Biochemical Properties of Human D-amino Acid Oxidase Variants and Their Potential Significance in Pathologies.
Biochemical Properties of Human D-amino Acid Oxidase Variants and Their Potential Significance in Pathologies.
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DOI：
10.3389/fmolb.2018.00055
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发表时间：
2018
影响因子：
5
通讯作者：
Murtas G
中科院分区：
文献类型：
--
作者：
Sacchi S;Cappelletti P;Murtas G
立体选择性黄素酶 D-氨基酸氧化酶 (DAAO) 催化中性和极性 D-氨基酸的氧化脱氨，产生相应的 α-酮酸、氨和过氧化氢。尽管其底物奇特且非典型，DAAO 在大多数真核生物中广泛表达。在哺乳动物（尤其是人类）中，DAAO 参与从肾脏中的 D-氨基酸解毒到中枢神经系统中的神经传递等相关生理过程，其中 DAAO 负责 D-丝氨酸的分解代谢，D-丝氨酸是 N-甲基-D-天冬氨酸受体的关键内源性共激动剂。最近，结构和功能研究凸显了人类 DAAO (hDAAO) 独特的生化特性。它似乎已经进化到可以对其活性进行严格调节，因此该酶可以精细地控制底物（例如大脑中的 D-丝氨酸）的浓度，而不会过度产生过氧化氢（一种潜在有毒的活性氧 (ROS)）。事实上，D-丝氨酸代谢失调可能是由 hDAAO 表达和活性水平改变引起的，与多种病理有关，从肾脏疾病到神经、神经退行性和精神疾病。 DAO 基因中只有一个突变与人类疾病明确相关。然而，数据库中报告了几种单核苷酸多态性 (SNP)，并且相应重组 hDAAO 变体的生化特征对于研究突变的影响非常重要。在这里，我们回顾了最近发表的数据，重点关注由已确认的 SNP 编码的氨基酸取代引起的结构和功能特性的修饰及其对 D-丝氨酸细胞水平的影响。还将讨论不同 hDAAO 变体在人类病理学中的潜在意义。
The stereoselective flavoenzyme D-amino acid oxidase (DAAO) catalyzes the oxidative deamination of neutral and polar D-amino acids producing the corresponding α-keto acids, ammonia, and hydrogen peroxide. Despite its peculiar and atypical substrates, DAAO is widespread expressed in most eukaryotic organisms. In mammals (and humans in particular), DAAO is involved in relevant physiological processes ranging from D-amino acid detoxification in kidney to neurotransmission in the central nervous system, where DAAO is responsible of the catabolism of D-serine, a key endogenous co-agonist of N-methyl-D-aspartate receptors. Recently, structural and functional studies have brought to the fore the distinctive biochemical properties of human DAAO (hDAAO). It appears to have evolved to allow a strict regulation of its activity, so that the enzyme can finely control the concentration of substrates (such as D-serine in the brain) without yielding to an excessive production of hydrogen peroxide, a potentially toxic reactive oxygen species (ROS). Indeed, dysregulation in D-serine metabolism, likely resulting from altered levels of hDAAO expression and activity, has been implicated in several pathologies, ranging from renal disease to neurological, neurodegenerative, and psychiatric disorders. Only one mutation in DAO gene was unequivocally associated to a human disease. However, several single nucleotide polymorphisms (SNPs) are reported in the database and the biochemical characterization of the corresponding recombinant hDAAO variants is of great interest for investigating the effect of mutations. Here we reviewed recently published data focusing on the modifications of the structural and functional properties induced by amino acid substitutions encoded by confirmed SNPs and on their effect on D-serine cellular levels. The potential significance of the different hDAAO variants in human pathologies will be also discussed.
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DOI：
10.1126/science.aaa3650
发表时间：
2015-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cirulli ET;Lasseigne BN;Petrovski S;Sapp PC;Dion PA;Leblond CS;Couthouis J;Lu YF;Wang Q;Krueger BJ;Ren Z;Keebler J;Han Y;Levy SE;Boone BE;Wimbish JR;Waite LL;Jones AL;Carulli JP;Day-Williams AG;Staropoli JF;Xin WW;Chesi A;Raphael AR;McKenna-Yasek D;Cady J;Vianney de Jong JM;Kenna KP;Smith BN;Topp S;Miller J;Gkazi A;FALS Sequencing Consortium;Al-Chalabi A;van den Berg LH;Veldink J;Silani V;Ticozzi N;Shaw CE;Baloh RH;Appel S;Simpson E;Lagier-Tourenne C;Pulst SM;Gibson S;Trojanowski JQ;Elman L;McCluskey L;Grossman M;Shneider NA;Chung WK;Ravits JM;Glass JD;Sims KB;Van Deerlin VM;Maniatis T;Hayes SD;Ordureau A;Swarup S;Landers J;Baas F;Allen AS;Bedlack RS;Harper JW;Gitler AD;Rouleau GA;Brown R;Harms MB;Cooper GM;Harris T;Myers RM;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
4.8
作者：
Caldinelli, L;Iametti, S;Pollegioni, L
通讯作者：
Pollegioni, L
影响因子：
5.4
作者：
Cappelletti, Pamela;Campomenosi, Paola;Sacchi, Silvia
通讯作者：
Sacchi, Silvia
影响因子：
8
作者：
Caldinelli, Laura;Molla, Gianluca;Pollegioni, Loredano
通讯作者：
Pollegioni, Loredano
影响因子：
4.7
作者：
Collingridge GL;Volianskis A;Bannister N;France G;Hanna L;Mercier M;Tidball P;Fang G;Irvine MW;Costa BM;Monaghan DT;Bortolotto ZA;Molnár E;Lodge D;Jane DE
通讯作者：
Jane DE