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首页> 外文期刊>Advances in enzyme regulation >Peptide inhibitors of mammalian ribonucleotide reductase.
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Peptide inhibitors of mammalian ribonucleotide reductase.

机译：哺乳动物核糖核苷酸还原酶的肽抑制剂。

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摘要

Mammalian ribonucleotide reductase (mRR) is a chemotherapeutic target. In common with other class Ia RRs, the enzyme is composed of two subunits (mR1 and mR2), with mR1 containing both the active site and allosteric effector sites and mR2 containing a stable tyrosyl radical that is essential for enzymatic activity. mRR is inhibited by Ac-FTLDADF (denoted P7), corresponding to the C-terminus of mR2, which competes with mR2 for binding to mR1. The enzyme has two physiologically important active forms, mR12mR22 and mR16(mR22)j (j=1-3), with high ATP concentrations favoring the latter. Here, we report on our progress in using structural and functional studies in conjunction with library screening to identify derivatives of tri-, tetra- and hexapeptides, and cyclic heptapeptides, having equal or significantly higher activities than P7 toward inhibition of one or both active forms. These identifications were made by screening candidate peptides both for their abilities to bind to mR1 competitively with P7 and to inhibit ribonucleotide reductase activity. A significant feature of both P7 and the newly identified derivatives is that they are stronger inhibitors of mR12mR22 than of mR16(mR22)j. For the tetrapeptides, this is due in part to their preferential binding to mR1 monomer. The possible application of these peptide derivatives in cancer chemotherapy, exploiting their preferential inhibition of mR12mR22, is considered.
机译：哺乳动物核糖核苷酸还原酶（mRR）是化学治疗的目标。与其他Ia类RR相同，该酶由两个亚基（mR1和mR2）组成，mR1既包含活性位点，也包​​含变构效应位点，而mR2包含稳定的酪氨酸基团，这对于酶促活性至关重要。 mRR被Ac-FTLDADF（表示为P7）抑制，它对应于mR2的C末端，后者与mR2竞争与mR1的结合。该酶具有两种重要的生理活性形式，即mR12mR22和mR16（mR22）j（j = 1-3），其中较高的ATP浓度有利于后者。在此，我们报告了我们在利用结构和功能研究与文库筛选相结合来鉴定三肽，四肽和六肽以及环状七肽衍生物方面的进展，这些衍生物具有与P7相同或明显更高的抑制一种或两种活性形式的活性。通过鉴定候选肽与P7竞争性结合mR1和抑制核糖核苷酸还原酶活性的能力来进行这些鉴定。 P7和新发现的衍生物的一个显着特征是它们是mR12mR22的抑制剂，比mR16（mR22）j更强。对于四肽，部分原因是它们与mR1单体的优先结合。考虑了这些肽衍生物通过优先抑制mR12mR22而在癌症化疗中的可能应用。

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