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Structure of a cephalosporin synthase

机译：头孢菌素合酶的结构

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摘要

Penicillins and cephalosporins are among the most widely used therapeutic agents. These antibiotics are produced from fermentation-derived materials as their chemical synthesis is not commercially viable. Unconventional steps in their biosynthesis are catalysed by Fe(Ⅱ)-dependent oxidases/oxygenases; isopenicillin N synthase (IPNS) creates in one step the bicyclic nucleus of penicillins, and deacetoxycephalosporin C synthase (DAOCS) catalyses the expansion of the penicillin nucleus into the nucleus of cephalosporins. Both enzymes use dioxygen-derived ferryl intermediates in catalysis but, in contrast to IPNS, the ferryl form of DAOCS is produced by the oxidative splitting of a co-substrate, 2-oxoglutarate (α-ketoglutarate). This route of controlled ferryl formation and reaction is common to many mono-nuclear ferrous enzymes, which participate in a broader range of reactions than their well-characterized counterparts, the haem enzymes. Here we report the first crystal structure of a 2-oxoacid-dependent oxygenase. High-resolution structures for apo-DAOCS, the enzyme complexed with Fe(Ⅱ), and with Fe(Ⅱ) and 2-oxoglutarate, were obtained from merohedrally twinned crystals. Using a model based on these structures, we propose a mechanism for ferryl formation.
机译：青霉素和头孢菌素是最广泛使用的治疗剂。这些抗生素由发酵来源的材料生产，因为它们的化学合成在商业上不可行。 Fe（Ⅱ）依赖性氧化酶/加氧酶催化其非常规的生物合成步骤。异青霉素N合酶（IPNS）一步形成青霉素的双环核，而脱乙酰氧基头孢菌素C合酶（DAOCS）催化青霉素核向头孢菌素核的扩展。两种酶在催化中均使用源自双氧的渡轮中间体，但与IPNS相比，DAOCS的渡轮形式是通过共底物2-氧代戊二酸酯（α-酮戊二酸酯）的氧化裂解而产生的。这种受控的小环形成和反应的途径是许多单核亚铁酶所共有的，它们比特征明确的对应物血红素酶参与的反应范围更广。在这里，我们报告的2-草酸依赖加氧酶的第一个晶体结构。从多面体孪晶获得了载脂蛋白DAOCS的高分辨率结构，该酶与Fe（Ⅱ），Fe（Ⅱ）和2-氧戊二酸络合。使用基于这些结构的模型，我们提出了形成小环的机制。

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