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首页> 外文期刊>The FEBS journal >Distinct biochemical properties of human serine hydroxymethyltransferase compared with the Plasmodium enzyme: implications for selective inhibition
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Distinct biochemical properties of human serine hydroxymethyltransferase compared with the Plasmodium enzyme: implications for selective inhibition

机译：人丝氨酸羟甲基转移酶与疟原虫酶的不同生化特性：选择性抑制的含义。

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摘要

Serine hydroxymethyltransferase (SHMT) catalyzes the transfer of a hydroxymethyl group from l-serine to tetrahydrofolate to yield glycine and 5,10-methylenetetrahydrofolate. Our previous investigations have shown that SHMTs from Plasmodium spp. (P.falciparum, Pf; P.vivax, Pv) are different from the enzyme from rabbit liver in that PlasmodiumSHMT can use d-serine as a substrate. In this report, the biochemical and biophysical properties of the Plasmodium and the human cytosolic form (hcSHMT) enzymes including ligand binding and kinetics were investigated. The data indicate that, similar to Plasmodium enzymes, hcSHMT can use d-serine as a substrate. However, hcSHMT displays many properties that are different from those of the Plasmodium enzymes. The molar absorption coefficient of hcSHMT-bound pyridoxal-5-phosphate (PLP) is much greater than PvSHMT-bound or PfSHMT-bound PLP. The binding interactions of hcSHMT and PlasmodiumSHMT with d-serine are different, as only the Plasmodium enzyme undergoes formation of a quinonoid-like species upon binding to d-serine. Furthermore, it has been noted that hcSHMT displays strong substrate inhibition by tetrahydrofolate (THF) (at THF >40m), compared with SHMTs from Plasmodium and other species. The pH-activity profile of hcSHMT shows higher activities at lower pH values corresponding to a pKa value of 7.8 +/- 0.1. Thiosemicarbazide reacts with hcSHMT following a one-step model [k1 of 12 +/- 0.6m-1 center dot s-1 and k-1 of (1.0 +/- 0.6)x10-3s-1], while the same reaction with PfSHMT involves at least three steps. All data indicated that the ligand binding environment of SHMT from human and Plasmodium are different, indicating that it should be possible to develop species-selective inhibitors in future studies. Database serine hydroxymethyltransferase, EC 2.1.2.1; 5,10-methylenetetrahydrofolate dehydrogenase, EC 1.5.1.5
机译：丝氨酸羟甲基转移酶（SHMT）催化羟甲基从1-丝氨酸转移到四氢叶酸中，生成甘氨酸和5,10-亚甲基四氢叶酸。我们以前的研究表明，疟原虫属物种的SHMT。 （恶性疟原虫，Pf;间日疟原虫，Pv）与来自兔肝的酶的不同之处在于，疟原虫SHMT可以使用d-丝氨酸作为底物。在此报告中，研究了疟原虫和人类胞质形式（hcSHMT）酶的生物化学和生物物理特性，包括配体结合和动力学。数据表明，类似于疟原虫酶，hcSHMT可以使用d-丝氨酸作为底物。但是，hcSHMT显示出许多不同于疟原虫酶的特性。与hcSHMT结合的5-磷酸吡x醛（PLP）的摩尔吸收系数比与PvSHMT结合或PfSHMT结合的PLP大得多。 hcSHMT和疟原虫SHMT与d-丝氨酸的结合相互作用是不同的，因为仅疟原虫酶与d-丝氨酸结合后会形成醌类物质。此外，已经注意到，与疟原虫和其他物种的SHMT相比，hcSHMT对四氢叶酸（THF）表现出强大的底物抑制作用（在THF> 40m时）。 hcSHMT的pH活性曲线在较低的pH值下显示出较高的活性，对应于7.8 +/- 0.1的pKa值。硫代氨基脲与hcSHMT遵循一步模型[k1为12 +/- 0.6m-1中心点s-1和k-1为（1.0 +/- 0.6）x10-3s-1]进行反应，而与PfSHMT涉及至少三个步骤。所有数据表明，人与疟原虫的SHMT的配体结合环境不同，这表明在将来的研究中应该有可能开发出物种选择性抑制剂。数据库丝氨酸羟甲基转移酶，EC 2.1.2.1; 5,10-亚甲基四氢叶酸脱氢酶，EC 1.5.1.5

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