Molecular and Genetic Characterization of Ferrochelatase.

Taketani, Shigeru

doi:10.1620/tjem.171.1

Cited by 19 publications

(38 citation statements)

References 90 publications

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“…An understanding of the enzyme at the molecular level is needed to elucidate how the metabolism of heme and iron metabolism is regulated (Taketani 1993). The mammalian enzyme is located in the innermembrane of mitochondria and faces the active site of the matrix (Taketani 1993). The mammalian enzyme contains a 2Fe-2S cluster in the carboxyl terminal region (Wu et al 2001;Ohgari et al 2005).…”

Section: Biosynthesis and Regulation Of Heme Metabolism In Mitochondriamentioning

confidence: 99%

“…However, protoporphyrin did not accumulate in iron-deficient cells or patients with ABC7 deficient-sideroblastic anemia/ataxia. Conversely, in patients with erythropoietic protoporphyria caused by ferrochelatase deficiency protoporphyrin but not iron is accumulated (Taketani 1993). Thus, the de novo synthesis of porphyrin is coupled to the availability of iron as a result of a translational induction of ALAS2 by iron (Ponka et al 1998).…”

Section: Biosynthesis and Regulation Of Heme Metabolism In Mitochondriamentioning

confidence: 99%

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Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

Taketani

2005

Tohoku J. Exp. Med.

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Iron is fastidiously utilized by living cells, since it is an essential element, but is toxic in excess. Cells take up iron via a transferrin-transferrin receptor-dependent endocytotic process. The iron thus taken up is used for essential biological functions including oxygen transport, electron transfer, and DNA synthesis. The intracellular level of iron is tightly controlled, through regulation of the cellular uptake of iron and the sequestering of low molecular labile iron into the storage protein ferritin. The known proteins of iron transport and storage, transferrin, transferrin receptor and ferritin, have been recently linked with a number of newly identified proteins that are responsible for inherited diseases of iron metabolisms and play critical roles in the maintenance of iron homeostasis. These proteins are involved in regulation of intracellular levels of iron, iron transport, and heme transport and the oxygen-dependent regulation of gene expression. On the other hand, most iron is transported into mitochondria and immediately used for the biosynthesis of heme in erythroid cells. The heme biosynthesis in mitochondria is coupled with the supply of iron, and the heme, exported from mitochondria, is utilized as prosthetic groups of hemeproteins. Furthermore, non-erythroid and erythroid cells possess the different regulatory systems for the biosynthesis of heme; iron positively regulates the biosynthesis in erythroid cells while heme negatively regulates it in non-erythroid cells. Because of the toxicity and insolubility of heme, the intracellular level of uncommitted heme is maintained at a low concentration (< 10 -9 M). The influx and efflux of heme also help to prevent cytotoxicity. Finally, heme-binding transcriptional factors such as Bach1 and NPAS2 regulate the transcription of several genes involved in the synthesis and degradation of heme-hemeproteins. The discovery of new molecules related to disorders of iron and heme metabolism is ascribable to a complete mechanistic understanding of the cellular network of iron homeostasis. The network of interactions that link iron and heme metabolisms with functions of cellular regulation involving oxidative stress and inflammations contributes to new insights into clinical aspects of disorders.

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Section: Biosynthesis and Regulation Of Heme Metabolism In Mitochondriamentioning

confidence: 99%

Section: Biosynthesis and Regulation Of Heme Metabolism In Mitochondriamentioning

confidence: 99%

Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

Taketani

2005

Tohoku J. Exp. Med.

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100

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“…1) FECH protein has a molecular mass of 40-42 kDa on SDS-PAGE analysis. Mammalian FECH is active as an homodimer, as analyzed by radiation inactivation and X-ray crystallography, 2,3) and contains an iron-sulfur cluster as a functional group.…”

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confidence: 99%

Porcine Ferrochelatase: The Relationship between Iron-Removal Reaction and the Conversion of Heme to Zn-Protoporphyrin

Chau

Ishigaki

Kataoka

et al. 2010

Bioscience, Biotechnology, and Biochemistry

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“…The ferrochelatases isolated from various sources all have very similar catalytic properties, indicating that the major features of the reaction are conserved (1)(2)(3)(4). Ferrochelatase genes and cDNAs have now been isolated and sequenced from bacteria (5-7), yeast (8), mammals (9 -11), and plants (12,13).…”

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confidence: 99%

“…Models have been proposed on the basis of kinetic studies, substrate specificity, and chemical modifications of certain amino acid residues and from analysis of the inhibition by N-alkylporphyrins (1)(2)(3)(4)16). The active site is believed to be an enclosed hydrophobic pocket (17), with cysteinyl (18) and arginyl (19) residues implicated in the binding of metal and porphyrin propionate(s).…”

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confidence: 99%

Probing the Active-site Residues in Saccharomyces cerevisiae Ferrochelatase by Directed Mutagenesis

Góra

Grzybowska

Rytka

et al. 1996

Journal of Biological Chemistry

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Ferrochelatase is a mitochondrial inner membranebound enzyme that catalyzes the insertion of ferrous iron into protoporphyrin, the terminal step in protoheme biosynthesis. The functional/structural roles of 10 invariant amino acid residues were investigated by sitedirected mutagenesis in the yeast Saccharomyces cerevisiae ferrochelatase. The mutant enzymes were expressed in a yeast strain lacking the ferrochelatase gene HEM15 and in Escherichia coli. The kinetic parameters of the mutant enzymes were determined for the enzymes associated with the yeast membranes and the enzymes in the bacterial soluble fraction. They were compared with the in vivo functioning of the mutant enzymes. The main conclusions are the following. Glu-314 is critical for catalysis, and we suggest that it is the base responsible for abstracting the N-pyrrole proton(s). His-235 is essential for metal binding. Asp-246 and Tyr-248 are also involved in metal binding in a synergistic manner. The K m for protoporphyrin was also increased in the H235L, D246A, and Y248L mutants, suggesting that the binding sites of the two substrates are not independent of each other. The R87A, Y95L, Q111E, Q273E, W282L, and F308A mutants had 1.2-2-fold increased V m and 4 -10-fold increased K m values for protoporphyrin, but the amount of heme made in vivo was 10 -100% of the normal value. These mutations probably affected the geometry of the active center, resulting in improper positioning of protoporphyrin.

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Molecular and Genetic Characterization of Ferrochelatase.

Cited by 19 publications

References 90 publications

Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

Porcine Ferrochelatase: The Relationship between Iron-Removal Reaction and the Conversion of Heme to Zn-Protoporphyrin

Probing the Active-site Residues in Saccharomyces cerevisiae Ferrochelatase by Directed Mutagenesis

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