Constructs of human neuropathy target esterase catalytic domain containing mutations related to motor neuron disease have altered enzymatic properties.
Constructs of human neuropathy target esterase catalytic domain containing mutations related to motor neuron disease have altered enzymatic properties.
复制标题
人类神经病靶酯酶催化结构域的构建与运动神经元有关的突变已改变酶特性。
DOI：
10.1016/j.toxlet.2010.03.1120
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发表时间：
2010-07-01
影响因子：
3.5
通讯作者：
Richardson, Rudy J.
中科院分区：
文献类型：
--
作者：
Hein, Nichole D.;Stuckey, Jeanne A.;Rainier, Shirley R.;Fink, John K.;Richardson, Rudy J.
关键词：
神经病靶标酯酶(NTE)是一种与有机磷(OP)化合物诱导的迟发性神经毒性(OPIDN)相关的磷脂酶/溶血磷脂酶。运动轴突远端变性在OPIDN和遗传性痉挛性截瘫(HSPs)中都存在。最近，在一种被称为NTE相关运动神经元病(NTE-MND)的新型过敏性紫杉醇(SPG39)患者中发现了NTE酯酶结构域的突变。其中两个突变，精氨酸890到组氨酸(R890H)和蛋氨酸1012到Valine(M1012V)，是在人类重组NTE催化结构域(Nest)中创建的，以测量可能的催化性质的变化。这些突变的酶降低了人工底物戊酸苯酯的比活性。此外，M1012V突变体对所测试的三种抑制剂：米非司酮、二异丙基氟磷酸盐和毒死蜱Oxon的双分子抑制速率常数(KI)都降低了。最后，虽然两种被OP化合物抑制的突变酶都表现出被亲核试剂重新激活(老化)的能力随时间变化的丧失，但M1012V突变体的影响更明显。综上所述，比活性、抑制和老化实验的结果表明，与NTE-MND相关的突变与NTE的酶学性质改变具有功能相关性。
Neuropathy target esterase (NTE) is a phospholipase/lysophospholipase associated with organophosphorus (OP) compound-induced delayed neurotoxicity (OPIDN). Distal degeneration of motor axons occurs in both OPIDN and the hereditary spastic paraplegias (HSPs). Recently, mutations within the esterase domain of NTE were identified in patients with a novel type of HSP (SPG39) designated NTE-related motor neuron disease (NTE-MND). Two of these mutations, arginine 890 to histidine (R890H) and methionine 1012 to valine (M1012V), were created in human recombinant NTE catalytic domain (NEST) to measure possible changes in catalytic properties. These mutated enzymes had decreased specific activities for hydrolysis of the artificial substrate, phenyl valerate. In addition, the M1012V mutant exhibited a reduced bimolecular rate constant of inhibition (ki) for all three inhibitors tested: mipafox, diisopropylphosphorofluoridate, and chlorpyrifos oxon. Finally, while both mutated enzymes inhibited by OP compounds exhibited altered time-dependent loss of their ability to be reactivated by nucleophiles (aging), more pronounced effects were seen with the M1012V mutant. Taken together, the results from specific activity, inhibition, and aging experiments suggest that the mutations found in association with NTE-MND have functional correlates in altered enzymological properties of NTE.
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DOI：
10.1093/annonc/mdp254
发表时间：
2009-08
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Hersey P;Bastholt L;Chiarion-Sileni V;Cinat G;Dummer R;Eggermont AM;Espinosa E;Hauschild A;Quirt I;Robert C;Schadendorf D
通讯作者：
Schadendorf D
影响因子：
6.1
作者：
JOHNSON, MK
通讯作者：
JOHNSON, MK
DOI：
10.1016/0005-2744(81)90175-3
发表时间：
1981-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
CLOTHIER, B;JOHNSON, MK;REINER, E
通讯作者：
REINER, E
影响因子：
4.1
作者：
JOHNSON, MK
通讯作者：
JOHNSON, MK
影响因子：
4.8
作者：
Atkins, J;Glynn, P
通讯作者：
Glynn, P