Fujita H
Department of Molecular Biology & Applied Physiology, Tohoku University School of Medicine, Sendai.
Tohoku J Exp Med. 1997 Oct;183(2):83-99. doi: 10.1620/tjem.183.83.
Two of the major organs producing heme are bone marrow and the liver. delta-Aminolevulinate synthase (ALAS) plays the key role to regulate heme biosynthesis in hepatocytes as well as in erythroid cells. In the liver, nonspecific (or housekeeping) isozyme of ALAS (ALAS-N) is expressed to be regulated by its end product, heme, in a negative feedback manner. The way to regulate ALAS-N in the liver is suitable to supply a constant level of heme for a family of drug metabolizing enzymes, cytochrome P-450 (CYP). In erythroid tissues, not only erythroid-specific isozyme of ALAS (ALAS-E) but also ALAS-N are expressed, and regulated by distinctive manners. Although heme regulates ALAS-N in a negative feedback manner even in erythroid cells, ALAS-E is upregulated by induced heme concentration. ALAS-N in undifferentiated erythroid cells, therefore, is suggested to produce heme for CYP, whereas heme for accumulating hemoglobin (Hb) in cells undergoing differentiation is synthesized via ALAS-E. In this article, we describe the molecular mechanisms to regulate heme biosynthesis in non-erythroid as well as in erythroid tissues, and discuss the pathological significance of the mechanisms in patients with inherited disorders, porphyrias.
产生血红素的两个主要器官是骨髓和肝脏。δ-氨基乙酰丙酸合酶（ALAS）在肝细胞和红细胞中对调节血红素生物合成起着关键作用。在肝脏中，ALAS的非特异性（或管家）同工酶（ALAS-N）表达，并受到其终产物血红素的负反馈调节。肝脏中调节ALAS-N的方式适合为一类药物代谢酶——细胞色素P-450（CYP）提供恒定水平的血红素。在红细胞组织中，不仅表达红细胞特异性的ALAS同工酶（ALAS-E），也表达ALAS-N，且以不同方式进行调节。尽管血红素在红细胞中也以负反馈方式调节ALAS-N，但ALAS-E会因血红素浓度升高而上调。因此，未分化红细胞中的ALAS-N被认为是为CYP产生血红素，而在分化中的细胞中，用于积累血红蛋白（Hb）的血红素是通过ALAS-E合成的。在本文中，我们描述了非红细胞组织和红细胞组织中调节血红素生物合成的分子机制，并讨论了这些机制在遗传性疾病卟啉症患者中的病理意义。
