Neckameyer W S, Coleman C M, Eadie S, Goodwin S F
Department of Pharmacological and Physiological Science, St Louis, University School of Medicine, MO 63104, USA.
Genes Brain Behav. 2007 Nov;6(8):756-69. doi: 10.1111/j.1601-183X.2007.00307.x. Epub 2007 Mar 21.
In Drosophila, one enzyme (Drosophila tryptophan-phenylalanine hydroxylase, DTPHu) hydroxylates both tryptophan to yield 5-hydroxytryptophan, the first step in serotonin synthesis, and phenylalanine, to generate tyrosine. Analysis of the sequenced Drosophila genome identified an additional enzyme with extensive homology to mammalian tryptophan hydroxylase (TPH), which we have termed DTRHn. We have shown that DTRHn can hydroxylate tryptophan in vitro but displays differential activity relative to DTPHu when using tryptophan as a substrate. Recent studies in mice identified the presence of two TPH genes, Tph1 and Tph2, from distinct genetic loci. Tph1 represents the non-neuronal TPH gene, and Tph2 is expressed exclusively in the brain. In this article, we show that DTRHn is neuronal in expression and function and thus represents the Drosophila homologue of Tph2. Using a DTRHn-null mutation, we show that diminished neuronal serotonin affects locomotor, olfactory and feeding behaviors, as well as heart rate. We also show that DTPHu functions in vivo as a phenylalanine hydroxylase in addition to its role as the peripheral TPH in Drosophila, and is critical for non-neuronal developmental events.
在果蝇中，有一种酶（果蝇色氨酸 - 苯丙氨酸羟化酶，DTPHu）可将色氨酸羟化生成5 - 羟色氨酸，这是血清素合成的第一步，同时也能将苯丙氨酸羟化生成酪氨酸。对已测序的果蝇基因组进行分析后，发现了另一种与哺乳动物色氨酸羟化酶（TPH）具有广泛同源性的酶，我们将其命名为DTRHn。我们已经证明，DTRHn在体外能够使色氨酸羟化，但以色氨酸作为底物时，相对于DTPHu表现出不同的活性。最近对小鼠的研究发现，存在两个来自不同基因位点的TPH基因，即Tph1和Tph2。Tph1代表非神经元TPH基因，而Tph2仅在大脑中表达。在本文中，我们表明DTRHn在表达和功能上具有神经元特性，因此代表了果蝇中Tph2的同源物。利用DTRHn基因敲除突变，我们发现神经元血清素减少会影响运动、嗅觉和进食行为以及心率。我们还表明，DTPHu在果蝇体内除了作为外周TPH发挥作用外，还作为苯丙氨酸羟化酶发挥功能，并且对非神经元发育事件至关重要。
