• Title/Summary/Keyword: Nucleoside

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Reaction Mechanism of Purine Nucleoside Phosphorylase and Effects of Reactive Agents for SH Group on the Enzyme in Saccharomyces cerevisiae (Saccharomyces cerevisiae에서 얻은 Purine Nucleoside Phosphorylase의 반응기작과 효소에 대한 Sulfhydryl Reagent의 영향)

  • Choi, Hye-Seon
    • Korean Journal of Microbiology
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    • v.32 no.3
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    • pp.222-231
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    • 1994
  • Kinetic analysis was done to elucidate the reaction mechanism of purine nucleoside phosphorylase (PNP) in Saccharomyces cerevisiae. The binary complexes of PNP${\cdot}$phosphate and PNP${\cdot}$ribose 1-phosphate were involved in the reaction mechanism. The initial velocity and product inhibition studies demonstrated were consistent with the predominant mechanism of the reaction being an ordered bi, bi reaction. The phosphate bound to the enzyme first, followed by nucleoside and base were the first product to leave, followed by ribose 1-phosphate. The kinetically suggested mechanism of PNP in S. cerevisiae was in agreement with the results of protection studies against the inactivation of the enzyme by sulfhydryl reagents, p-chloromercuribenzoate (PCMB) and 5,5'-dithiobisnitrobenzoate (DTNB). PNP was protected by ribose 1-phosphate and phosphate, but not by nucleoside or base, supporting the reaction order of ordered bi, bi mechanism. PCMB or DTNB-inactivated PNP was totally reactivated by dithiothreitol (DTT) and the activity was returned to the level of 77% by 2-mercaptoethanol, indicating that inactivation was reversible. The kinetic behavior of the PCMB-inactivated enzyme had been changed with higher $K_m$ value of inosine and lower $V_m$, and was restored by DTT. Inactivation of enzyme by DTNB showed similar pattern of K sub(m) value with that by PCMB, but had not changed the $V_m$ value, significantly. Negative cooperativity was not found with PCMB or DTNB treated PNP at high concentration of phosphate.

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Effect of Serum Concentration on Inhibition of Nucleoside Transport by Multidrug Resistance Inhibitor BIBW22 (혈청 농도가 다제내성 억제제 BIBW22의 nucleoside 수송에 미치는 영향)

  • ;Hong-Xing Chen;Uwe Bamberger;Yung-Chi Cheng;Thomae GmbH
    • Biomolecules & Therapeutics
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    • v.3 no.2
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    • pp.116-121
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    • 1995
  • Some multidrug resistance inhibitors have been known to be influenced by the serum concentration. In this study, effect of serum concentration on inhibition of nucleoside transport by BIBW22, a new multidrug resistance inhibitor derived from dipyridamole (DPM), was studied. When 5% or 100% (v/v) of fetal bovine serum (FBS) was contained in the culture, DPM dose for which nucleoside transport was inhibited by 50% (lD$_{50}$) was 0.42 $\mu$M or 1.17 $\mu$M, respectively. BIBW22 also showed the same trend as DPM did in response to increase of FBS concentration. However, ID$_{50}$ value for DPM in the absence or presence of human plasma was 0.007 $\mu$M or 1.02 $\mu$M respectively showing 145 times increase of ID$_{50}$ value. ID$_{50}$ value for BIBW22 in the presence of human plasma was 0.028 $\mu$M showing only 5 times increase in ID$_{50}$ value. This result suggests that potency of BIBW22 was much less affected by the plasma concentration and BIBW22 could be a good candidate for a clinical use in multidrug resistance treatment.treatment.

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Metabolic Role of Glyoxylate on the Biosynthesis of Serratia marcescens Purine Nucleoside Phosphorylase (Serratia marcescens Purine Nucleoside Phosphorylase의 생합성에 대한 글리옥실산의 대사적 역할)

  • 방선권
    • The Korean Journal of Food And Nutrition
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    • v.12 no.1
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    • pp.43-49
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    • 1999
  • The effects of purine catabolites in growth media on the Serratia marcescens purine nucleoside phos-phorylase activity were examined. The enzyme activity was decreased above 60% by guanosine(5 to 15mM). The enzyme activity was not affected at low concentration of inosine (0.1∼1mM). The en-zyme activity was decreased approximately by 40∼50% in the presence of high concentrations of aden-osine hypoxanthine and xanthine (5∼15mM) but was not affected at low concentration of adenosine hypoxanthine and xanthine (0.1∼0.5mM). However the enzyme activity was increase by 20% with low concentrations of uric acid(0.5mN). but was decreased by 80% with high concentrations of same purine catabolite (15mM). Also the enxzyme activity was increased by 20% with low concentrations of glyoxylate (0.5mM) final degradative product of uric acid but was decreased by 30∼50% with high con-centrations of glyoxylate (3∼15mM). The enzyme activity was decreased approximately by 20% by the simultaneous addition of inosine hypoxanthine and uricacid at 5mM each whereas it was increased by 22 and 33% by the combination of inosine and uric acid three purine catabolites at 0.5mM respectively These data suggest that S. marcescens purine nucleoside phosphorylase is positively regulated by a glyox-ylate concentration and then may play a regulatory role in a purine catabolism.

