Functional analysis of Mpk1-mediated cell wall integrity signaling pathway in the thermotolerant methylotrophic yeast Hansenula polymorpha

Kim, Hyunah,Thak, Eun Jung,Yeon, Ji Yoon,Sohn, Min Jeong,Choo, Jin Ho,Kim, Jeong-Yoon,Kang, Hyun Ah MICROBIOLOGICAL SOCIETY OF KOREA 2018 JOURNAL OF MICROBIOLOGY -SEOUL- Vol.56 No.1

Understanding the characteristics and regulation mechanisms of cell wall integrity (CWI) in yeast is important not only for basic research but also in biotechnological applications. We found significantly different CWIs in two representative strains of the thermotolerant methylotrophic yeast Hansenula polymorpha. Compared to the A16 strain (classified as Ogataea polymorpha), the DL1-L strain (classified as Ogataea parapolymorpha) has a thinner cell wall that was found to be more fragile following long-term cultivation and more sensitive to zymolyase. To gain a deeper insight into this difference, we compared the characteristics of the Mpk1p-mediated CWI signaling pathway in the two strains. While a DL1-L mutant deficient in Mpk1p (<TEX>$mpk1{\Delta}$</TEX>) showed severe growth retardation at both normal and high growth temperatures and in the presence of cell-wall disrupting agents, the A16 <TEX>$mpk1{\Delta}$</TEX> mutant displayed only a mild defect in cell growth. Sorbitol effect on rescuing growth retardation was different in the two <TEX>$mpk1{\Delta}$</TEX> strains, which could partly be ascribed to subtle differences in the activation of HOG pathway. Among the cell wall disruptors evaluated, only caffeine clearly increased phosphorylation of Mpk1p in DL1-L, but not in A16. A transcriptome analysis of the DL1-L strain revealed that caffeine significantly increased the expression of a subset of cell-wall related genes in an Mpk1p-dependent manner, but not the expected Rlm1-target genes. Taken together, our data support an essential role for Mpk1p in maintaining CWI in H. polymorpha, although the requirement for Mpk1p and its regulation under diverse stress conditions varies depending on the strain background.

돋보衣기: 시각장애인의 온라인 쇼핑 경험 증진을 위한 모바일 애플리케이션의 구현

오현아(Hyunah Oh),추지예(Jiye Choo),윤예빈(Yebin Yun),정지원(Jiwon Jeong),오유란(Uran Oh) 한국HCI학회 2019 한국HCI학회 학술대회 Vol.2019 No.2

한국 정보통신 기술 협회에서 제정한 한국 모바일 애플리케이션 접근성 지침서는 장애인, 고령자 등이 비장애인과 동등하게 모바일 애플리케이션 콘텐츠에 접근할 수 있도록 제작 시 준수해야하는 지침에 관해 기술하고 있다. 하지만, 대부분의 온라인 쇼핑몰은 지침을 준수하지 않고, 상품에 대한 정보가 텍스트가 아닌 이미지로 제공된다. 그렇기에, 많은 시각장애인이 온라인 쇼핑몰 이용에 큰 불편함을 느끼는 실정이다. 따라서, 현 온라인 쇼핑 환경을 조사하고 이를 개선하기 위해 총 74 명을 대상으로 설문조사를 진행하였고, 조사 결과를 바탕으로 설계한 시각장애인을 위한 광학문자인식 기반 모바일 온라인쇼핑 애플리케이션인 `돋보衣기(이하 돋보의기)`를 제안한다. 본 연구는 시각장애인의 쇼핑만을 도울 뿐만이 아니라 일반적인 온라인 콘텐츠의 제한적인 접근성을 해결할 수 있을 것으로 사료된다.

IKK <i>β </i> inhibitor identification: a multi-filter driven novel scaffold

Nagarajan, Shanthi,Choo, Hyunah,Cho, Yong Seo,Shin, Kye Jung,Oh, Kwang-Seok,Lee, Byung Ho,Pae, Ae Nim BioMed Central 2010 BMC bioinformatics Vol.11 No.suppl7

<P><B>Background</B></P><P>Nuclear factor kappa B (NF-κB) is a chief nuclear transcription factor that controls the transcription of various genes; and its activation is tightly controlled by Inhibitor kappa B kinase (IKK). The irregular transcription of NF-κB has been linked to auto-immune disorders, cancer and other diseases. The IKK complex is composed of three units, IKK<I>α</I>, IKK<I>β</I>, and the regulatory domain NEMO, of which IKK<I>β </I>is well understood in the canonical pathway. Therefore, the inhibition of IKK<I>β </I>by drugs forms the molecular basis for anti-inflammatory drug research.</P><P><B>Results</B></P><P>The ligand- and structure-based virtual screening (VS) technique has been applied to identify IKK<I>β </I>inhibitors from the ChemDiv database with 0.7 million compounds. Initially, a 3D-QSAR pharmacophore model has been deployed to greatly reduce the database size. Subsequently, recursive partitioning (RP) and docking filters were used to screen the pharmacophore hits. Finally, 29 compounds were selected for IKKβ enzyme inhibition assay to identify a novel small molecule inhibitor of IKK<I>β </I>protein.</P><P><B>Conclusions</B></P><P>In the present investigation, we have applied various computational models sequentially to virtually screen the ChemDiv database, and identified a small molecule that has an IC<SUB>50 </SUB>value of 20.3<I>μ</I>M. This compound is novel among the known IKK<I>β </I>inhibitors. Further optimization of the hit compound can reveal a more potent anti-inflammatory agent.</P>

