Cytosolic retinoid dehydrogenases govern ubiquitous metabolism of retinol to retinaldehyde followed by tissue-specific metabolism to retinoic acid
Cytosolic retinoid dehydrogenases govern ubiquitous metabolism of retinol to retinaldehyde followed by tissue-specific metabolism to retinoic acid
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DOI：
10.1016/s0009-2797(02)00204-1
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发表时间：
2003-02-01
影响因子：
5.1
通讯作者：
Molotkov, A
中科院分区：
文献类型：
--
作者：
Duester, G;Mic, FA;Molotkov, A
维生素A（视黄醇）控制生长和发育的能力取决于视黄醇向视黄酸（RA）的组织特异性代谢。RA然后作为类维生素A受体信号传导的配体起作用。小鼠遗传学研究支持胞质醇脱氢酶（ADH）在第一步（视黄醇氧化为视黄醇）中的作用，以及胞质视黄醇脱氢酶（RALDH）在第二步（视黄醇氧化为RA）中的作用。缺乏ADH 3的小鼠存活率降低，生长缺陷可以通过膳食补充视黄醇来挽救，而ADHI或ADH 4损失的影响仅在分别遭受维生素A过量或缺乏的小鼠中注意到。此外，ADH I和ADH 4的遗传缺陷不具有累加效应，验证了这些酶在类维生素A代谢中的单独作用。至于RA合成的第二步，RALDH 2的无效突变是胚胎致死的，消除了大部分中胚层RA合成，而RALDH 1的缺失仅消除了胚胎背侧视网膜中的RA合成，对发育没有明显影响。对RA拯救的RALDH 2突变体的分析也揭示了RALDH 3和至少一种另外的酶在胚胎中产生RA组织特异性。总的来说，这些遗传发现表明，视黄醇代谢为视黄醇醛不是组织限制性的，因为它是由遍在表达的ADH 3（低活性形式）以及组织特异性表达的ADHI和ADH 4（高活性形式）催化的。相比之下，由于鉴定的所有酶都是组织特异性的，因此视黄醇进一步代谢为RA是组织限制性的。出现的一个重要概念是，催化第二步的酶的选择性表达限制了能够将视黄醇完全代谢为RA以启动类维生素A信号的组织。(C)2002爱思唯尔科学爱尔兰有限公司保留所有权利。
The ability of vitamin A (retinol) to control growth and development depends upon tissue-specific metabolism of retinol to retinoic acid (RA). RA then functions as a ligand for retinoid receptor signaling. Mouse genetic studies support a role for cytosolic alcohol dehydrogenases (ADH) in the first step (oxidation of retinol to retinaldehyde) and a role for cytosolic retinaldehyde dehydrogenases (RALDH) in the second step (oxidation of retinaldehyde to RA). Mice lacking ADH3 have reduced survival and a growth defect that can be rescued by dietary retinol supplementation, whereas the effect of a loss of ADHI or ADH4 is noticed only in mice subjected to vitamin A excess or deficiency, respectively. Also, genetic deficiency of both ADH I and ADH4 does not-have additive effects, verifying separate roles for these enzymes in retinoid metabolism. As for the second step of RA synthesis, a null mutation of RALDH2 is embryonic lethal, eliminating most mesodermal RA synthesis, whereas loss of RALDH1 eliminates RA synthesis only in the embryonic dorsal retina with no obvious effect on development. Analysis of RA-rescued RALDH2 mutants has also revealed that RALDH3 and at least one additional enzyme produce RA tissue-specifically in embryos. Collectively, these genetic findings indicate that metabolism of retinol to retinaldehyde is not tissue-restricted as it is catalyzed by ubiquitously-expressed ADH3 (a low activity form) as well as by tissue-specifically expressed ADHI and ADH4 (high activity forms). In contrast, further metabolism of retinaldehyde to RA is tissue-restricted as all enzymes identified are tissue-specific. An important concept to emerge is that selective expression of enzymes catalyzing the second step is what limits the tissues that can completely metabolize retinol to RA to initiate retinoid signaling. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.