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Synthesis of azide congeners of preQ1 as potential substrates for tRNA guanine transglycosylase
Journal of Heterocyclic Chemistry ( IF 2.0 ) Pub Date : 2020-12-30 , DOI: 10.1002/jhet.4220 Allen F. Brooks 1 , George A. Garcia 1 , Hollis D. Showalter 1
Journal of Heterocyclic Chemistry ( IF 2.0 ) Pub Date : 2020-12-30 , DOI: 10.1002/jhet.4220 Allen F. Brooks 1 , George A. Garcia 1 , Hollis D. Showalter 1
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PreQ1 (2) is a precursor of queuine (1) that in eubacteria is incorporated into transfer RNA (tRNA) by tRNA guanine transglycosylase (TGT) before being further elaborated into queuine. The queuine modification is unusual and occurs across all eukaryotes and eubacteria with few exceptions, but its function remains unclear. As the modified nucleotide occurs through incorporation of a specially synthesized nucleotide instead of via modification of a genetically encoded base, a study of the sites of modification by prepared probes is possible. We report the synthesis of two novel azide congeners (3,4) of preQ1 for this purpose. The evaluation of their interaction with TGT shows that both probes act as weak competitive inhibitors of guanine exchange of guanine(34) tRNATyr with a Ki of ~70 μM. However, we could not show that these are substrates for TGT‐catalyzed incorporation into tRNA. We believe the reason for this is a marked loss of binding due to the azide functionality of 3 and 4 abrogating the possibility of two hydrogen bonds to the carbonyl group of Leu231 and Met260 of TGT, previously observed for the terminal methylene amine of preQ1 by x‐ray crystallography.
中文翻译：
合成preQ1的叠氮化物同类物作为tRNA鸟嘌呤转糖基酶的潜在底物
PreQ 1（2）是Quuine（1）的前体，它在真细菌中通过tRNA鸟嘌呤转糖基糖苷酶（TGT）掺入转移RNA（tRNA）中，然后进一步加工成队列。排队修饰是不寻常的，几乎发生在所有真核生物和真细菌中，但其功能尚不清楚。由于修饰的核苷酸是通过掺入专门合成的核苷酸而不是通过遗传编码的碱基修饰而产生的，因此通过制备的探针对修饰位点进行研究是可能的。我们报告两种新型叠氮同类物（合成3，4 PREQ的）1以此目的。他们与TGT相互作用的评估表明，这两种探针均作为弱竞争性鸟嘌呤（34）tRNA Tyr的鸟嘌呤交换的竞争性抑制剂，K i约为70μM。但是，我们无法证明这些是TGT催化并入tRNA的底物。我们认为其原因是由于3和4的叠氮化物官能团导致结合力的明显丧失，从而消除了两个氢键与TGT的Leu231和Met260的羰基键合的可能性，以前曾通过preQ 1的末端亚甲基胺观察到X射线晶体学。
更新日期：2020-12-30
中文翻译：
合成preQ1的叠氮化物同类物作为tRNA鸟嘌呤转糖基酶的潜在底物
PreQ 1（2）是Quuine（1）的前体，它在真细菌中通过tRNA鸟嘌呤转糖基糖苷酶（TGT）掺入转移RNA（tRNA）中，然后进一步加工成队列。排队修饰是不寻常的，几乎发生在所有真核生物和真细菌中，但其功能尚不清楚。由于修饰的核苷酸是通过掺入专门合成的核苷酸而不是通过遗传编码的碱基修饰而产生的，因此通过制备的探针对修饰位点进行研究是可能的。我们报告两种新型叠氮同类物（合成3，4 PREQ的）1以此目的。他们与TGT相互作用的评估表明，这两种探针均作为弱竞争性鸟嘌呤（34）tRNA Tyr的鸟嘌呤交换的竞争性抑制剂，K i约为70μM。但是，我们无法证明这些是TGT催化并入tRNA的底物。我们认为其原因是由于3和4的叠氮化物官能团导致结合力的明显丧失，从而消除了两个氢键与TGT的Leu231和Met260的羰基键合的可能性，以前曾通过preQ 1的末端亚甲基胺观察到X射线晶体学。
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