Water-Soluble and Cleavable Quercetin–Amino Acid Conjugates as Safe Modulators for P-Glycoprotein-Based Multidrug Resistance

Kim, Mi Kyoung,Choo, Hyunah,Chong, Youhoon American Chemical Society 2014 Journal of medicinal chemistry Vol.57 No.17

<P>Quercetin–amino acid conjugates with alanine or glutamic acid moiety attached at 7-<I>O</I> and/or 3-<I>O</I> position of quercetin were prepared, and their multidrug resistance (MDR)-modulatory effects were evaluated. A quercetin–glutamic acid conjugate, 7-<I>O</I>-Glu-Q (<B>3a</B>), was as potent as verapamil in reversing MDR and sensitized MDR MES-SA/Dx5 cells to various anticancer drugs with EC<SUB>50</SUB> values of 0.8–0.9 μM. Analysis on Rh-123 accumulation confirmed that <B>3a</B> inhibits drug efflux by Pgp, and Pgp ATPase assay showed that <B>3a</B> interacts with the drug-binding site of Pgp to stimulate its ATPase activity. Physicochemical analysis of <B>3a</B> revealed that solubility, stability, and cellular uptake of quercetin were significantly improved by the glutamic acid promoiety, which eventually dissociates from <B>3a</B> to produce quercetin and quercetin metabolites in intracellular milieu. Taken together, potent MDR-modulating activity along with intracellular conversion into the natural flavonoid quercetin warrants development of the quercetin–amino acid conjugates as safe MDR modulators.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2014/jmcmar.2014.57.issue-17/jm500290c/production/images/medium/jm-2014-00290c_0016.gif'></P>

Neuropathic pain-alleviating effects of pyrazole-conjugated arylsulfonamides as 5-HT₆ receptor antagonists

Hong, Jin Ri,Choo, Hyunah,Nam, Ghilsoo Pergamon Press 2017 Bioorganic & medicinal chemistry letters Vol.27 No.17

<P><B>Abstract</B></P> <P>A novel series of arylsulfonylaminomethyl-3-(1-phenyl-5-isopropyl)pyrazoles was evaluated for serotonin receptor subtype 6 (5-HT<SUB>6</SUB>R) antagonistic effects <I>in vitro</I>. We also investigated their neuropathic pain-alleviating effects <I>in vivo</I> using a rat spinal nerve ligation (SNL) model. Bicyclic aromatic sulfonamino groups, such as naphthalene and quinolin-substituted derivatives, showed good 5-HT<SUB>6</SUB> inhibitory activity <I>in vitro</I>. Among them, selected compounds, <B>12</B> and <B>13</B>, having 8-quinoylsulfonamino groups, showed potent neuropathic pain-alleviating effects in the rat model.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

3D QSAR pharmacophore model based on diverse IKKβ inhibitors.

Nagarajan, Shanthi,Ahmed, Asif,Choo, Hyunah,Cho, Yong Seo,Oh, Kwang-Seok,Lee, Byung Ho,Shin, Kye Jung,Pae, Ae Nim Springer 2011 JOURNAL OF MOLECULAR MODELING Vol.17 No.2

<P>The inhibitor kappaB kinase β (IKKβ) is a serine-threonine protein kinase that is critically involved in the activation of the transcription factor nuclear factor kappa B (NF-κB) in response to various inflammatory stimuli. IKKβ-selective inhibitors could prove useful for the treatment of inflammatory diseases. In the absence of structural information, a ligand-based approach can serve as an alternative to the virtual screening of large databases. We have developed a 3D QSAR pharmacophore model based on 23 IKKβ inhibitors with 3 nM??IC(50)??50000 nM. A four-feature pharmacophore containing a hydrophobic (Hy) feature, two ring aromatic (RA) features, and a hydrogen bond donor (D) feature was constructed. It yielded a correlation coefficient of 0.93 with experimentally determined activity data, and a correlation coefficient of 0.77 with training set activity data. The best hypothesis, Hypo 1, was validated by estimating the activities of 136 compounds in a test set. As well as the correlation analysis and test set activity estimation, a Fisher's validation test was conducted at the 95% confidence level. The pharmacophore model's specificity and selectivity were determined in an exhaustive enrichment study.</P>

Novel JAK1-selective benzimidazole inhibitors with enhanced membrane permeability

Kim, Hyungmi,Kim, Mi Kyoung,Choo, Hyunah,Chong, Youhoon Elsevier 2016 Bioorganic & medicinal chemistry letters Vol.26 No.14

