Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany.
FASEB J. 2021 Jun;35(6):e21648. doi: 10.1096/fj.202100366R.
Serotonin is an important signaling molecule in the periphery and in the brain. The hydroxylation of tryptophan is the first and rate-limiting step of its synthesis. In most vertebrates, two enzymes have been described to catalyze this step, tryptophan hydroxylase (TPH) 1 and 2, with expression localized to peripheral and neuronal cells, respectively. However, animals lacking both TPH isoforms still exhibit about 10% of normal serotonin levels in the blood demanding an additional source of the monoamine. In this study, we provide evidence by the gain and loss of function approaches in in vitro and in vivo systems, including stable-isotope tracing in mice, that phenylalanine hydroxylase (PAH) is a third TPH in mammals. PAH contributes to serotonin levels in the blood, and may be important as a local source of serotonin in organs in which no other TPHs are expressed, such as liver and kidney.
血清素是外周和大脑中一种重要的信号分子。色氨酸的羟化作用是其合成的第一步和限速步骤。在大多数脊椎动物中，已经描述了两种酶来催化这一步，即色氨酸羟化酶（TPH）1 和 2，其表达分别定位于外周细胞和神经元细胞。然而，缺乏两种 TPH 同工型的动物在血液中仍表现出约 10%的正常血清素水平，这需要单胺的额外来源。在这项研究中，我们通过体外和体内系统的功能获得和丧失方法提供了证据，包括在小鼠中的稳定同位素示踪，证明苯丙氨酸羟化酶（PAH）是哺乳动物中的第三种 TPH。PAH 有助于血液中的血清素水平，并且可能是没有其他 TPH 表达的器官（如肝脏和肾脏）中局部产生血清素的重要来源。
