血紅素生物合成是哺乳動物中受生物鐘控制（通過限制節(jié)律的酶“氨基果糖酸鹽合成酶-1”進行）的重要過程之一。現(xiàn)在,，這一關系的一個互補方面被發(fā)現(xiàn)了：在活體中,，生物鐘基因mPer1和mPer2在一個涉及NPAS2的通道中由血紅素調節(jié),，而NPAS2 是一種神經蛋白，它既是核心生物鐘機制的一部分,，又調節(jié)“氨基果糖酸鹽合成酶 -1”的生成,。而且，鈷胺素（維生素B12）和血紅素相互競爭來與NPAS2和生物鐘蛋白mPER2結合,，但對mPer1和mPer2的表達有相反影響,。這說明，卟啉衍生物（B12含有卟啉）是如癌癥等生物節(jié)律失調疾病的潛在治療藥物,，而且通過細胞周期調節(jié)物質與生物鐘之間的聯(lián)系,，還可用在接受化學療法和放射療法的患者身上。
Reciprocal regulation of haem biosynthesis and the circadian clock in mammals
The circadian clock is the central timing system that controls numerous physiological processes. In mammals, one such process is haem biosynthesis, which the clock controls through regulation of the rate-limiting enzyme aminolevulinate synthase 1 (Alas1). Several members of the core clock mechanism are PAS domain proteins, one of which, neuronal PAS 2 (NPAS2), has a haem-binding motif. Indeed, haem controls activity of the BMAL1–NPAS2 transcription complex in vitro by inhibiting DNA binding in response to carbon monoxide. Here we show that haem differentially modulates expression of the mammalian Period genes mPer1 and mPer2 in vivo by a mechanism involving NPAS2 and mPER2. Further experiments show that mPER2 positively stimulates activity of the BMAL1–NPAS2 transcription complex and, in turn, NPAS2 transcriptionally regulates Alas1. Vitamin B12 and haem compete for binding to NPAS2 and mPER2, but they have opposite effects on mPer2 and mPer1 expression in vivo. Our data show that the circadian clock and haem biosynthesis are reciprocally regulated and suggest that porphyrin-containing molecules are potential targets for therapy of circadian disorders.
