Vanner Stephanie A, Li Xiang, Zvanych Rostyslav, Torchia Jonathon, Sang Jing, Andrews David W, Magarvey Nathan A
Department Chemistry & Chemical Biology, McMaster University, M.G. DeGroote Institute for Infectious Disease Research, 1200 Main St. W, Hamilton, Ontario L8N 3Z5, Canada.
Mol Biosyst. 2013 Nov;9(11):2712-9. doi: 10.1039/c3mb70219g.
Evolution of natural products, and particularly those resulting from microbial assembly line-like enzymes, such as polyketide (PK) and nonribosomal peptides (NRP), has resulted in a variety of pharmaceutically important and chemically diverse families of molecules. The antimycin-type depsipeptides are one such grouping, with a significant level of diversity and members that have noted activities against key targets governing human cellular apoptosis (e.g. Bcl-xL and GRP78). Chemical variance originates from ring size, with 9-, 12-, 15-, and 18-membered classes, and we show that such distinctions influence their molecular targeting. Further, we present here a systematic interrogation of the chemistry and assembly line evolution of antimycin-type analogues by conducting metabolomic profiling and biosynthetic gene cluster comparative analysis of the depsipeptide assembly lines for each member of the antimycin-group. Natural molecular evolution principles of such studies should assist in artificial re-combinatorializing of PK and NRP assembly lines.
天然产物的进化，尤其是那些由类似微生物装配线的酶产生的天然产物，如聚酮化合物（PK）和非核糖体肽（NRP），已经产生了各种具有重要药学意义且化学性质多样的分子家族。抗霉素型缩肽就是这样一类，具有显著的多样性水平，其成员对控制人类细胞凋亡的关键靶点（如Bcl-xL和GRP78）具有显著活性。化学差异源于环的大小，有9元、12元、15元和18元的类别，我们表明这种差异会影响它们的分子靶向。此外，我们通过对抗霉素组每个成员的缩肽装配线进行代谢组学分析和生物合成基因簇比较分析，对抗霉素型类似物的化学和装配线进化进行了系统研究。此类研究的自然分子进化原理应有助于PK和NRP装配线的人工重组。
