Structural basis of substrate selectivity of Δ(1)-pyrroline-5-carboxylate dehydrogenase (ALDH4A1): semialdehyde chain length.
Structural basis of substrate selectivity of Δ(1)-pyrroline-5-carboxylate dehydrogenase (ALDH4A1): semialdehyde chain length.
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DOI：
10.1016/j.abb.2013.07.024
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发表时间：
2013-10-01
影响因子：
3.9
通讯作者：
Tanner, John J.
中科院分区：
文献类型：
--
作者：
Pemberton, Travis A.;Tanner, John J.
酶Δ1-吡咯啉-5-羧酸（P5 C）脱氢酶（又名P5 CDH和ALDH 4A 1）是一种醛脱氢酶，催化γ-谷氨酸半醛氧化为l-谷氨酸。报道了小鼠P5 CDH与戊二酸、琥珀酸、丙二酸、乙醛酸和乙酸络合的晶体结构。结构用于建立结构-活性关系，其描述半醛碳链长度和醛基相对于半胱氨酸亲核试剂和含氧阴离子空穴的位置。有效的4-碳和5-碳底物共有的共同特征是足够长以跨越活性位点底部的锚环和活性位点顶部的氧阴离子孔之间的距离。无活性的2-和3-碳半醛结合锚环，但太短而不能到达氧阴离子孔。还检查了乙醛酸、丙二酸、琥珀酸、戊二酸和L-谷氨酸对P5 CDH的抑制。对于乙醛酸，Ki值为0.27 mM，对于琥珀酸，Ki值为58 mM，对于戊二酸，Ki值为30 mM，对于l-谷氨酸，Ki值为12 mM。奇怪的是，丙二酸盐不是抑制剂。Ki的趋势可能反映了游离抑制剂的羧酸盐去溶剂化的惩罚与酶-抑制剂复合物中形成的补偿氢键的数量之间的权衡。
The enzyme Δ1-pyrroline-5-carboxylate (P5C) dehydrogenase (aka P5CDH and ALDH4A1) is an aldehyde dehydrogenase that catalyzes the oxidation of γ-glutamate semialdehyde to l-glutamate. The crystal structures of mouse P5CDH complexed with glutarate, succinate, malonate, glyoxylate, and acetate are reported. The structures are used to build a structure-activity relationship that describes the semialdehyde carbon chain length and the position of the aldehyde group in relation to the cysteine nucleophile and oxyanion hole. Efficient 4- and 5-carbon substrates share the common feature of being long enough to span the distance between the anchor loop at the bottom of the active site and the oxyanion hole at the top of the active site. The inactive 2- and 3-carbon semialdehydes bind the anchor loop but are too short to reach the oxyanion hole. Inhibition of P5CDH by glyoxylate, malonate, succinate, glutarate, and l-glutamate is also examined. The Ki values are 0.27 mM for glyoxylate, 58 mM for succinate, 30 mM for glutarate, and 12 mM for l-glutamate. Curiously, malonate is not an inhibitor. The trends in Ki likely reflect a trade-off between the penalty for desolvating the carboxylates of the free inhibitor and the number of compensating hydrogen bonds formed in the enzyme-inhibitor complex.
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DOI：
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发表时间：
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影响因子：
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发表时间：
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期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
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