Alcohol and aldehyde dehydrogenases: retinoid metabolic effects in mouse knockout models.
Alcohol and aldehyde dehydrogenases: retinoid metabolic effects in mouse knockout models.
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DOI：
10.1016/j.bbalip.2011.04.004
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发表时间：
2012-01
期刊：
影响因子：
--
通讯作者：
Duester G
中科院分区：
文献类型：
--
作者：
Kumar S;Sandell LL;Trainor PA;Koentgen F;Duester G
视黄酸（RA）是维生素A（视黄醇）的活性代谢产物，其控制生长和发育。RA合成的第一步由醇脱氢酶（ADH）和视黄醇脱氢酶（RDH）家族的酶控制，所述酶催化视黄醇氧化为视黄醇醛。RA合成的第二步由醛脱氢酶（ALDH）家族的成员控制，也称为视黄醇脱氢酶（RALDH），其进一步氧化视黄醇以产生RA。RA作为DNA结合RA受体的配体发挥作用，直接调节特定靶基因的转录。通过开发小鼠ADH、RDH和RALDH功能丧失模型，维生素A代谢途径的阐明和维生素A代谢产物内源性功能的研究得到了极大的改善。ADH基因敲除已证明该酶家族在出生后清除过量视黄醇以防止维生素A毒性和在维生素A缺乏症期间产生RA以保证出生后存活中的作用。由乙基亚硝基脲产生的Rdh10中的点突变已经证明，Rdh10在胚胎发育期间产生RA合成所需的大量视黄醇。Raldh1、Raldh2和Raldh3敲除已经证明RALDH1、RALDH2和RALDH3产生胚胎发生期间所需的大部分RA。这些小鼠模型作为工具工具提供新的洞察类维生素A的功能。
Retinoic acid (RA) is the active metabolite of vitamin A (retinol) that controls growth and development. The first step of RA synthesis is controlled by enzymes of the alcohol dehydrogenase (ADH) and retinol dehydrogenase (RDH) families that catalyze oxidation of retinol to retinaldehyde. The second step of RA synthesis is controlled by members of the aldehyde dehydrogenase (ALDH) family also known as retinaldehyde dehydrogenase (RALDH) that further oxidize retinaldehyde to produce RA. RA functions as a ligand for DNA-binding RA receptors that directly regulate transcription of specific target genes. Elucidation of the vitamin A metabolic pathway and investigation of the endogenous function of vitamin A metabolites has been greatly improved by development of mouse ADH, RDH, and RALDH loss-of-function models. ADH knockouts have demonstrated a postnatal role for this enzyme family in clearance of excess retinol to prevent vitamin A toxicity and in generation of RA for postnatal survival during vitamin A deficiency. A point mutation in Rdh10 generated by ethylnitrosourea has demonstrated that RDH10 generates much of the retinaldehyde needed for RA synthesis during embryonic development. Raldh1, Raldh2, and Raldh3 knockouts have demonstrated that RALDH1, RALDH2, and RALDH3 generate most of the RA needed during embryogenesis. These mouse models serve as instrumental tools for providing new insight into retinoid function.
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