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Heme is synthesized in all cell types in aerobic organisms. Hydroxy-methylbilane synthase (HMBS) and uroporphyrinogen III synthase (UROS) catalyze two consecutive reactions in the heme biosynthetic path-way, generating the first linear and the first cyclic tetrapyrroles, respec-tively. Each of the HMBS and UROS genes contains the two separate promoters that generate ubiquitous and erythroid-specific mRNAs. | ỊFEBS Journal Hypoxia decreases the expression of the two enzymes responsible for producing linear and cyclic tetrapyrroles in the heme biosynthetic pathway Patrick D. Vargas1 Kazumichi Furuyama1 Shigeru Sassa2 and Shigeki Shibahara1 1 Department of Molecular Biology and Applied Physiology Tohoku University Schoolof Medicine Miyagi Japan 2 Laboratory of BiochemicalHematology Rockefeller University New York NY USA Keywords erythroid cells heme hepatocyte hypoxiainducible factor 1 porphyria Correspondence K. Furuyama Department of Molecular Biology and Applied Physiology Tohoku University Schoolof Medicine 2-1 Seiryo-machi Aoba-ku Sendai Miyagi 980-8575 Japan Fax 81 22 717 8118 Tel 81 22 717 8115 E-mail k-furuya@mail.tains.tohoku.ac.jp Received 16 July 2008 revised 30 September 2008 accepted 2 October 2008 doi 10.1111 j.1742-4658.2008.06723.x Heme is synthesized in all cell types in aerobic organisms. Hydroxymethylbilane synthase HMBS and uroporphyrinogen III synthase UROS catalyze two consecutive reactions in the heme biosynthetic pathway generating the first linear and the first cyclic tetrapyrroles respectively. Each of the HMBS and UROS genes contains the two separate promoters that generate ubiquitous and erythroid-specific mRNAs. Despite the functional significance of HMBS and UROS regulation of their gene expression remains to be investigated. Here we showed that hypoxia 1 O2 decreased the expression of ubiquitous mRNAs for HMBS and UROS by three- and twofold respectively in human hepatic cells HepG2 and Hep3B whereas the expression of ubiquitous and erythroid HMBS and UROS mRNAs remained unchanged in erythroid cells YN-1 and K562 . Unexpectedly hypoxia did not decrease the half-life of HMBS mRNA 8.4 h under normoxia versus 9.1 h under hypoxia or UROS mRNA 9.0 versus 10.4 h in hepatic cells. It is therefore unlikely that a change in mRNA stability is responsible for the hypoxia-mediated decrease in the expression levels of these mRNAs. Furthermore expression .
