(2S,4R)-2-amino-4-hydroxy-5-oxo-valeric acid | 106454-68-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2S,4R)-2-amino-4-hydroxy-5-oxo-valeric acid
• 英文别名: γ-Hydroxy-L-glutaminsaeure-δ-semialdehyd；(2S,4R)-2-Amino-4-hydroxy-5-oxo-valeriansaeure；4-Hydroxyglutamate semialdehyde；(2S,4R)-2-azaniumyl-4-hydroxy-5-oxopentanoate
• CAS: 106454-68-6
• 化学式: C₅H₉NO₄
• 分子量: 147.131
• InChiKey: XCXUZPXOFFRGGP-DMTCNVIQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.1
• 重原子数：
  10
• 可旋转键数：
  4
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  101
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  水 、 (2S,4R)-2-amino-4-hydroxy-5-oxo-valeric acid 、 nicotinamide adenine dinucleotide 生成 (2S,4R)-2-amino-4,5-dihydroxy-5-oxopentanoate 、 氢(+1)阳离子 、 NADH
  参考文献：
  名称：

  The Three-Dimensional Structural Basis of Type II Hyperprolinemia

  摘要：

  Type II hyperprolinemia is an autosomal recessive disorder caused by a deficiency in Delta(1)-pyrroline-5-carboxylate dehydrogenase (P5CDH; also known as ALDH4A1), the aldehyde dehydrogenase that catalyzes the oxidation of glutamate semialdehyde to glutamate. Here, we report the first structure of human P5CDH (HsP5CDH) and investigate the impact of the hyperprolinemia-associated mutation of Ser352 to Leu on the structure and catalytic properties of the enzyme. The 2.5-angstrom-resolution crystal structure of HsP5CDH was determined using experimental phasing. Structures of the mutant enzymes S352A (2.4 angstrom) and S352L (2.85 angstrom) were determined to elucidate the structural consequences of altering Ser352. Structures of the 93% identical mouse P5CDH complexed with sulfate ion (1.3 angstrom resolution), glutamate (1.5 angstrom), and NAD(+) (1.5 angstrom) were determined to obtain high-resolution views of the active site. Together, the structures show that Ser352 occupies a hydrophilic pocket and is connected via water-mediated hydrogen bonds to catalytic Cys348. Mutation of Ser352 to Leu is shown to abolish catalytic activity and eliminate NAD(+) binding. Analysis of the S352A mutant shows that these functional defects are caused by the introduction of the nonpolar Leu352 side chain rather than the removal of the Ser352 hydroxyl. The S352L structure shows that the mutation induces a dramatic 8-angstrom rearrangement of the catalytic loop. Because of this conformational change, Ser349 is not positioned to interact with the aldehyde substrate, conserved Glu447 is no longer poised to bind NAD(+), and Cys348 faces the wrong direction for nucleophilic attack. These structural alterations render the enzyme inactive. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.jmb.2012.04.010
• 作为产物：
  描述：

  L-羟基脯氨酸 生成 (2S,4R)-2-amino-4-hydroxy-5-oxo-valeric acid
  参考文献：
  名称：

  Adams; Goldstone, Journal of Biological Chemistry, 1960, vol. 235, p. 3492,3497

  摘要：

  DOI：

文献信息

• Lang; Mayer, Biochemische Zeitschrift, 1953, vol. 324, p. 237,238
  作者：Lang、Mayer

  DOI：——

  日期：——
• Taggart; Krakaur, Journal of Biological Chemistry, 1949, vol. 177, p. 641,644, 645
  作者：Taggart、Krakaur

  DOI：——

  日期：——
• The Three-Dimensional Structural Basis of Type II Hyperprolinemia
  作者：Dhiraj Srivastava、Ranjan K. Singh、Michael A. Moxley、Michael T. Henzl、Donald F. Becker、John J. Tanner

  DOI：10.1016/j.jmb.2012.04.010

  日期：2012.7

  Type II hyperprolinemia is an autosomal recessive disorder caused by a deficiency in Delta(1)-pyrroline-5-carboxylate dehydrogenase (P5CDH; also known as ALDH4A1), the aldehyde dehydrogenase that catalyzes the oxidation of glutamate semialdehyde to glutamate. Here, we report the first structure of human P5CDH (HsP5CDH) and investigate the impact of the hyperprolinemia-associated mutation of Ser352 to Leu on the structure and catalytic properties of the enzyme. The 2.5-angstrom-resolution crystal structure of HsP5CDH was determined using experimental phasing. Structures of the mutant enzymes S352A (2.4 angstrom) and S352L (2.85 angstrom) were determined to elucidate the structural consequences of altering Ser352. Structures of the 93% identical mouse P5CDH complexed with sulfate ion (1.3 angstrom resolution), glutamate (1.5 angstrom), and NAD(+) (1.5 angstrom) were determined to obtain high-resolution views of the active site. Together, the structures show that Ser352 occupies a hydrophilic pocket and is connected via water-mediated hydrogen bonds to catalytic Cys348. Mutation of Ser352 to Leu is shown to abolish catalytic activity and eliminate NAD(+) binding. Analysis of the S352A mutant shows that these functional defects are caused by the introduction of the nonpolar Leu352 side chain rather than the removal of the Ser352 hydroxyl. The S352L structure shows that the mutation induces a dramatic 8-angstrom rearrangement of the catalytic loop. Because of this conformational change, Ser349 is not positioned to interact with the aldehyde substrate, conserved Glu447 is no longer poised to bind NAD(+), and Cys348 faces the wrong direction for nucleophilic attack. These structural alterations render the enzyme inactive. (C) 2012 Elsevier Ltd. All rights reserved.
• Adams; Goldstone, Journal of Biological Chemistry, 1960, vol. 235, p. 3492,3497
  作者：Adams、Goldstone

  DOI：——

  日期：——
• Structural basis of substrate selectivity of Δ1-pyrroline-5-carboxylate dehydrogenase (ALDH4A1): Semialdehyde chain length
  作者：Travis A. Pemberton、John J. Tanner

  DOI：10.1016/j.abb.2013.07.024

  日期：2013.10

  The enzyme Delta(1)-pyrroline-5-carboxylate (P5C) dehydrogenase (aka P5CDH and ALDH4A1) is an aldehyde dehydrogenase that catalyzes the oxidation of gamma-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 K-i 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 K-i 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. (C) 2013 Elsevier Inc. All rights reserved.