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首页> 外文学位 >Hypostatin, a new small molecule inhibitor of plant cell expansion, is glyco-activated in vivo.
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Hypostatin, a new small molecule inhibitor of plant cell expansion, is glyco-activated in vivo.

机译：Hypostatin是一种新的植物细胞扩张小分子抑制剂，在体内被糖激活。

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摘要

Natural variation in humans in the response to a bioactive or drug-like small organic molecule is defined as pharmacogenetic variation. Studies have shown that variation in both drug metabolism genes and drug target loci can cause inter-individual variation in drug response. For example, sequence differences in UDP-glucuronosyl transferases (UGTs), which glycosylate xenobiotics, can affect drug sensitivity by affecting rates of drug detoxification. Although this subject has been explored extensively in humans, the biological pervasiveness of pharmacogenetic variation had not been systematically examined. If pervasive, pharmacogenetic variation in model systems could be used for both functional studies and to gain deeper insight into the mechanisms of this important form of natural variation. To examine this question, 8 geographically diverse Arabidopsis accessions were screened on a 10,000 member chemical library. I focused on new inhibitors of cell expansion in the etiolated hypocotyl. In total, 742 chemicals (7.4%) caused greater than 20% inhibition of hypocotyl cell expansion. 11 weak polymorphic chemicals were uncovered, as well as a strong polymorphic hypocotyl cell expansion inhibitor, named hypostatin. My work has firmly established the existence of pharmacogenetic variation in Arabidopsis.;To understand the mechanism of this variation, I characterized the molecular basis of variation in hypostatin sensitivity. Genetic analysis of F1, F2 and recombination inbred lines (RIL) of crosses between Col and Ler (which show differential sensitivity) showed that hypostatin resistance is determined by a single recessive locus, named HYR1. Map-based cloning showed that HYR1 encodes a UDP-glycosyltransferase (UGT71B2) that has no substrate documented and a known pharmacogenetic factor related humans. My research has shown that hypostatin-sensitive Arabidopsis accessions encode functional HYR1 proteins that glucosylate hypostatin in vivo and convert it into an activated form. Hypostatin resistant accessions contain non-function HYR1 proteins and cannot glucosylate hypostatin. Hypostatin is, therefore, a pro-drug that is activated by glucosylation, a process I have called glycoactivation. Collectively, my data show that natural variation can be used to gain insight into the mechanism of action of new compounds and that there are biochemical similarities between plant and human pharmacogenetic loci.
机译：人类对生物活性或类似药物的有机小分子的反应中的自然变异被定义为药物遗传变异。研究表明，药物代谢基因和药物靶基因座的变异均可引起药物反应的个体差异。例如，糖基化异种生物的UDP-葡萄糖醛酸转移酶（UGT）的序列差异可通过影响药物排毒的速率来影响药物敏感性。尽管已经在人类中广泛地探索了这个主题，但是尚未系统地研究药物遗传学变异的生物学普遍性。如果普遍存在，则模型系统中的药物遗传变异既可以用于功能研究，又可以深入了解这种重要形式的自然变异的机理。为了研究这个问题，在10,000个成员的化学文库中筛选了8个地理上不同的拟南芥种质。我研究了黄化胚轴中新的细胞膨胀抑制剂。总共有742种化学药品（7.4％）对下胚轴细胞的扩张产生了大于20％的抑制作用。发现了11种弱多态化学物质，以及一种强多态下胚轴细胞扩张抑制剂，称为hypostatin。我的工作牢固地确定了拟南芥中药理遗传学变异的存在。为了了解这种变异的机理，我对低他汀类药物敏感性变异的分子基础进行了表征。对F1，F2和Col与Ler之间杂交的近交重组自交系（RIL）进行遗传分析（显示出不同的敏感性）表明，降血沉素的耐药性由单个隐性基因座HYR1决定。基于图谱的克隆显示，HYR1编码没有底物和已知与人遗传药理因子有关的UDP-糖基转移酶（UGT71B2）。我的研究表明，对hypostatin敏感的拟南芥登录号编码了功能性HYR1蛋白，该蛋白在体内葡萄糖基化了hypostatin，并将其转化为活化形式。 Hypostatin抗性登录品包含无功能的HYR1蛋白，不能糖基化他汀。因此，Hypostatin是一种通过糖基化激活的前药，这一过程我称为糖激活。总的来说，我的数据表明，自然变异可用于深入了解新化合物的作用机理，并且植物和人类药物遗传学基因座之间存在生化相似性。

著录项

  • 作者

    Zhao, Yang.;

  • 作者单位

    University of Toronto (Canada).;

  • 授予单位 University of Toronto (Canada).;
  • 学科 Biology Molecular.;Biology Genetics.;Biology Botany.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 153 p.
  • 总页数 153
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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