血红素生物合成是哺乳动物中受生物钟控制（通过限制节律的酶“氨基果糖酸盐合成酶-1”进行）的重要过程之一。现在，这一关系的一个互补方面被发现了：在活体中，生物钟基因mPer1和mPer2在一个涉及NPAS2的通道中由血红素调节，而NPAS2 是一种神经蛋白，它既是核心生物钟机制的一部分，又调节“氨基果糖酸盐合成酶 -1”的生成。而且，钴胺素（维生素B12）和血红素相互竞争来与NPAS2和生物钟蛋白mPER2结合，但对mPer1和mPer2的表达有相反影响。这说明，卟啉衍生物（B12含有卟啉）是如癌症等生物节律失调疾病的潜在治疗药物，而且通过细胞周期调节物质与生物钟之间的联系，还可用在接受化学疗法和放射疗法的患者身上。
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.
