卡普拉霉素(Caprazamycin)是具有抑制細菌體內之磷酸-N-乙酰胞壁酰-五肽轉位酶 (MraY) 的核苷類抗生素的成員之一。雖然已有許多研究探討此抗生素之生物合成，但至今仍尚未完整。本研究進一步確定了數個參與卡普拉霉素生物合成之關鍵酵素的活性機轉，並針對兩種特殊非血基質的α-酮戊二酸依賴性酶 Cpz10 和 Cpz15進行蛋白質結構解析與作用機轉探討。在實驗結果中，Cpz15被證實其功能為將尿苷單磷酸轉化為5-尿苷醛的起始酶而非先前所認定的β-羥化酶。相反的，Cpz10則在此研究中被確認是β-羥化酶，能在體外試驗中將卡普拉霉素生合成之中間產物化合物 10羥基化為化合物 11。同時在剔除Cpz10基因片段之鍊黴菌發酵體內試驗中，我們發現到卡普拉霉素生合成之中間產物12的生成。此結果驗證了先前體外試驗的結果，β-羥化作用能驅使隨後的酰化反應來完成隨後的生物合成作用，並在爾後的環化作用扮演一關鍵酵素。在解析蛋白質結構的研究中，發現到中間產物化合物10在Cpz10的反應中心裡與活性胺基酸之pro-S氫原子形成六配位的構型來調控其立體選擇性與區域選擇性的反應作用。除此之外，Cpz10也同時招募了兩個鐵離子（Fe1 和 Fe2），其中Fe1 作為反應中心； Fe2 負責電荷轉移。此結果同時得到了 NBO 計算、 EPR 分析、迴聲動力學中的電荷流測試、氧化態判定與配位幾何分析的支持。本研究中結合了酵素生化測試、體內與體外生物活性測試與相關生物物理分析來促進我們對卡普拉霉素生物合成酵素的了解，同時也對於開發新一代此類型核苷類抗生素來對抗多重藥性病原體提供了一個更有效率的方法。

Caprazamycin is a member of nucleoside antibiotics inhibiting phospho-N-acetylmuramyl-pentapeptide translocase (MraY). The biosynthesis of nucleoside antibiotics has been studied to considerable extent but still far from completion. The present study determined the biochemical roles for selected enzymes involved in the biosynthesis of caprazamycin, particularly for two non-heme αKG-dependent enzymes Cpz10 and Cpz15. Cpz15 that was previously assigned as a β-hydroxylase is instead the starter enzyme converting uridine mono phosphate to uridine 5’ aldehyde. In contrast, Cpz10 is the actual β-hydroxylase hydroxylating synthetic compound 10 to compound 11 in vitro. Cpz10 was parallelly examined in vivo using the gene-deletion mutant Δcpz10, by which the major product collected is compound 12 agreeing with the in vitro result. The β-hydroxylation enables subsequent acylation toward full-blown biological activity and acts as a check point permitting the seven-membered ring formation. Crystal structures revealed that compound 10 is placed above the sixth coordinate with the pro-S hydrogen atom of β-carbon exposed to the sixth coordinate accounting for reaction regioselectivity/stereoselectivity. Beyond that, Cpz10 recruits two irons (Fe1 and Fe2): Fe1 serves as the reaction center; Fe2 is responsible for charge transfer. This finding is supported by NBO calculation and EPR analysis, echoing dynamic changes in charge flow, oxidation status, and coordination geometry during the Cpz10-mediated reaction. In conjunction with biochemical determination for other related enzymes, the in vitro, in vivo and biophysical profiling advance our understanding of caprazamycin biosynthesis, which is conducive to pathway engineering to generate more effective nucleoside antibiotics against multidrug resistant pathogens.

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