Harris Lawrence D, Harijan Rajesh K, Ducati Rodrigo G, Evans Gary B, Hirsch Brett M, Schramm Vern L
The Ferrier Research Institute, Victoria University of Wellington , 69 Gracefield Rd, Lower Hutt, 5010, New Zealand.
Department of Biochemistry, Albert Einstein College of Medicine , Bronx, New York 10461, United States.
ACS Chem Biol. 2018 Jan 19;13(1):152-160. doi: 10.1021/acschembio.7b00601. Epub 2017 Dec 14.
Phosphoribosyl transferases (PRTs) are essential in nucleotide synthesis and salvage, amino acid, and vitamin synthesis. Transition state analysis of several PRTs has demonstrated ribocation-like transition states with a partial positive charge residing on the pentose ring. Core chemistry for synthesis of transition state analogues related to the 5-phospho-α-d-ribosyl 1-pyrophosphate (PRPP) reactant of these enzymes could be developed by stereospecific placement of bis-phosphate groups on an iminoaltritol ring. Cationic character is provided by the imino group and the bis-phosphates anchor both the 1- and 5-phosphate binding sites. We provide a facile synthetic path to these molecules. Cyclic-nitrone redox methodology was applied to the stereocontrolled synthesis of three stereoisomers of a selectively monoprotected diol relevant to the synthesis of transition-state analogue inhibitors. These polyhydroxylated pyrrolidine natural product analogues were bis-phosphorylated to generate analogues of the ribocationic form of 5-phosphoribosyl 1-phosphate. A safe, high yielding synthesis of the key intermediate represents a new route to these transition state mimics. An enantiomeric pair of iminoaltritol bis-phosphates (L-DIAB and D-DIAB) was prepared and shown to display inhibition of Plasmodium falciparum orotate phosphoribosyltransferase and Saccharomyces cerevisiae adenine phosphoribosyltransferase (ScAPRT). Crystallographic inhibitor binding analysis of L- and D-DIAB bound to the catalytic sites of ScAPRT demonstrates accommodation of both enantiomers by altered ring geometry and bis-phosphate catalytic site contacts.
磷酸核糖转移酶（PRTs）在核苷酸合成与补救、氨基酸及维生素合成过程中至关重要。对多种PRTs的过渡态分析表明，其具有核糖阳离子样过渡态，且在戊糖环上带有部分正电荷。通过在亚氨基阿卓糖醇环上立体定向引入双磷酸基团，可开发出与这些酶的5-磷酸-α-D-核糖基1-焦磷酸（PRPP）反应物相关的过渡态类似物的合成核心化学方法。亚氨基基团赋予阳离子特性，双磷酸基团则同时锚定1-磷酸和5-磷酸结合位点。我们提供了一条简便的合成这些分子的途径。环硝酮氧化还原方法被应用于立体控制合成与过渡态类似物抑制剂合成相关的选择性单保护二醇的三种立体异构体。这些多羟基化吡咯烷天然产物类似物经双磷酸化生成5-磷酸核糖基1-磷酸核糖阳离子形式的类似物。关键中间体的安全、高产率合成代表了一条通往这些过渡态模拟物的新路线。制备了一对对映体亚氨基阿卓糖醇双磷酸盐（L-DIAB和D-DIAB），并证明它们对恶性疟原虫乳清酸磷酸核糖转移酶和酿酒酵母腺嘌呤磷酸核糖转移酶（ScAPRT）具有抑制作用。对结合到ScAPRT催化位点的L-DIAB和D-DIAB进行晶体学抑制剂结合分析表明，两种对映体通过改变环几何形状和双磷酸催化位点接触得以容纳。
