吡哆醇-5′-磷酸的 Z 异构体是人类吡哆醇-5′-磷酸氧化酶的有效抑制剂,而吡哆醇-5′-磷酸氧化酶是维生素 B6 修复途径中的关键酶,也是潜在的化疗靶点

Claudio Graziani, Anna Barile, Lorenzo Antonelli, Annarita Fiorillo, Andrea Ilari, Fabrizio Vetica, Martino Luigi di Salvo, Alessandro Paiardini, Angela Tramonti, Roberto Contestabile
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引用次数: 0

摘要

吡哆醛-5′-磷酸(PLP)是维生素 B6 的催化活性形式,在许多代谢过程中充当辅助因子。在人体中,PLP 是在吡哆醛(am)ine 5′-磷酸氧化酶(PNPO)和吡哆醛激酶(PDXK)催化的反应中产生的。PNPO 和 PDXK 都参与了许多肿瘤的癌变过程。在急性髓性白血病(PDXK)、卵巢癌和乳腺癌(PNPO)模型中,沉默 PNPO 和 PDXK 编码基因可显著缩小肿瘤体积,降低肿瘤细胞的侵袭性。在本研究中,我们证明了吡哆醇-5′-十二碳二烷基磷酸(PLP-R)--一种其他作者在恶性细胞系上测试过的PLP类似物--能减少增殖,在体外通过竞争和异位机制混合抑制PNPO。我们还发现,根据我们的预测,这种抑制剂的未磷酸化前体(PL-R)具有更有利的药代动力学特性,但它会被 PDXK 磷酸化,从而转化为 PLP-R。在此基础上,我们提出了一种新型原药-药物系统的原型,作为开发新的、潜在的抗肿瘤药物的有益起点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The Z isomer of pyridoxilidenerhodanine 5′‐phosphate is an efficient inhibitor of human pyridoxine 5′‐phosphate oxidase, a crucial enzyme in vitamin B6 salvage pathway and a potential chemotherapeutic target
Pyridoxal 5′‐phosphate (PLP), the catalytically active form of vitamin B6, acts as a cofactor in many metabolic processes. In humans, PLP is produced in the reactions catalysed by pyridox(am)ine 5′‐phosphate oxidase (PNPO) and pyridoxal kinase (PDXK). Both PNPO and PDXK are involved in cancer progression of many tumours. The silencing of PNPO and PDXK encoding genes determines a strong reduction in tumour size and neoplastic cell invasiveness in models of acute myeloid leukaemia (in the case of PDXK) and ovarian and breast cancer (in the case of PNPO). In the present work, we demonstrate that pyridoxilidenerhodanine 5′‐phosphate (PLP‐R), a PLP analogue that has been tested by other authors on malignant cell lines reporting a reduction in proliferation, inhibits PNPO in vitro following a mixed competitive and allosteric mechanism. We also show that the unphosphorylated precursor of this inhibitor (PL‐R), which has more favourable pharmacokinetic properties according to our predictions, is phosphorylated by PDXK and therefore transformed into PLP‐R. On this ground, we propose the prototype of a novel prodrug‐drug system as a useful starting point for the development of new, potential, antineoplastic agents.
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