School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate, 028-3694, Japan.
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, 862-0973, Japan.
Chembiochem. 2018 Mar 16;19(6):535-539. doi: 10.1002/cbic.201700584. Epub 2018 Feb 6.
Himeic acid A, which is produced by the marine fungus Aspergillus japonicus MF275, is a specific inhibitor of the ubiquitin-activating enzyme E1 in the ubiquitin-proteasome system. To elucidate the mechanism of himeic acid biosynthesis, feeding experiments with labeled precursors have been performed. The long fatty acyl side chain attached to the pyrone ring is of polyketide origin, whereas the amide substituent is derived from leucine. These results suggest that a polyketide synthase-nonribosomal peptide synthase (PKS-NRPS) is involved in himeic acid biosynthesis. A candidate gene cluster was selected from the results of genome sequencing analysis. Disruption of the PKS-NRPS gene by Agrobacterium-mediated transformation confirms that HimA PKS-NRPS is involved in himeic acid biosynthesis. Thus, the him biosynthetic gene cluster for himeic acid in A. japonicus MF275 has been identified.
希美酸 A 是由海洋真菌 Aspergillus japonicus MF275 产生的，是泛素-蛋白酶体系统中泛素激活酶 E1 的特异性抑制剂。为了阐明希美酸生物合成的机制，已经进行了用标记前体的饲喂实验。连接到吡喃酮环上的长脂肪酸侧链来源于聚酮化合物，而酰胺取代基则来自亮氨酸。这些结果表明，一种聚酮合酶-非核糖体肽合酶（PKS-NRPS）参与了希美酸的生物合成。从基因组测序分析的结果中选择了一个候选基因簇。通过农杆菌介导的转化破坏 PKS-NRPS 基因证实了 HimA PKS-NRPS 参与了希美酸的生物合成。因此，已经鉴定出 A. japonicus MF275 中希美酸的 him 生物合成基因簇。
