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首页> 外文OA文献 >Mechanism of horseradish peroxidase inactivation by benzhydrazide: a critical evaluation of arylhydrazides as peroxidase inhibitors.
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Mechanism of horseradish peroxidase inactivation by benzhydrazide: a critical evaluation of arylhydrazides as peroxidase inhibitors.

机译：苯肼使辣根过氧化物酶失活的机理：作为过氧化物酶抑制剂的芳基肼的关键评价。

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摘要

Many compounds are oxidized by haem enzymes, such as peroxidases and cytochromes P450, to highly reactive intermediates that function as enzyme inactivators. To evaluate the potential of arylhydrazides as selective metabolically activated peroxidase inhibitors, the mechanism of HRPC (horseradish peroxidase isoenzyme C) inhibition by BZH (benzhydrazide) was investigated in detail. No oxygen consumption was detected in BZH solutions at pH 7.0-12.0, but addition of HRPC resulted in significant O2 uptake above pH 8.0, indicating that the enzyme catalyses BZH oxidation. Addition of H2O2 to HRPC plus BZH activates the latter as an inhibitor. This involves the three-electron oxidation of BZH in one-electron steps by the peroxidase catalytic intermediates, Compounds I and II, to produce a benzoyl radical that covalently alters the active site and inhibits peroxidase activity. Alternatively, the benzoyl radical could be produced by di-imide (NH=NH) elimination from the BZH radical. Production of Compound III (oxyperoxidase) followed by p-670 (m/z =583, biliverdin-like derivative) was observed for HRPC incubated with excess H2O2, and the addition of BZH resulted in an increase in the rate of p-670 production. BZH is an inefficient inhibitor of HRPC with a K(I) of 80 muM, an apparent inactivation rate constant (k(inact)) of 0.035 min(-1), and an IC50 of 1.0 mM. This prompted the investigation of HRPC inactivation by a series of related arylhydrazides with known binding affinities for HRPC. The hydrazide with the highest affinity (2-naphthoichydrazide; K(d)=5.2 muM) was also found to be the most effective inhibitor with K(I), k(inact) and IC50 values of 14 muM, 0.14 min(-1) and 35 muM, respectively.
机译：许多化合物被血红素酶（如过氧化物酶和细胞色素P450）氧化为高活性的中间体，这些中间体起酶的灭活剂的作用。为了评估芳基酰肼作为选择性代谢活化过氧化物酶抑制剂的潜力，详细研究了BZH（苯甲酰肼）抑制HRPC（辣根过氧化物酶同工酶C）的机理。在pH 7.0-12.0的BZH溶液中未检测到氧气消耗，但是添加HRPC导致pH 8.0以上的大量O2吸收，表明该酶催化BZH氧化。在HRPC和BZH中加入H2O2可以激活后者作为抑制剂。这涉及过氧化物酶催化中间体化合物I和II在一个电子步骤中对BZH进行三电子氧化，以产生可共价改变活性位点并抑制过氧化物酶活性的苯甲酰基。可替代地，可以通过从BZH基团中消除二酰亚胺（NH ＝ NH）来产生苯甲酰基基团。对于与过量H2O2孵育的HRPC，观察到先生成化合物III（过氧化物酶），然后生成p-670（m / z = 583，biliverdin样衍生物），BZH的添加导致p-670生成速率的增加。 BZH是HRPC的无效抑制剂，K（I）为80μM，表观失活速率常数（k（inact））为0.035 min（-1），IC50为1.0 mM。这促使人们通过一系列已知的对HRPC的亲和力相关的芳基酰肼研究了HRPC的失活。亲和力最高的酰肼（2-萘甲酰肼; K（d）= 5.2μM）也被发现是最有效的抑制剂，K（I），k（inact）和IC50值为14μM，0.14 min（-1） ）和35μM。

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