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題 名 | Molecular Mechanisms of Resistance of Plasmodium Falciparum to Antifolates=惡性瘧對抗葉酸藥物抗藥性的分子機制 |
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作 者 | 蕭孟芳; 李佩紋; | 書刊名 | 光田醫學雜誌 |
卷 期 | 2:4 2007.09[民96.09] |
頁 次 | 頁65-73 |
分類號 | 418.286 |
關鍵詞 | 惡性瘧; 抗葉酸藥物; 抗藥性; 雙氫葉酸還原酶; 雙氫喋呤合成酶; Plasmodium falciaprum; Antifolates; Drug resistance; Dihydrofolate reductase; DHFR; Dihydropteroate synthase; DHPS; Pyrimethamine-sulfadoxine; PYR; SDX; |
語 文 | 英文(English) |
中文摘要 | 所有瘧疾感染治療皆需使用有效的抗瘧藥物-包括??類藥如奎寧、氯奎寧、抗葉酸藥物及青蒿衍生物。目前臨床上使用的抗瘧藥物中以抗葉酸藥物有最明確的分子標的物-即標的葉酸代謝途徑中的功能酵素-雙氫葉酸還原?(dihydrofolate reductase,簡稱DHFR)及雙氫喋呤合成?(dihydropteroate synthase,簡稱DHPS)。葉酸輔因子是DNA合成及胺基酸代謝的必需物質,抗葉酸藥物的作用機制是還原葉酸輔因子是DNA合成及胺基酸代謝所必須。傳統上抗葉酸藥物分為二類—第一類抗葉酸藥物為磺胺藥物(sulfonamides and sulfones),機制為藥物和受質共同競爭DJHPS的活化位置來抑制雙氫喋呤形成。第二類抗瘧藥物為乙胺嘧啶(pyrimethamine)和雙胍類(biguanides),其作用機制為抑制DHFR,然後阻斷雙氫葉酸還原為四氫葉酸。對DHFR和DHPS抑制劑產生抗藥性是因為此兩時重酵素基因改碼產生單點突變,導致胺基酸序列組態改變。DHFR和DHPS的基因突變區間位置在Pyrimethamine-sulfadoxine(PYR/SDX)治療失敗的分離蟲株中發現,其中較顯著的突變有DHFR基因序列16(Ala>Val)、108 (Ser>Asn/Thr)、51(Asn>Ile)、59(Cys>Arg)、(Ile>Leu)以及DHPS基因序列436(Ser>Ala/Phe)、437(Ala>Gly)、540(Lys>Glu)、581(Ala>Gly)、613(Ala>Thr/Ser)。DHFR和DHPS的突變是漸進式的產生,目前咸信DHFR或DHPS任一種酵素基因出現單一點突變或是兩種酵素基因皆出現單一點突變,以PYR/SDX治療仍可望抑制DHFR和DHPS。相反的,若DHFR出現三點突變-S108N, C59R,和N51I,則不論DHPS基因是否有雙點突變(如A437G和A581G或K540E),以PYR/SDX治療,則註定失敗。 |
英文摘要 | In malaria inflection, treatment of all cases requires the use of an effective antimalarial drug. These include the quinoline based drugs such as quinine and chloroquine, the antifolates and the artemisinin derivatives. Among the antimalarial drugs currently in clinical use, the antifolates have the best defined molecular targets, namely the enzymes dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS), which function in the folate metabolic pathway. The products of this pathway, reduced folate cofactors, are essential for DNA synthesis and the metabolism of certain amino acids. The antifolates are traditionally classified into 2 groups. Type 1 antifolates (sulfonamides and sulfones) prevent the formation of dihydropteroate catalyzed by dihydropteroate synthase (DHPS) by competing for the active sites of DHPS; type 2 anfifolates (pyrimethamine and biguanides) inhibit dihydrofolate reductase (DHFR), thus preventing the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate by DHFR. Resistance to DHFR and DHPS inhibitors in conferred by single mutations of the gene encoding for the respective enzyme, resulting in substitutions in the amino acid chain. Areas of the DHFR and DHPS genes with identified mutations are found in isolates that fail to respond to pyrimethamine-sulfadoxine (PYR/SDX treatment, notably at codons 16(Ala>Val), 108 (Ser>Asn/Thr), 51(Asn>Ile), 59(Cys>Arg), and 164(Ile>Leu) of the DHFR gene and at codons 436(Ser>Ala/Phe), 437(Ala>Gly), 540(Lys>Glu), 581(Ala>Gly), and 613(Ala>Thr/Ser) of the DHPS gene. DHFR and DHPS mutations occur in a progressive, stepwise fashion. There is general agreement that single mutation in one or both gene are expected to be inhibited by PYR/SDX. In contrast, isolates carrying the triple mutation in DHFR (S108N, C59R, and N51I), with or without the double mutation in DHPS (A437G and A581G or K540E), are bound to cause treatment failure. |
本系統中英文摘要資訊取自各篇刊載內容。