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Structural Insights for β-Lactam Antibiotics
( Dogyeoung Kim ),( Sumin Kim ),( Yongdae Kwon ),( Yeseul Kim ),( Hyunjae Park ),( Kiwoong Kwak ),( Hyeonmin Lee ),( Jung Hun Lee ),( Kyung-min Jang ),( Donghak Kim ),( Sang Hee Lee ),( Lin-woo Kang ) 한국응용약물학회 2023 Biomolecules & Therapeutics(구 응용약물학회지) Vol.31 No.2
Antibiotic resistance has emerged as a global threat to modern healthcare systems and has nullified many commonly used antibiotics. β-Lactam antibiotics are among the most successful and occupy approximately two-thirds of the prescription antibiotic market. They inhibit the synthesis of the peptidoglycan layer in the bacterial cell wall by mimicking the D-Ala-D-Ala in the pentapeptide crosslinking neighboring glycan chains. To date, various β-lactam antibiotics have been developed to increase the spectrum of activity and evade drug resistance. This review emphasizes the three-dimensional structural characteristics of β-lactam antibiotics regarding the overall scaffold, working mechanism, chemical diversity, and hydrolysis mechanism by β-lactamases. The structural insight into various β-lactams will provide an in-depth understanding of the antibacterial efficacy and susceptibility to drug resistance in multidrug-resistant bacteria and help to develop better β-lactam antibiotics and inhibitors.
Donghak Kim,Young-Ran Lim,Hyoung-Goo Park,Beom Joon Kim,Young-Jin Chun 한국독성학회 2009 Toxicological Research Vol.25 No.1
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and related halogenated aromatic hydrocarbons elicit a diverse spectrum of biochemical and toxic responses in laboratory animals and mammalian cells in culture. Toxicity and carcinogenicity of TCDD is well established but the molecular mechanism is still poorly understood. Here, we found the noble responsive genes to TCDD using the differential display analysis. Treatment of HepG2 cells with TCDD showed a significantly different mRNA expression pattern from the untreated cells in differential display analysis. The differentially displayed bands were isolated and used as probes in dot blot and Northern blot analyses. Of thirty-five isolated differentially displayed bands, only two bands were confirmed as positive in dot blot and Northern blot analyses. The nucleotides sequences of these clones were analyzed and the search of Genebank database revealed that one clone is highly homologous with RanBP2 (Ras-related nuclear protein binding protein2; 92%) and the other is an unknown gene. RanBP2 is a nucleoporin with SUMO E3 ligase activity that functions in both nucleocytoplasmic transport and mitosis and its role as a novel tumor suppressor has been recently proposed. Thus, these results may suggest the clue elucidating the toxic mechanism of TCDD through RanBP2.
Inhibition of cytochrome P450 2B6 by Astragalus extract mixture HT042
Kim Harim,Lee Yejin,Kim Vitchan,Lee Rowoon,Bae Soo Kyung,Kwak Mi-Kyoung,Lee Sung Hoon,Kim Donghak 한국독성학회 2020 Toxicological Research Vol.36 No.3
Astragalus extract mixture (AEM) HT042 is a functional food approved by the MFDS (Korean FDA) for increasing height. It comprises a mixture of three standardized extracts from Astragalus membranaceus root, Eleutherococcus senticosus stem, and Phlomis umbrosa root. In this study, drug–functional food interaction was analyzed using six major human cytochrome P450 enzymes. The inhibitory effect of AEM HT042 on P450 activities was studied using a P450–NADPH P450 reductase reconstitution system. Among the six P450 enzymes (1A2, 2A6, 2B6, 2D6, 2C9, and 3A4), only P450 2B6 activity was markedly decreased by AEM HT042 addition. The bupropion hydroxylation activity of P450 2B6 was analyzed using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS). A calculated IC50 value of 10.62 μg/ml was obtained. To identify the inhibitory compounds in the mixture, four active compounds in AEM HT042 were analyzed. Shanzhiside methylester exhibited inhibitory effects on P450 2B6, whereas formononetin, eleutheroside E, and sesamoside did not affect P450 2B6 activity at all. Our results suggest that shanzhiside methylester in AEM HT042 is responsible for the inhibitory effect on P450 2B6 metabolism. Characterization of the inhibitory effect on P450 can help determine the safe administration of functional foods along with many clinical drugs that are metabolized by P450.
A STUDY ON THE INITIAL CHARACTERISTICS OF DOMESTIC SPENT NUCLEAR FUELS FOR LONG TERM DRY STORAGE
Kim, Juseong,Yoon, Hakkyu,Kook, Donghak,Kim, Yongsoo Korean Nuclear Society 2013 Nuclear Engineering and Technology Vol.45 No.3
During the last three decades, South Korean nuclear power plants have discharged about 5,950 tons of spent fuel and the maximum burn-up reached 55 GWd/MTU in 2002. This study was performed to support the development of Korean dry spent fuel storage alternatives. First, we chose V5H-$17{\times}17$ and KSFA-$16{\times}16$ as representative domestic spent fuels, considering current accumulation and the future generation of the spent fuels. Examination reveals that their average burn-ups have already increased from 33 to 51 GWd/MTU and from 34.8 to 48.5 GWd/MTU, respectively. Evaluation of the fuel characteristics shows that at the average burn-up of 42 GWd/MTU, the oxide thickness, hydrogen content, and hoop stress ranged from $30{\sim}60{\mu}m$, 250 ~ 500 ppm, and 50 ~ 75 MPa, respectively. But when burn-up exceeds 55 GWd/MTU, those characteristics can increase up to 100 ${\mu}m$, 800 ppm, and 120 MPa, respectively, depending on the power history. These results demonstrate that most Korean spent nuclear fuels are expected to remain within safe bounds during long-term dry storage, however, the excessive hoop stress and hydrogen concentration may trigger the degradation of the spent fuel integrity early during the long-term dry storage in the case of high burn-up spent fuels exceeding 45 GWd/MTU.
