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首页> 外文期刊>Biochimica et Biophysica Acta. General Subjects >Interactions of cellular histidine triad nucleotide binding protein 1 with nucleosides 5′-O-monophosphorothioate and their derivatives - Implication for desulfuration process in the cell
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Interactions of cellular histidine triad nucleotide binding protein 1 with nucleosides 5′-O-monophosphorothioate and their derivatives - Implication for desulfuration process in the cell

机译：细胞组氨酸三联体核苷酸结合蛋白1与核苷5'-O-单硫代磷酸酯及其衍生物的相互作用-细胞脱硫过程的意义

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Background One of the activities of histidine triad nucleotide-binding protein 1 (Hint1) under in vitro conditions is the conversion of nucleoside 5′-O-phosphorothioate (NMPS) to its 5′-O-phosphate (NMP), which is accompanied by the release of hydrogen sulfide. Methods Non-hydrolyzable derivatives of AMPS and dCMPS, each containing the residue able to form a covalent bond in nucleic acid-protein complexes via photocrosslinking (at 308 nm), were applied at the complexing experiments with recombinant and cellular Hint1. The cellular lysates prepared after RNAi-mediated knockdown of Hint1 were incubated with AMPS and the level of desulfuration was measured. Results Recombinant Hint1 and Hint1 present in the cellular lysate of A549 cells, formed complexes with the used substrate analogs. Computer modeling experiments, in which the ligand was docked at the binding pocket, confirmed that direct interactions between Hint1 and the screened analogs are possible. Using RNAi technology, we demonstrated lowered levels of AMPS substrate desulfuration in reactions that employed the cell lysates with a reduced Hint1 level. Conclusions The enzymatic conversion of AMPS to AMP occurred with the participation of cellular Hint1, the protein, which is present in all organisms. General significance The intracellular Hint1 could be responsible for the in vivo desulfuration of nucleosides-5′-monophosphorothioate, thus it can contribute to the phosphorothioate oligonucleotides metabolism. H2S released during this process may participate in several physiological processes, thus NMPSs can be precursors/donors of H2S in vivo and can be used to study the effects of this gas in biological systems. Moreover, the controlled delivery of (d)NMPSs into cells may be of medicinal utility.
机译：背景在体外条件下，组氨酸三联体核苷酸结合蛋白1（Hint1）的活性之一是将核苷5'-O-硫代磷酸酯（NMPS）转化为其5'-O-磷酸酯（NMP），同时伴随着释放出硫化氢。方法AMPS和dCMPS的不可水解衍生物分别包含能够通过光交联（在308 nm）在核酸-蛋白质复合物中形成共价键的残基，用于重组和细胞Hint1的复合实验。 RNAi介导的Hint1敲除后制备的细胞裂解液与AMPS孵育，并测量脱硫水平。结果存在于A549细胞的细胞裂解物中的重组Hint1和Hint1与使用的底物类似物形成复合物。配体停靠在结合袋处的计算机建模实验证实，Hint1与筛选的类似物之间可能存在直接相互作用。使用RNAi技术，我们证明在使用细胞裂解物且Hint1水平降低的反应中，AMPS底物脱硫水平降低。结论AMPS向AMP的酶促转化发生在细胞Hint1的参与下，该蛋白存在于所有生物中。一般意义细胞内Hint1可能负责5'-单硫代磷酸核苷的体内脱硫，因此可以促进硫代磷酸酯寡核苷酸的代谢。在此过程中释放的H2S可能参与多个生理过程，因此NMPS可以是体内H2S的前体/供体，并可用于研究该气体在生物系统中的作用。而且，（d）NMPSs向细胞中的受控递送可能具有医学用途。

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