tylosin

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: tylosin
• 英文别名: 2-[(4R,5S,6S,7R,9R,11E,13E,15R,16R)-6-[(2R,3R,4R,5S,6R)-5-[(2S,5S,6S)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl]-5,9,13-trimethyl-2,10-dioxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde
• 化学式: C₄₆H₇₇NO₁₇
• 分子量: 916.114
• InChiKey: WBPYTXDJUQJLPQ-HHRDBWAZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  64
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  239
• 氢给体数：
  5
• 氢受体数：
  18

ADMET

代谢

链霉菌属弗拉德菌的泰乐菌素生物合成（tyl）基因簇包含辅助基因，这些基因编码通常与初级代谢相关的功能。这些基因的破坏不会导致生存能力的丧失，因为基因组其他位置也存在着等效基因（可能用于“看家”目的）。tyl簇还包含两个编码在数据库中没有类似蛋白质的产品的基因。两个辅助基因，metF（编码N5，N10-亚甲基四氢叶酸还原酶）和metK（编码S-腺苷甲硫氨酸合成酶），位于tyl簇中一个“未知”基因（orf9）的两侧。在所有这三个基因都被破坏的弗拉德菌菌株中，泰乐菌素的产量降低了，尽管这种影响在添加了甘氨酸甜菜碱的培养基中变得不明显，甘氨酸甜菜碱可以给四氢叶酸池提供甲基。显然，辅助基因被招募到tyl簇的一个后果是增强了次级代谢期间的转甲基能力。

The tylosin-biosynthetic (tyl) gene cluster of Streptomyces fradiae contains ancillary genes that encode functions normally associated with primary metabolism. These can be disrupted without loss of viability, since equivalent genes (presumably used for 'housekeeping' purposes) are also present elsewhere in the genome. The tyl cluster also contains two genes that encode products unlike any proteins in the databases. Two ancillary genes, metF (encoding N5,N10-methylenetetrahydrofolate reductase) and metK, encoding S-adenosylmethionine synthase, flank one of the 'unknown' genes (orf9) in the tyl cluster. In a strain of S. fradiae in which all three of these genes were disrupted, tylosin production was reduced, although this effect was obscured in media supplemented with glycine betaine which can donate methyl groups to the tetrahydrofolate pool. Apparently, one consequence of the recruitment of ancillary genes into the tyl cluster is enhanced capacity for transmethylation during secondary metabolism.

来源:Hazardous Substances Data Bank (HSDB)

代谢

关于致病性诺卡氏菌对大环内酯类抗生素（沙尔霉素和泰乐菌素）的敏感性研究显示，大多数被检测的诺卡氏菌种类对这两种抗生素都有很高的耐药性，尽管N. nova（诺卡氏菌属的一个种）对此有一定的敏感性。N. asteroides IFM 0339（一种诺卡氏菌）通过在2'-OH位的糖基化或糖基化并还原20位的甲酰基团，将这些大环内酯类抗生素转化为无活性的代谢物。通过核磁共振（NMR）和质谱（MS）数据确定了代谢物的结构，分别为2'-[O-(beta-D-吡喃葡萄糖基)]沙尔霉素（2），2'-[O-(beta-D-吡喃葡萄糖基)]泰乐菌素（5）和20-二氢-2'-[O-(beta-D-吡喃葡萄糖基)]泰乐菌素（4）。

Studies on the susceptibility of pathogenic Nocardia to macrolide antibiotics, chalcomycin and tylosin, showed that most of the Nocardia species examined were highly resistant to both antibiotics, although N. nova was moderately susceptible. N. asteroides IFM 0339 converted these macrolides into inactive metabolites by glycosylation at 2'-OH or glycosylation and reduction of the 20-formyl group. The structures of the metabolites were determined from NMR and MS data to be 2'-[O-(beta-D-glucopyranosyl)]chalcomycin (2), 2'-[O-(beta-D-glucopyranosyl)]tylosin (5) and 20-dihydro-2'-[O-(beta-D-glucopyranosyl)]tylosin (4).

来源:Hazardous Substances Data Bank (HSDB)

代谢

泰乐菌素是由链霉菌属的Streptomyces fradiae通过聚酮代谢和三种脱氧己糖的合成相结合产生的，其中mycaminose是首先添加到聚酮苷元上的，tylactone（protylonolide）是前体。此前，破坏编码将mycaminose附着到苷元的基因（tylMII）意外地使后者积累消失，这提出了S. fradiae中聚酮代谢和脱氧己糖生物合成之间可能存在联系的可能性。然而，当时无法排除另一种解释，即对不参与mycaminose代谢的其他基因表达的影响可能导致了这种现象。在这里，展示了破坏四个特定参与mycaminose生物合成的基因（tylMI--III和tylB）中的任何一个都会引起类似的反应，这证实了mycaminosyl-tylactone的产生直接影响S. fradiae中的聚酮代谢。在类似的条件下，当mycaminose生物合成被基因破坏特异性阻断时，通过外源添加糖基化的泰乐菌素前体可以恢复tylactone的积累。此外，还发现某些非泰乐菌素途径的其他大环内酯类化合物也能引起定性的类似效果。比较刺激性大环内酯类化合物的结构将有助于研究其刺激性机制。

Tylosin is produced by Streptomyces fradiae via a combination of polyketide metabolism and synthesis of three deoxyhexose sugars, of which mycaminose is the first to be added to the polyketide aglycone, tylactone (protylonolide). Previously, disruption of the gene (tylMII) encoding attachment of mycaminose to the aglycone unexpectedly abolished accumulation of the latter, raising the possibility of a link between polyketide metabolism and deoxyhexose biosynthesis in S. fradiae. However, at that time, it was not possible to eliminate an alternative explanation, namely, that downstream effects on the expression of other genes, not involved in mycaminose metabolism, might have contributed to this phenomenon. Here, it is shown that disruption of any of the four genes (tylMI--III and tylB) specifically involved in mycaminose biosynthesis elicits a similar response, confirming that production of mycaminosyl-tylactone directly influences polyketide metabolism in S. fradiae. Under similar conditions, when mycaminose biosynthesis was specifically blocked by gene disruption, accumulation of tylactone could be restored by exogenous addition of glycosylated tylosin precursors. Moreover, certain other macrolides, not of the tylosin pathway, were also found to elicit qualitatively similar effects. Comparison of the structures of stimulatory macrolides will facilitate studies of the stimulatory mechanism.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在链霉菌Streptomyces fradiae中，有三种糖基转移酶参与泰乐菌素的生物合成。首先添加到多酮糖苷元（泰乳糖酮）上的糖是麦卡米糖，编码麦卡米糖基转移酶的基因是orf2*（tylM2）。然而，有针对性的破坏orf2*基因并没有在通常有利于泰乐菌素生产的条件下导致泰乳糖酮的积累；相反，泰乳糖酮的合成实际上被彻底取消了。这部分可能是由于orf2*基因下游基因表达受到了极性效应的影响，特别是orf4*（ccr）基因，它编码肉桂酰辅酶A还原酶，这是一种为多酮代谢提供4碳延伸单元的酶。然而，这并不能完全解释现象，因为当orf2*基因被重新引入到破坏的菌株中时，泰乐菌素的生产恢复了约10%的野生型水平。当泰乐菌素的糖基化前体被喂养给破坏的菌株时，它们被转化为泰乐菌素，证实了与泰乐菌素