Engineered biosynthesis of novel polyketides: evidence for temporal, but not regiospecific, control of cyclization of an aromatic polyketide precursor.
Engineered biosynthesis of novel polyketides: evidence for temporal, but not regiospecific, control of cyclization of an aromatic polyketide precursor.
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DOI：
10.1016/1074-5521(94)90012-4
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发表时间：
1994-12-01
影响因子：
--
通讯作者：
Khosla, C
中科院分区：
文献类型：
--
作者：
Fu, H;Hopwood, D A;Khosla, C
背景：芳香族聚酮合酶（PKS）催化不同长度的聚酮链的形成和环化，产生一系列已被证明具有医学意义的化合物。据信，对环化区域特异性的初步控制是通过最小的 PKS 来实现的，该最小的 PKS 由聚酮化合物生物合成的三个基本成分组成，催化分子内醛醇缩合到链的中间。随后的环化反应要么由 PKS 的其他组分催化，要么在没有特定催化剂的情况下发生。结果：SEK4b（一种最小 PKS 的新型八酮化合物产物）的结构和生物合成研究揭示了一种不寻常的环化模式。第一次环化（羟醛缩合）发生在未还原的聚酮化合物主链前体的甲基末端。随后是半缩酮形成和内酯化。 SEK4b 的整体结构与 SEK4 相似，SEK4 是同一基因工程菌株的先前鉴定的产物，仅在共同稠环系统周围的甲基和吡喃酮基团的位置不同。然而，这两种分子的生物合成途径却截然不同。在没有稍后在途径中起作用的 PKS 成分（芳香酶和环化酶）的情况下，SEK4b 的产量相对于 SEK4 要高得多。结论：在该环化途径中，环化的区域特异性不直接由最小 PKS 控制。相反，我们认为酶通过控制链释放的时间来影响环化。链释放和环化可以与合成同时进行。其他 PKS 亚基似乎可以稳定 PKS 与新生链的复合物，防止过早释放。
BACKGROUND: Aromatic polyketide synthases (PKSs) catalyze the formation and cyclization of polyketide chains of variable lengths, generating a family of compounds of proven medical significance. Initial control over the regiospecificity of cyclization is believed to be exercised by the minimal PKS, composed of the three essential components for polyketide biosynthesis, which catalyzes an intramolecular aldol condensation towards the middle of the chain. Subsequent cyclization reactions are either catalyzed by additional components of the PKS, or occur in the absence of specific catalysts.RESULTS: Structural and biosynthetic studies on SEK4b, a novel octaketide product of a minimal PKS, revealed an unusual cyclization pattern. The first cyclization (an aldol condensation) occurs at the methyl end of the unreduced polyketide backbone precursor. This is followed by hemiketal formation and lactonization. The overall structure of SEK4b is similar to that of SEK4, a previously-identified product of the same genetically-engineered strain, differing only in the positions of a methyl and a pyrone group around a common fused-ring system. The biosynthetic pathways of the two molecules are quite different, however. The yield of SEK4b relative to SEK4 is much higher in the absence of PKS components (aromatases and cyclases) acting later in the pathway.CONCLUSIONS: In this cyclization pathway, the regiospecificity of cyclization is not directly controlled by the minimal PKS. Instead, we propose that the enzyme influences cyclization by controlling the timing of chain release. Chain release and cyclization may be concurrent with synthesis. Other PKS subunits appear to stabilize the complex of the PKS with the nascent chain, preventing premature release.