Synthesis and evaluation of 1-deoxy-D-xylulose 5-phosphoric acid analogues as alternate substrates for methylerythritol phosphate synthase
Synthesis and evaluation of 1-deoxy-D-xylulose 5-phosphoric acid analogues as alternate substrates for methylerythritol phosphate synthase
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DOI：
10.1021/jo048022h
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发表时间：
2005-03-18
影响因子：
3.6
通讯作者：
Poulter, CD
中科院分区：
文献类型：
--
作者：
Fox, DT;Poulter, CD
合成了四种脱氧木酮糖磷酸（DXP）类似物，并将其作为甲基异戊基磷酸（MEP）合酶的底物/抑制剂进行了评价。在类似物CF 3-DXP（1）、CF2-DXP（2）和CF-DXP（3）中，DXP的Cl上的三个甲基氢依次被氟取代。在第四种类似物Et-DXP（4）中，DXP中的甲基被乙基部分取代。类似物1、2和4在正常催化条件下不是MEP合酶的底物，而是适度的抑制剂，IC 50值分别为2.0、3.4和6.2 mM。相反，3是一个很好的基板（k（cat）= 38 s（-1），K-m = 227 μ M）与周转率类似的天然基板。这些结果是一致的逆羟醛/羟醛机制，而不是一个α-酮醇重排的酶催化转化DXP MEP。
[GRAPHICS]Four deoxyxylulose phosphate (DXP) analogues were synthesized and evaluated as substrates/ inhibitors for methylerythritol phosphate (MEP) synthase. In analogues CF3-DXP (1), CF2-DXP (2), and CF-DXP (3), the three methyl hydrogens at Cl of DXP were sequentially replaced by fluorine. In the fourth analogue, Et-DXP (4), the methyl group in DXP was replaced by an ethyl moiety. Analogues 1, 2, and 4 were not substrates for MEP synthase under normal catalytic conditions and were instead modest inhibitors with IC50 values of 2.0, 3.4, and 6.2 mM, respectively. In contrast, 3 was a good substrate (k(cat) = 38 s(-1), K-m = 227 mu M) with a turnover rate similar to that of the natural substrate. These results are consistent with a retro-aldol/aldol mechanism rather than an a-ketol rearrangement for the enzyme-catalyzed conversion of DXP to MEP.