Genome mining and genetic analysis of cypemycin biosynthesis reveal an unusual class of posttranslationally modified peptides
Genome mining and genetic analysis of cypemycin biosynthesis reveal an unusual class of posttranslationally modified peptides
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DOI：
10.1073/pnas.1008608107
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发表时间：
2010-09-14
影响因子：
11.1
通讯作者：
Bibb, Mervyn
中科院分区：
文献类型：
--
作者：
Claesen, Jan;Bibb, Mervyn
氨基酸的翻译后修饰赋予核糖体合成的肽一系列结构特征和活性，其中许多具有有效的抗微生物或其他生物活性。赛培霉素是由链霉菌OH-4156产生的一种广泛修饰的线性肽，具有有效的体外抗小鼠白血病细胞活性。赛培霉素不含羊毛硫醚桥，但表现出羊毛硫醚抗生素的一些结构特征，特别是脱水苏氨酸（脱氢丁炔）和C-末端S-[（Z）-2-氨基乙烯基]-D-半胱氨酸。因此，它被归类为后修饰肽的羊毛硫抗生素家族的成员。赛培霉素还具有两个L-别异亮氨酸残基和一个N-末端N，N-二甲基丙氨酸，这两个氨基酸修饰都是独特的。我们鉴定并异源表达了cypemycin生物合成基因簇，并对每个基因进行了突变分析。我们表明，即使是以前描述的修改进行不寻常的酶或通过一个修饰途径无关lantibiotic生物合成。生物信息学分析揭示了广泛发生的cypemycin样基因簇内的细菌王国，并在degenea。赛培霉素是一类不寻常的翻译后修饰的核糖体合成肽（利拉苷）的创始成员。
Posttranslational modification of amino acids confers a range of structural features and activities on ribosomally synthesized peptides, many of which have potent antimicrobial or other biological activities. Cypemycin is an extensively modified linear peptide produced by Streptomyces sp. OH-4156 with potent in vitro activity against mouse leukemia cells. Cypemycin does not contain lanthionine bridges but exhibits some of the structural features of lantibiotics, notably dehydrated threonines (dehydrobutyrines) and a C-terminal S-[(Z)-2-aminovinyl]-D-cysteine. Consequently it was classified as a member of the lantibiotic family of posttranslationally modified peptides. Cypemycin also possesses two L-allo-isoleucine residues and an N-terminal N,N-dimethylalanine, both unique amino acid modifications. We identified and heterologously expressed the cypemycin biosynthetic gene cluster and performed a mutational analysis of each individual gene. We show that even the previously described modifications are carried out by unusual enzymes or via a modification pathway unrelated to lantibiotic biosynthesis. Bioinformatic analysis revealed the widespread occurrence of cypemycin-like gene clusters within the bacterial kingdom and in the Archaea. Cypemycin is the founding member of an unusual class of posttranslationally modified ribosomally synthesized peptides, the linaridins.