Univ. Reims Champagne-Ardenne ICMR, CNRS UMR 7312, 51687, Reims Cedex 2, France.
Equipe Chimie Biologique et Applications Thérapeutiques, Institut de Chimie de Strasbourg UMR 7177, Université de Strasbourg/CNRS, 4, rue Blaise Pascal, 67070, Strasbourg, France.
Chemistry. 2022 May 25;28(30):e202200241. doi: 10.1002/chem.202200241. Epub 2022 Apr 20.
IspG (also called GcpE) is an oxygen-sensitive [4Fe-4S] enzyme catalyzing the penultimate step of the methylerythritol phosphate (MEP) pathway, a validated target for drug development. It converts 2-C-methyl-d-erythritol-2,4-cyclo-diphosphate (MEcPP) into (E)-4-hydroxy-3-methyl-but-2-enyl-1-diphosphate (HMBPP). The reaction, assimilated to a reductive dehydration, involves redox partners responsible for the formal transfer of two electrons to substrate MEcPP. The 2-vinyl analogue of MEcPP was designed to generate conjugated species during enzyme catalysis, with the aim of providing new reactive centers to be covalently trapped by neighboring amino acid residues. The synthesized substrate analogue displayed irreversible inhibition towards IspG. Furthermore, we have shown that electron transfer occurs prior to inhibition; this might designate conjugated intermediates as probable affinity tags through covalent interaction at the catalytic site. This is the first report of an irreversible inhibitor of the IspG metalloenzyme.
IspG（也称为 GcpE）是一种氧敏[4Fe-4S]酶，催化甲基赤藓醇磷酸（MEP）途径的倒数第二步，该途径是药物开发的有效靶点。它将 2-C-甲基-d-赤藓醇-2,4-环二磷酸（MEcPP）转化为（E）-4-羟基-3-甲基-丁-2-烯基-1-二磷酸（HMBPP）。该反应类似于还原脱水，涉及负责将两个电子正式转移到底物 MEcPP 的氧化还原伴侣。MEcPP 的 2-乙烯基类似物旨在在酶催化过程中生成共轭物种，目的是为邻近的氨基酸残基提供可共价捕获的新反应中心。合成的底物类似物对 IspG 表现出不可逆抑制。此外，我们已经表明，电子转移发生在抑制之前；这可能将共轭中间体指定为可能的亲和标记，通过在催化位点发生共价相互作用。这是首例报道 IspG 金属酶的不可逆抑制剂。
