Rational design, synthesis and evaluation of first generation inhibitors of the Giardia lamblia fructose-1,6-biphosphate aldolase.
Rational design, synthesis and evaluation of first generation inhibitors of the Giardia lamblia fructose-1,6-biphosphate aldolase.
复制标题
DOI：
10.1016/j.jinorgbio.2010.12.012
复制
发表时间：
2011-04
影响因子：
3.9
通讯作者：
Mariano, Patrick S.
中科院分区：
文献类型：
--
作者：
Li, Zhimin;Liu, Zhengang;Cho, Dae Won;Zou, Jiwen;Gong, Maozhen;Breece, Robert M.;Galkin, Andrey;Li, Ling;Zhao, Hong;Maestas, Gabriel D.;Tierney, David L.;Herzberg, Osnat;Dunaway-Mariano, Debra;Mariano, Patrick S.
关键词：
基于3-羟基-2-吡啶酮和1，2-二羟基吡啶骨架设计了蓝氏贾第鞭毛虫果糖1，6-二磷酸醛缩酶（GlFBPA）的抑制剂，该酶将果糖1，6-二磷酸（FBP）转化为二羟丙酮磷酸和甘油醛3-磷酸，所述骨架定位两个带负电荷的四面体基团以与底物磷酸结合残基相互作用，所述底物磷酸结合残基是催化Asp 83的氢键供体，和Zn 2+结合基团。测定了所合成的膦酸/磷酸酯取代的3-羟基-2-吡啶酮和二羟基吡啶对GlFBPA催化的FBP反应的抑制活性。发现3-羟基-2-吡啶酮抑制剂8与GlFBPA结合的亲和力（Ki = 14 μM）与FBP（Km = 2 μM）或其惰性类似物TBP（Ki = 1 μM）相当。GlFBPA-抑制剂8复合物（2.3 μ m）的X射线结构显示，8以通过计算机对接预测的方式结合至活性位点，除了与Zn 2+的配位。吡啶酮环O=C-C-OH相对于Zn 2+的观察到的距离和取向与强相互作用不一致。为了确定溶液中的GlFBPA-抑制剂8络合物中是否发生Zn 2+配位，测量EXAFS光谱。由三个酶组氨酸配体和来自吡啶酮环O=C-C-OH的氧原子组成的四配位几何结构被指示。在最近报道的II类FBPA的结构中的Zn 2+配位几何形状的分析表明，强的Zn 2+配位被保留为烯二醇盐样过渡态，占Zn 2+配位对8至GlFBPA的结合的最小贡献。
Inhibitors of the Giardia lamblia fructose 1,6-bisphosphate aldolase (GlFBPA), which transforms fructose 1,6-bisphosphate (FBP) to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, were designed based on 3-hydroxy-2-pyridone and 1,2-dihydroxypyridine scaffolds that position two negatively charged tetrahedral groups for interaction with substrate phosphate binding residues, a hydrogen bond donor to the catalytic Asp83, and a Zn2+ binding group. The inhibition activities for the GlFBPA catalyzed reaction of FBP of the prepared alkyl phosphonate/phosphate substituted 3-hydroxy-2-pyridinones and a dihydroxypyridine were determined. The 3-hydroxy-2-pyridone inhibitor 8 was found to bind to GlFBPA with an affinity (Ki = 14 μM) that is comparable to that of FBP (Km = 2 μM) or its inert analog TBP (Ki = 1 μM). The X-ray structure of the GlFBPA-inhibitor 8 complex (2.3 Å) shows that 8 binds to the active site in the manner predicted by in silico docking with the exception of coordination with Zn2+. The observed distances and orientation of the pyridone ring O=C-C-OH relative to Zn2+ are not consistent with a strong interaction. To determine if Zn2+coordination occurs in the GlFBPA-inhibitor 8 complex in solution, EXAFS spectra were measured. A four coordinate geometry comprised of the three enzyme histidine ligands and an oxygen atom from the pyridone ring O=C-C-OH was indicated. Analysis of the Zn2+ coordination geometries in recently reported structures of class II FBPAs suggests that strong Zn2+ coordination is reserved for the enediolate-like transition state, accounting for minimal contribution of Zn2+ coordination to binding of 8 to GlFBPA.
登录
查看更多内容
影响因子：
3.5
作者：
Henze, K;Morrison, HG;Müller, M
通讯作者：
Müller, M
DOI：
10.1111/j.1550-7408.1989.tb01073.x
发表时间：
1989-03-01
期刊：
JOURNAL OF PROTOZOOLOGY
影响因子：
--
作者：
JARROLL, EL;MANNING, P;LINDMARK, DG
通讯作者：
LINDMARK, DG
DOI：
10.1016/0035-9203(88)90278-7
发表时间：
1988-01-01
影响因子：
2.2
作者：
BOREHAM, PFL;PHILLIPS, RE;SHEPHERD, RW
通讯作者：
SHEPHERD, RW
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL
影响因子：
4.3
作者：
Fonvielle, Matthieu;Coincon, Mathieu;Therisod, Michel
通讯作者：
Therisod, Michel