The siderophore desferrioxamine B (DFOB, 1) native to Streptomyces pilosus is biosynthesized by the DesABCD enzyme cluster. DesA-mediated decarboxylation of l-lysine gives 1,5-diaminopentane (DP) for processing by DesBCD. S. pilosus culture medium was supplemented with rac-1,4-diamino-2-fluorobutane (rac-FDB) to compete against DP to generate fluorinated analogues of DFOB, as agents of potential clinical interest. LC-MS/MS analysis identified fluorinated analogues of DFOB with one, two, or three DP units (binary notation: 0) exchanged for one (DFOA-F₁[001] (2), DFOA-F₁[010] (3), DFOA-F₁[100] (4)), two (DFOA-F₂[011] (5), DFOA-F₂[110] (6), DFOA-F₂[101] (7)), or three (DFOA-F₃[111] (8)) rac-FDB units (binary notation: 1). The two sets of constitutional isomers 2–4 and 5–7 arose from the position of the substrates in the N-acetyl, internal, or amine-containing regions of the DFOB trimer. N-Acetylated fluorinated DFOB analogues were formed where the rac-FDB substrate was positioned in the amine region (e.g., N-Ac-DFOA-F₁[001] (2a)). Other analogues contained two hydroxamic acid groups and three amide bonds. Experiments using rac-FDB, R-FDB, or S-FDB showed a similar species profile between rac-FDB and R-FDB. These data are consistent with the following. (i) DesB can act on rac-FDB. (ii) DesC can act directly on rac-FDB. (iii) The products of DesBC or DesC catalysis of rac-FDB can undergo a second round of DesC catalysis at the free amine. (iv) DesD catalysis of these products gives N,N′-diacetylated compounds. (v) A minimum of two hydroxamic acid groups is required to form a viable DesD-substrate(s) precomplex. (vi) One or more DesBCD-catalyzed steps in DFOB biosynthesis is enantioselective. This work has provided a potential path to access fluorinated analogues of DFOB and new insight into its biosynthesis.

中文翻译：

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前体定向生物合成中去铁氧胺B的氟化类似物为DesBCD的容量提供了新的见解

毛链霉菌天然的铁载体去铁草胺B（DFOB，1）由DesABCD酶簇生物合成。DesA介导的1-赖氨酸的脱羧生成1,5-二氨基戊烷（DP），供DesBCD处理。S.曲菌培养基补充有外消旋-1,4-二氨基-2-氟丁烷（外消旋-FDB）对抗DP竞争以产生DFOB的氟化类似物，作为潜在的临床感兴趣的试剂。LC-MS / MS分析确定了DFOB的氟化类似物，其中一个，两个或三个DP单元（二进制表示法：0）交换为一个（DFOA-F ₁ [001]（2），DFOA-F ₁ [010]（3），DFOA-F ₁ [100]（4）），两个（DFOA-F ₂ [011]（5），DFOA-F ₂ [110]（6），DFOA-F ₂ [101]（7）），或三个（DFOA-F ₃ [111]（8））rac -FDB单位（二进制表示法：1）。两组结构异构体2 – 4和5 – 7从底物在DFOB三聚体的N-乙酰基，内部或含胺区域中的位置产生。Ñ -Acetylated氟化形成DFOB类似物，其中外消旋-FDB基板定位在胺的区域（例如，Ñ -Ac-DFOA-F ₁ [001]（2A））。其他类似物包含两个异羟肟酸基团和三个酰胺键。使用rac -FDB，R -FDB或S -FDB进行的实验显示了rac -FDB和R -FDB之间的物种分布相似。这些数据与以下数据一致。（i）DesB可以对rac -FDB起作用。（ii）DesC可以直接对rac -FDB起作用。（iii）DesBC或DesC催化rac的产物-FDB可以在游离胺上进行第二轮DesC催化。（iv）这些产物的DeSD催化产生N，N′-二乙酰化的化合物。（v）至少需要两个异羟肟酸基团才能形成可行的DesD底物预配合物。（vi）DFOB生物合成中DesBCD催化的一个或多个步骤是对映选择性的。这项工作提供了一种潜在的途径来获取DFOB的氟化类似物，并为其生物合成提供了新的见识。