides (COSs) with different molecular weight and degree of deacetylation were examined for their inhibitory effects against AChE. The 90-COSs exhibited potent AChE inhibitory activities compared to 50-COSs, while 90-MMWCOS (1000-5000 Da) in the 90-COSs showed the highest activity. Cell culture experiment revealed that 90-MMWCOS suppressed the level of AChE protein expression and AChE activity induced by Abeta(25-35) in PC12 cell lines.
ESTHER : Lee_2009_Bioorg.Med.Chem.Lett_19_860
PubMedSearch : Lee_2009_Bioorg.Med.Chem.Lett_19_860
PubMedID: 19097785

Title : Enhanced degradation and toxicity reduction of dihexyl phthalate by Fusarium oxysporum f. sp. pisi cutinase - Kim_2007_J.Appl.Microbiol_102_221
Author(s) : Kim YH , Seo HS , Min J , Kim YC , Ban YH , Han KY , Park JS , Bae KD , Gu MB , Lee J
Ref : J Appl Microbiol , 102 :221 , 2007
Abstract : AIMS: This research aims to investigate the efficiency of two lipolytic enzymes--fungal cutinase and yeast esterase--upon the biodegradation of dihexyl phthalate (DHP).
METHOD AND RESULTS: During the enzymatic degradation of DHP dissolved in methanol, several degradation products were detected and their time-course changes were monitored using GC/MS. The DHP-degradation rate of cutinase was surprisingly high; i.e. almost 70% of the initial DHP (500 mg l(-1)) was decomposed within 4.5 h. Although the same amount of esterase was employed, more than 85% of the DHP remained after 3 days. Almost all the DHP was converted by cutinase into 1,3-isobenzofurandione (IBF), whereas hexyl methyl phthalate and IBF were abundantly produced by esterase. In addition, the toxicities of the DHP-degraded products by esterase were evaluated using various recombinant bioluminescent bacteria, which caused oxidative and protein damage, whereas the hydrolysis products from cutinase never caused any cellular damage in the methanol-containing reaction system.
CONCLUSIONS: Cutinase starts to act as a DHP-degrader much earlier and faster than esterase, with high stability in ester-hydrolytic activity, therefore a plausible approach to the practical application of cutinase for DHP degradation in the DHP-contaminated environments may be possible. SIGNIFICANCE AND IMPACT OF THE STUDY: This study describes the enhanced degradation and detoxification of DHP using Fusarium oxysporum f. sp. pisi cutinase.
ESTHER : Kim_2007_J.Appl.Microbiol_102_221
PubMedSearch : Kim_2007_J.Appl.Microbiol_102_221
PubMedID: 17184338
Gene_locus related to this paper: fusox-CUT