Biosynthesis of a natural polyketide-isoprenoid hybrid compound, furaquinocin A: Identification and heterologous expression of the gene cluster
Biosynthesis of a natural polyketide-isoprenoid hybrid compound, furaquinocin A: Identification and heterologous expression of the gene cluster
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DOI：
10.1128/jb.188.4.1236-1244.2006
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发表时间：
2006-02-01
影响因子：
3.2
通讯作者：
Dairi, T
中科院分区：
文献类型：
--
作者：
Kawasaki, T;Hayashi, Y;Dairi, T
Furaquinocin (FQ) A是一种天然的聚酮-类异戊二烯杂化化合物，由链霉菌属菌株KO-3988产生，具有较强的抗肿瘤活性。作为了解这种独特且具有药用价值的化合物的生物合成机制的第一步，我们利用放线菌中甲羟戊酸（NW）途径基因簇的侧翼区域普遍存在的类异戊二烯生物合成基因簇克隆了一个FQ a生物合成基因簇。有趣的是，链霉菌（Streptomyces sp.）菌株KO-3988是第一个具有两种不同甲羟戊酸途径基因簇的微生物。通过在lividans链霉菌TK23中的异源表达，我们能够在MV途径基因簇（MV2）的上游和下游区域定位一个含有FQ a生物合成基因（fur基因）的25 kb DNA区域。这是第一个基因簇负责生物合成聚酮-类异戊二烯杂化化合物的例子。我们还证实，在之前从菌株KO-3988中克隆的另一个MV途径基因簇（MV1）的上游区域存在四个负责维吉epinol[3-羟基吡玛拉-9(11)，15-二烯]生物合成的基因。这是具有这些生物合成功能的原核酶的第一个例子。通过系统发育分析，鉴定出这两个MV通路簇可能是独立分布在菌株KO-3988中（同源物），而不是一个簇是由另一个簇（同源物）的重复产生的。
Furaquinocin (FQ) A, produced by Streptomyces sp. strain KO-3988, is a natural polyketide-isoprenoid hybrid compound that exhibits a potent antitumor activity. As a first step toward understanding the biosynthetic machinery of this unique and pharmaceutically useful compound, we have cloned an FQ A biosynthetic gene cluster by taking advantage of the fact that an isoprenoid biosynthetic gene cluster generally exists in flanking regions of the mevalonate (NW) pathway gene cluster in actinomycetes. Interestingly, Streptomyces sp. strain KO-3988 was the first example of a microorganism equipped with two distinct mevalonate pathway gene clusters. We were able to localize a 25-kb DNA region that harbored FQ A biosynthetic genes (fur genes) in both the upstream and downstream regions of one of the MV pathway gene clusters (MV2) by using heterologous expression in Streptomyces lividans TK23. This was the first example of a gene cluster responsible for the biosynthesis of a polyketide-isoprenoid hybrid compound. We have also confirmed that four genes responsible for viguiepinol [3-hydroxypimara-9(11),15-diene] biosynthesis exist in the upstream region of the other MV pathway gene cluster (MV1), which had previously been cloned from strain KO-3988. This was the first example of prokaryotic enzymes with these biosynthetic functions. By phylogenetic analysis, these two MV pathway clusters were identified as probably being independently distributed in strain KO-3988 (orthologs), rather than one cluster being generated by the duplication of the other cluster (paralogs).