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研究生:陳媛孃
研究生(外文):Yung-Liang Chen
論文名稱:I.雞母珠毒蛋白質(Abrin-a)胺基酸排列順序之研究II.合成化合物—Butenolid衍生物抗癌作用機制之研究
論文名稱(外文):I. Studies on the amino acid sequencingof Abrin-a II. Studies on the antitumor activity of Butenolid derivatives
指導教授:林榮耀林榮耀引用關係
指導教授(外文):Jung-Yaw Lin
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:生化學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:1993
畢業學年度:81
語文別:中文
論文頁數:150
中文關鍵詞:雞母珠毒蛋白質胺基酸排列順序Butenolid 衍生物
外文關鍵詞:Abrin-aAmino acid sequencingButinolid derivatives
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Part I.雞母珠毒蛋白質(Abrin-a)胺基酸排列順序之研究:雞母珠毒蛋白
質 (Abrin-a of Abrus precatorius)係由A鏈與B鏈兩個次單元體所組成
。將 Abrin-a羧甲基化(Carboxylmethylation)後,A鏈以Trypsin,
Chymotrypsin, Staphylococcus aureus V8 protease和Thermolysin水
解;B鏈則以Trypsin ,Chymotrypsin,Staphylococcus aureus V8
protease,Lysyl endopepti- dase和Thermolysin水解所得胜■訂出其胺
基酸排列順序。將此蛋白質胺基酸排列順序與從核■酸推測出的胺基酸排
列順序比較,發現二者不完全相同 ,顯示雞母珠毒蛋白質含有其他之異型(
Isoforms)毒蛋白質。此外,比較雞母珠毒蛋白質與蓖麻子毒蛋白質(
Ricin-D)的胺基酸排列順序發現其A鏈有 42%之相似性,而B鏈則有59%之相
似性。B鏈係由兩個單元體(Domain)所組成 ,而每個單元體則含有(a、b、
g)三個次單元體(Subdomain),每個次單元體約由40個胺基酸殘基組成。顯
示在演化上Abrin-a與Ricin-D係源自一相同的始祖。Abrin-a A chain則
與Ricin-D A chain有Glu164,Ala165,Arg167, Asn196,Trp198,Ser202保
留之胺基酸,可能與其N-glycosidase活性有關。我們利用試管內(in
vitro)細胞生長抑制(Inhibition of cell growth),蛋白質生合成抑制(
Inhibition of protein biosynthesis),RNA生合成抑制(Inhibition of
RNA biosynthesis)以及DNA生合成抑制(Inhibition of DNA
biosynthesis)系統從數十種合成化合物(Synthesized compounds)來篩選
具有抗癌活性的物質。結果發現4-acetoxybutenolide(命名為158G),
erythro-di-4-butenolidyl-ether(159A)及threo-di-4-butenolidyl
eth- er(159B)。這三種Butenolid衍生物具有抗癌活性,其抑制子宮頸癌
細胞( HeLa cells)百分之五十細胞生長濃度分別是158G:0.01mg/ml:159
A:0.03mg /ml;159B:0.02mg/ml。抑制子宮頸癌細胞百分之五十蛋白質生
合成之濃度分別是158G:0.05mg/ml;159A:0.91mg/ml;159B:0.89mg/ml。抑
制子宮頸癌細胞百分之五十RNA生合成之濃度分別是158G:5.01mg/ml;159
A:0.74mg/ml; 159B:0.55mg/ml。以及抑制子宮頸癌細胞百分之五十DNA生
合成之濃度分別是158G:7.42mg/ml;159A:0.25mg/ml;159B:0.15 mg/ml。
此外,以裸鼠進行這三種Butenolide衍生物的生物體內(in vivo)試驗,發
現這三種的化合物對於植入裸鼠背部的子宮頸癌具有部份治療效果。
Abrin-a is a toxic glycoprotein found in the seeds of Abrus pre-
catorius.It consists of two chains,A chain and B chain. The
amino acid sequence of A chain was determined by analysis of
peptides obtained from the S-carboxymethylated protein by
digestion with trypsin,chymotrypsin,Staphylococcus auerus V8
protease and thermolysin;while that of S-carboxymethylated B
chain was determined by digestion with trypsin,chymotrypsin,
Staphylococcus aureus V8 protease,lysyl endopeptidase and
thermolysin.The amino acid sequence of Abrin-a is not identical
with that predicted previously by nucleotide sequencing,
indicating the presence of isoforms of Abrin-a.Comparison of
the amino acid sequence of Abrin-a A chain with that of Ricin-D
A chain reveals 42% sequence identity; while B chain 59% .
Abrin-a B chain also appears to consist of two do- mains,each
domain with three subdomains(a,b and g)of about 40 amino acid
residues.It suggests that Abrin-a and Ricin-D evolu- tionarily
come from the same ancestor.Abrin-a A chain has Glu164, Ala165,
Arg167,Asn196,Trp198 and Ser202 which are also conserved to
Ricin-D A chain and may involve in catalytic sites of N-glyco-
sidase activity.Three of them exhibit potent antitumor activity
on HeLa cells.They are 4-acetoxy-butenolide(nomenclature as
158G) ,erythro-di-4-butenolidyl ether(159A) and threo-di-4-
butenolidyl ether(159B)all belonging to butenolid
derivatives.50% cell growth inhibitory concentations of 158G,159
A and 159B was determined to be 0.01mg/ml,0.03mg/ml and 0.02 mg/
ml,respectively. 50% protein biosynthesis-inhibition
concentration of 158G,159A and 159B was 0.05mg/ml,0.91mg/ml and
0.89mg/ml,respectively. 50%RNA biosynthe- sis-inhibition
concentration of 158G,159A and 159B was 5.01 mg/ml ,0.74mg/ml
and 0.55mg/ml,respectively. 50% DNA biosynthesis-inhi- bition
concentration of 158G,159A and 159B were 7.42mg/ml,0.25mg/ ml
and 0.15mg/ml,respectively.This compounds showed an antitumor
against the growth of cervix uteri tumor in nude mice.
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