<P><B>Abstract</B></P> <P>The previously identified Janus kinase 1 (JAK1)-selective inhibitor, 1-(2-aminoethyl)-2-(piperidin-4-yl)-1<I>H</I>-benzo[<I>d</I>]imidazole-5-carboxamide (<B>2</B>), suffered from low cell permeability, which resulted in poor pharmacokinetic properties. In this study, by introducing less polar hydrogen bond donors at <I>N</I> <SUP>1</SUP> (a hydroxyalkyl or a methylaminoalkyl group) and C2 (a cyclohexanol group) positions, a series of novel benzimidazole derivatives were prepared, which exhibited selective JAK1 inhibitory activity (IC<SUB>50</SUB> against JAK1=0.08–0.15μM; JAK1-selectivity=26–40 fold vs JAK2, 12–23 fold vs JAK3, and 38–54 fold vs Tyk2) along with significantly increased lipophilicity (3.3–15.8 times) as well as membrane permeability (6.3–12 times).</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

TMSOTf-Promoted Addition of Alkynes to Aldehydes: A Novel Synthesis of Chroman-4-ones

Park, Ji Yeon,Ullapu, Punna Reddy,Choo, Hyunah,Lee, Jae Kyun,Min, Sun-Joon,Pae, Ae Nim,Kim, Youseung,Baek, Du-Jong,Cho, Yong Seo WILEY-VCH Verlag 2008 EUROPEAN JOURNAL OF ORGANIC CHEMISTRY Vol.2008 No.32

<P>A novel synthetic method to prepare chalcones 2 and chroman-4-ones 3 by TMSOTf-promoted addition of alkynes 1 to various aldehydes has been developed. The ratios of chalcones 2, chroman-4-ones 3 and hydrated products 4 varied depending upon the substituents R (nBu, phenyl, H and TMS) on the alkynes 1. We also describe the transformation of the chalcones 2 to the corresponding chroman-4-ones 3 under basic conditions. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)</P> <B>Graphic Abstract</B> <P>A novel synthetic method to prepare chalcones and chroman-4-ones by TMSOTf-promoted addition of alkynes to various aldehydes has been developed. The ratios of chalcones, chroman-4-ones and hydratedproducts vary depending upon the substituents on the alkynes. We also describe the transformation of the chalcones to the corresponding chroman-4-ones under basic conditions. <img src='wiley_img/1434193X-2008-2008-32-EJOC200800782-fig000.gif' alt='wiley_img/1434193X-2008-2008-32-EJOC200800782-fig000'> </P>

Facile synthesis of 4″-<i>O</i>-alkyl-(-)-EGCG derivatives through regioselective deacetylative alkylation

Seo, Yujin,Kim, Mi Kyoung,Choo, Hyunah,Chong, Youhoon Informa UK (TaylorFrancis) 2017 Synthetic communications Vol.47 No.7

<P>Therapeutic potential of the D-ring methyl ethers of (-)-epigallocatechin-3- gallate [(-)- EGCG] warrants extensive structure-activity relationship study of various D-ring ethers of (-)-EGCG but, for this purpose, efficient synthetic strategy needs to be developed. In this study, efficient preparation of the 4 ''-O-alkyl-(-)-EGCGs (4a-e) was demonstrated using KI/K2CO3-promoted deacetylative alkylation of peracetyl (-)-EGCG, which could be broadly utilized for the preparation of various D-ring alkyl ethers of (-)-EGCG and thereby extensive structure-activity relationship study.</P>

Production of deoxygenated high carbon number hydrocarbons from furan condensates: Hydrodeoxygenation of biomass-based oxygenates

Seo, Jangwoo,Kwon, Ji Sun,Choo, Hyunah,Choi, Jae-Wook,Jae, Jungho,Suh, Dong Jin,Kim, Shin,Ha, Jeong-Myeong Elsevier 2019 CHEMICAL ENGINEERING JOURNAL -LAUSANNE- Vol.377 No.-

<P><B>Abstract</B></P> <P>Two-step hydrodeoxygenation of furan trimers using supported Ni catalysts was successfully performed by substituting expensive noble metal catalysts for hydrodeoxygenation, which can contribute to the development of feasible hydrodeoxygenation processes with which to prepare high-carbon-number hydrocarbon fuels. Although more cracking of hydrocarbon products was observed for the Ni catalysts, the substitution of noble metal catalysts with Ni catalysts was successful, leading to good HDO activity. The combination of the first step of Ni/CeO<SUB>2</SUB> (hydrogenation) and the second step of Ni/tungstated zirconia (hydrodeoxygenation) led to complete deoxygenation, achieving 87.8% of the theoretical maximum yield of the oil phase product, which is slightly lower than the value of 91.1% for the combination of the first step of Pd/C (hydrogenation) and Ru/tungstated zirconia (hydrodeoxygenation). The roles of first-step hydrogenation were revealed as the hydrogenation of unsaturated furan rings and the hydrolysis of saturated furan rings.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Two-step hydrodeoxygenation of biomass-derivatives using Ni catalysts produces diesel-like fuels. </LI> <LI> Ni catalysts exhibit a good deoxygenation activity comparable to that of noble metals. </LI> <LI> Saturation and hydrolysis of furan rings occur during the first step hydrogenation. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>