4-Hydroxy-2-oxoglutarate aldolase inactivity in primary hyperoxaluria type 3 and glyoxylate reductase inhibition.
4-Hydroxy-2-oxoglutarate aldolase inactivity in primary hyperoxaluria type 3 and glyoxylate reductase inhibition.
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DOI：
10.1016/j.bbadis.2012.06.014
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发表时间：
2012-10
影响因子：
6.2
通讯作者：
Lowther, W. Todd
中科院分区：
文献类型：
--
作者：
Riedel, Travis J.;Knight, John;Murray, Michael S.;Milliner, Dawn S.;Holmes, Ross P.;Lowther, W. Todd
编码 4-羟基-2-酮戊二酸醛缩酶 (HOGA) 的基因突变与原发性高草酸尿症 3 型 (PH3) 中草酸盐的过量产生有关。该酶是线粒体内羟脯氨酸降解途径的最后一步，并催化 4-羟基-2-酮戊二酸 (HOG) 裂解为丙酮酸和乙醛酸。尚未进行分析来评估所识别突变的后果，特别是对于那些产生全长或接近全长蛋白质的变体。在本研究中，检测了九种 PH3 人类 HOGA 变体的表达、稳定性和活性。使用大肠杆菌和转染的中国仓鼠卵巢 (CHO) 细胞中产生的重组蛋白，发现所有九种 PH3 变体都相当不稳定，有聚集倾向，并且不保留可测量的活性。 PH3 患者的尿液、血清和肝脏样本中证实存在 HOG 积聚。为了确定在没有 HOGA 活性的情况下 HOG 如何被裂解，评估了 N-乙酰神经氨酸醛缩酶 (NAL) 裂解 HOG 的能力。 NAL 对 HOG 表现出最小的活性。还评估了线粒体中预期的 HOG 积累是否会抑制乙醛酸还原酶 (GR)（该酶在 PH2 中突变）。 GR 被 HOG 抑制，但不被 2-羟基戊二酸或 2-酮戊二酸抑制。因此，PH3 中草酸盐过量产生的分子基础的一个假设组成部分似乎是 HOG 对 GR 的抑制，从而导致与 PH2 相似的表型。
Mutations in the gene encoding for 4-hydroxy-2-oxoglutarate aldolase (HOGA) are associated with an excessive production of oxalate in Primary Hyperoxaluria type 3 (PH3). This enzyme is the final step of the hydroxyproline degradation pathway within the mitochondria and catalyzes the cleavage of 4-hydroxy-2-oxoglutarate (HOG) to pyruvate and glyoxylate. No analyses have been performed to assess the consequences of the mutations identified, particularly for those variants that produce either full-length or nearly full-length proteins. In this study, the expression, stability, and activity of nine PH3 human HOGA variants were examined. Using recombinant protein produced in Escherichia coli as well as transfected Chinese hamster ovary (CHO) cells, it was found that all nine PH3 variants are quite unstable, have a tendency to aggregate, and retain no measurable activity. A buildup of HOG was confirmed in the urine, sera and liver samples from PH3 patients. To determine how HOG is cleaved in the absence of HOGA activity, the ability of N-acetylneuraminate aldolase (NAL) to cleave HOG was evaluated. NAL showed minimal activity towards HOG. Whether the expected buildup of HOG in mitochondria could inhibit glyoxylate reductase (GR), the enzyme mutated in PH2, was also evaluated. GR was inhibited by HOG but not by 2-hydroxyglutarate or 2-oxoglutarate. Thus, one hypothetical component of the molecular basis for the excessive oxalate production in PH3 appears to be the inhibition of GR by HOG, resulting in a phenotype similar to PH2.
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影响因子：
3.9
作者：
Evans, Genevieve;Schuldt, Linda;Gerrard, Juliet A.
通讯作者：
Gerrard, Juliet A.
影响因子：
3.7
作者：
Riedel TJ;Johnson LC;Knight J;Hantgan RR;Holmes RP;Lowther WT
通讯作者：
Lowther WT
影响因子：
4.1
作者：
Lumb, MJ;Birdsey, GM;Danpure, CJ
通讯作者：
Danpure, CJ
DOI：
10.1016/j.bbapap.2005.08.004
发表时间：
2005-12-01
影响因子：
3.2
作者：
Mdluli, K;Booth, MPS;Rumsby, G
通讯作者：
Rumsby, G
影响因子：
5.6
作者：
Booth, Michael P. S.;Conners, R.;Brady, R. Leo
通讯作者：
Brady, R. Leo