Biosynthesis of the unique amino acid side chain of butirosin: Possible protective-group chemistry in an acyl carrier protein-mediated pathway
Biosynthesis of the unique amino acid side chain of butirosin: Possible protective-group chemistry in an acyl carrier protein-mediated pathway
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DOI：
10.1016/j.chembiol.2005.04.010
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发表时间：
2005-06-01
影响因子：
--
通讯作者：
Spencer, JB
中科院分区：
文献类型：
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作者：
Li, YY;Llewellyn, NM;Spencer, JB
布替罗辛A和B是天然存在的氨基糖苷类抗生素，具有（2S）-4-氨基-2-羟基丁酸酯（AHBA）侧链。已显示将AHBA半合成添加到临床上有价值的氨基糖苷类抗生素中，以改善其药理学性质并防止其被涉及细菌耐药性的许多氨基糖苷类修饰酶灭活。我们在这里报告，AHBA的生物合成从L-谷氨酸，编码在以前确定的butirosin生物合成基因簇，收益通过中间体拴到一个特定的酰基载体蛋白（酸）。该途径的五个组成部分已被纯化和表征，包括ACP（BTRO），ATP依赖性连接酶（BTRO），磷酸吡哆醛依赖性脱羧酶（BtrK），和两个组件黄素依赖性单加氧酶系统（BtrO和以前未报道的BtrV）。提出的生物合成途径包括ACP衍生的γ-氨基丁酸中间体的γ-谷氨酰化，这可能是生物合成中保护基化学的一个罕见实例。
Butirosins A and B are naturally occurring aminoglycoside antibiotics that have a (2S)-4-amino-2-hydroxybutyrate(AHBA) side chain. Semisynthetic addition of AHBA to clinically valuable aminoglycoside antibiotics has been shown both to improve their pharmacological properties and to prevent their deactivation by a number of aminoglycoside-modifying enzymes involved in bacterial resistance. We report here that the biosynthesis of AHBA from L-glutamate, encoded within a previously identified butirosin biosynthetic gene cluster, proceeds via intermediates tethered to a specific acyl carrier protein (ACID). Five components of the pathway have been purified and characterized, including the ACP (Btrl), an ATP-dependent ligase (Btrl), a pyridoxal phosphate-dependent decarboxylase (BtrK), and a two-component flavin-dependent monooxygenase system (BtrO and the previously unreported BtrV). The proposed biosynthetic pathway includes a gamma-glutamylation of an ACP-derived gamma-aminobutyrate intermediate, possibly a rare example of protective group chemistry in biosynthesis.