Human Cytochrome P450 Metabolic Activation in Chemical Toxicity
Donghak Kim,Young-Jin Chun 한국독성학회 2007 Toxicological Research Vol.23 No.3
Cytochrome P450 (P450) enzymes are the major catalysts involved in the biotransformation of various drugs, pollutants, carcinogens, and many endogenous compounds. Most of chemical carcinogens are not active by themselves but they require metabolic activation. P450 isozymes play a pivotal role in the metabolic activation. The activation of arylamines and heterocyclic arylamines (HAAs) involves critical N-hydroxylation, usually by P450. CYP1A2 plays an important role in these reactions. Broad exposure to many of these compounds might cause carcinogenicity in animals and humans. On the other hand, P450s can be also involved in the bioactivation of other chemicals including alcohols, aflatoxin B1, acetaminophen, and trichloroethylene, both in humans and in experimental animals. Understanding the P450 metabolic activation of many chemicals is necessary to develop rational strategies for prevention of their toxicities in human health. An important part is the issues of extrapolation between species in predicting risks and variation of P450 enzyme activities in humans.
Simplified adaptor for stereotactic surgery in non-human primates
Kim, Hyung-Sun,Byun, Donghak,Kim, Ra Gyung,Kang, Goo-Hwa,Park, Ji-Young,Yang, Young-Su,Han, Su-Cheol,Kim, Hyoung-Ihl Elsevier 2018 Journal of neuroscience methods Vol.295 No.-
<P><B>Abstract</B></P> <P><B>Background</B></P> <P>It is challenging for researchers performing stereotactic procedures to transition from small animals to non-human primate (NHP) experiments. The NHP stereotactic atlas is based on ear-bar zero (EBZ), which is an anatomical reference frame that is not visible during surgery. Most current NHP stereotactic systems require high-cost MRI or CT imaging and complex computer processing to determine the stereotactic coordinates, limiting the procedure to those with significant expertise.</P> <P><B>New method</B></P> <P>We have designed a simplified adaptor consisting of a circular arc for coronal tilt, a carrier for electrodes or cannulas, and an anchor to attach the adaptor to a conventional stereotactic frame. Our adaptor allows easy identification of the EBZ with the help of an anchor notch, and provides digital distance sensors without the need for imaging data or computer processing. Our system enables the use of trajectories that avoid injury to important structures and vessels.</P> <P><B>Results</B></P> <P>We tested the accuracy of our system using simulated targeting with phantoms, and demonstrated sub-millimeter accuracy. Infusion of methylene blue also showed satisfactory staining in target structures deep in the brain.</P> <P><B>Comparison with existing methods</B></P> <P>This system does not require high-cost imaging and extra training to determine EBZ. Once EBZ is set automatically by the system itself, targeting is similar to that in small animal stereotactic procedure.</P> <P><B>Conclusion</B></P> <P>Our simple adaptor will aid researchers who plan to conduct experiments involving stereotactic surgery in NHPs.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A simple adaptor is proposed for stereotactic surgery in non-human primates. </LI> <LI> This adaptor can be attached to a conventional animal stereotactic frame. </LI> <LI> It allows identification of ear bar zero without imaging and computer processing. </LI> <LI> Simulation study shows the submillimeter precision in targeting. </LI> <LI> The proposed system will be useful for unexperienced translational researcher. </LI> </UL> </P>
Steroidogenic cytochrome P450 enzymes as drug target
Kim Changmin,Jeong Eunseo,Lee Yoo-bin,Kim Donghak 한국독성학회 2024 Toxicological Research Vol.40 No.3
Human cytochrome P450 (CYP) enzymes are composed of 57 individual enzymes that perform monooxygenase activities. They have diverse physiological roles in metabolizing xenobiotics and producing important endogenous compounds, such as steroid hormones and vitamins. At least seven CYP enzymes are involved in steroid biosynthesis. Steroidogenesis primarily occurs in the adrenal glands and gonads, connecting each reaction to substrates and products. Steroids are essential for maintaining life and significantly contribute to sexual differentiation and reproductive functions within the body. Disorders in steroid biosynthesis can frequently cause serious health problems and lead to the development of diseases, such as prostate cancer, breast cancer, and Cushing’s syndrome. In this review, we provide current updated knowledge on the major CYP enzymes involved in the biosynthetic process of steroids, with respect to their enzymatic mechanisms and clinical implications for the development of new drug candidates.