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Synthesis of Novel Carbovir Analogue

  • Kim, Ai-hong;Hong, Joon-Hee
    • Bulletin of the Korean Chemical Society
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    • v.27 no.7
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    • pp.976-980
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    • 2006
  • The synthesis of 4'-phenyl and 1'-methyl doubly branched carbocyclic nucleoside was accomplished from 2-hydroxy acetophenone. The 4'-phenyl group was installed via a [3,3]-sigmatropic rearrangement reaction, and the carbonyl addition of methylmagnesium bromide was used to introduce the 1'-methyl group. Cyclization of divinyl 9 was performed using $2^{nd}$ generation Grubbs catalyst. The coupling of cyclopentenol 12$\alpha$ with 6-chloropurine by Mitsunobu reaction and desilylation was used to synthesize the target nucleoside 15.

Synthesis and Antiviral Evaluation of 1'-Branched-5'-Norcarbocyclic Adenosine Phosphonic Acid Analogues

  • Oh, Chang-Hyun;Yoo, Kyung-Ho;Hong, Joon-Hee
    • Bulletin of the Korean Chemical Society
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    • v.31 no.9
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    • pp.2473-2478
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    • 2010
  • Novel 1'-methyl-5'-norcarbocyclic adenosine phosphonic acid analogues were synthesized using an acyclic stereoselective route from commercially available 3,3-diethoxy-propan-1-ol 4. The synthesized nucleoside phosphonate 19 and phosphonic acid 21 were subjected to antiviral screening against various viruses.

HIV-1 RT (reverse transcriptase) 저해제에 대한 내성 발현 기전

  • 임광진
    • Proceedings of the Korean Society of Applied Pharmacology
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    • 1995.10a
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    • pp.67-69
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    • 1995
  • reverse transcription은 AIDS를 일으킨다고 알려진 바이러스인 HIV-1의 번식에는 필수적이나 인체 세포에는 필수적이 아니기에 이 단계를 표적으로 하는 AIDS 치료제가 우선적으로 개발되었다. 그 단계에 필요한 효소가 바이러스에 의해 만들어진 RT이며 이 효소의 작용을 저해하는 nucleoside 유도체들인 AZT, DDC, DDI 들이 현재 AIDS 환자의 치료에 사용되고 있다. 이들 nucleoside 유도체들은 세포안으로 들어가 triphosphate 형태로 변화된 후 dNTP와 상경적으로 경쟁하며 합성 중인 바이러스의 DNA에 들어가 DNA의 합성을 정지시켜 바이러스의 증식을 억제한다. 그러나, 이들 nucleoside 유도체들은 치료용량에서 심한 독성을 나타낼 뿐만 아니라 장기 투여시 내성을 나타내는 바이러스가 생겨나 AIDS의 치료를 불가능하게 하고 있다.

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Carboacyciic nucleoside계 항 바이러스제 개발에 관한 연구

  • 김희두
    • Proceedings of the Korean Society of Applied Pharmacology
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    • 1993.04a
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    • pp.41-41
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    • 1993
  • 현재 유일하게 AIDS 치료제로 허가된 AZT를 비롯하여 항 virus 효과를 나타내는 약물의 대부분은 구조적으로 Nucleoside계에 속하는 화합물로서 수많은 약리학적 연구 및 합성 화학적 연구가 이루어져 왔다. 특히 합성 화학적 측면에서 이들 화합물의 합성은 크게 두 가지로 나누어지는데 그것은 Sugar 부위의 변형을 통한 방법과 염기 부위의 변형을 통한 방법에 의해 새로운 항 바이러스제를 개발하는 것이다. 최근의 연구 동향에 있어서 주목할 만한 변화의 하나는 Sugar 부위의 구조적 변형을 시도하는데 있어서 종래의 5원환 형태에서 환이개열된 형태의 Acyclic Nucleoside에 대한 연구가 이루어져 좋은 효과를 거두고 있다는 사실이다. Acyclovir, Ganciclovir 등의 개발이 그것이다. 본 연구에서는 이와 같은 Acyclic Nucleoside계의 새로운 항 virus제를 합성하여 그 생리 활성을 검색하고자 한다.

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Synthesis of Novel Mercaptophenyl Carbocyclic C-Nucleoside Analogue Using Sequential [3,3]-Sigmatropic Rearrangement and Ring-closing Metathesis

  • Li, Hua;Hong, Joon-Hee
    • Bulletin of the Korean Chemical Society
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    • v.29 no.4
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    • pp.847-850
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    • 2008
  • Novel mercaptophenyl carbocyclic C-nucleoside analogue was synthesized via a cyclopentenol intermediate 10, which was prepared using a sequential [3,3]-sigmatropic rearrangement and ring-closing metathesis (RCM). Friedel-Crafts alkylation was then used to couple the thiophenol.

Understanding the RNA-Specificity of HCV RdRp: Implications for Anti-HCV Drug Discovery

  • Kim, Jin-young;Chong, You-hoon
    • Bulletin of the Korean Chemical Society
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    • v.27 no.1
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    • pp.59-64
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    • 2006
  • Unlike other viral polymerases, HCV RNA-dependent RNA polymerase (RdRp) has not been successfully inhibited by nucleoside analogues presumably due to its strong substrate specificity for RNA. Thus, in order to understand the RNA-specificity of HCV RdRp, the structural characteristics of the active site was investigated. The hereto unknown 2-OH binding pocket at the active site of RdRp provides invaluable implication for the development of novel anti-HCV nucleoside analogues.