重建人體鞘脂代謝網路並探討酵素調控最適化

Reconstruction of the human sphingolipid metabolic network and optimization of enzyme regulation

柯欣妤(Ke Shinyu)

指導教授 ： 王逢盛

國立中正大學/工學院/化學工程學系/碩士(2012年)

摘要

神經鞘脂類(Sphingolipid)廣泛存於全身細胞中，不只可組成細胞膜結構，亦可傳遞訊號，調控細胞存亡。其代謝途徑中間產物神經醯胺(Ceramide)與鞘氨醇-1-磷酸(Sphingosine 1-phosphate)更分別被稱為抑癌脂質及促癌脂質，目前市面上的化療藥物，如：唐黴素注射劑(Daunorubicin)、醫百幸注射劑(Etoposide)等，皆被證實促使神經醯胺生成，進而使細胞凋亡。
本研究综合文獻及資料庫生物信息，重建整合人體鞘脂代謝途徑，使網路圖譜涵蓋脂肪酸代謝、磷脂代謝及醣解途徑。並運用系統生物學概念，使用軟體工具確認此代謝網路為滿秩矩陣系統，在最大Sphingomyelin phosphodiesterase及最小Sphinganine kinase催化速率此多目標函數情況下，最能夠累積神經醯胺並同時最小生成鞘氨醇-1-磷酸。並於此多目標情況下調控酵素活性，模擬生物體受干擾狀態下的最適通量分布，獲得結果Serine palmitoyltransferase、3-dehydrosphinganine reductase及Hexokinase此三酵素為此系統必須酵素，Ceramide synthase酵素為最具影響神經醯胺生成量的酵素，此模擬結果相符於化療藥物所激活酵素，藉此達到醫療效果。

關鍵字

神經鞘脂 ； 代謝網路

並列摘要

Sphingolipids are widely existed in the cells, which are not only the composition of cell membrane structure but also transmit signals regulating cell survival. Its metabolic pathway intermediates Ceramide and Sphingosine 1-phosphate are known as Tumor suppressor lipid and Cancer-promoting lipid respectively. Currently chemotherapy drugs, such as: Daunorubicin and Etoposide are known to promote Ceramide generation, thereby enabling apoptosis.
In this research, we integrate literature and biological databases information into the human sphingolipid metabolic pathway, which include fatty acid metabolism, phospholipid metabolism and the glycolytic pathway. We adopt the system biology concept to confirm this system for the full rank matrix, and then we regulate enzyme activity in the case of Maximum Sphingomyelin phosphodiesterase and minimum Sphinganine kinase catalytic rate to learn about organisms' response and meaning. Finally, we conclude that Serine palmitoyltransferase, 3-dehydrosphinganine reductase and Hexokinase are indispensable enzymes in this system, Ceramide synthase is the main Ceramide synthesizer enzyme, consistent with the chemotherapy drug experiment results.

並列關鍵字

Sphingolipid ； Metabolic network

參考文獻

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