Disease relevance of hemH

• A certain mutation in hemK gene rescues the photosensitive phenotype of a ferrochelatase-deficient (hemH) mutant in Escherichia coli [1].
• Leptospira biflexa allelic exchange mutants containing an inactivated hemH gene were recovered only when exogenous haemin was present [2].
• Also in other Yersinia spp., the locus downstream of the hemH gene is occupied by gene clusters associated with LPS biosynthesis [3].
• Analysis of the Bradyrhizobium japonicum hemH gene and its expression in Escherichia coli [4].
• Cloning and overexpression of the Rhodobacter capsulatus hemH gene [5].

High impact information on hemH

• The chemotaxis machinery was needed for the light-induced tumbling response in the hemH mutant [6].
• Therefore, a point mutation in the coding region of the ferrochelatase gene is the genetic defect in some patients with protoporphyria [7].
• Since other mutations in the genes involved in the biosynthesis of heme can cure the photosensitivity, the light-induced cell death appears to be brought about by the accumulation of protoporphyrin IX, one of the substrates of ferrochelatase [8].
• Ferrochelatase consisting of wild-type and mutated subunits from patients with a dominant-inherited disease, erythropoietic protoporphyria, is an active but unstable dimer [9].
• Ferrochelatase is a mitochondrial inner membrane-bound enzyme that catalyzes the insertion of ferrous iron into protoporphyrin, the terminal step in protoheme biosynthesis [10].

Chemical compound and disease context of hemH

• Using Escherichia coli strain VS101, whose hemH gene encoding the ferrochelatase is partially defective, we isolated and analyzed a clone (designated XWH-1) from a X phage library of soybean (Glycine max) cDNA, which exhibited weak complementation activity against the light sensitivity of VS101 [11].

Biological context of hemH

• Five of them, including an amber mutant, are defective in a gene that maps near 11 minutes on the linkage map of the chromosome, and this gene has been designated visA [12].
• The nucleotide sequence of the visA gene was determined [12].
• One of the possible explanations is that the genotoxic effect due to damage of hemH, shortage of heme and/or accumulating of protoporphyrin IX makes mutagenesis impossible [13].
• The predicted amino acid sequence of malarial FC is highly conserved and fairly well conserved by comparison with other orthologues [14].
• To establish a system for overproduction of the ferrochelatase [EC 4.99.1.1] from Escherichia coli, a plasmid designated pFC3 was constructed [15].

Anatomical context of hemH

• The hemH mutant failed to insert functional SQR into the cytoplasmic membrane, and the catalytic portion of SQR [the flavoprotein subunit (Fp) and the iron-sulfur protein subunit (Ip)] was localized in the cytoplasm of the cell [16].
• These results demonstrated that the cucumber hemH gene encodes a ferrochelatase which presumably functions for heme biosynthesis in non-photosynthetic tissues, such as hypocotyls and roots, and suggested the presence of other types of ferrochelatase in cucumber, one of which is located in thylakoid membranes of chloroplasts [17].
• It is proposed that the multiplicity of genes for PPO and FeC in higher plants could be related to differential expression in differently developing tissues rather than to targeting of different gene products to different organelles [18].
• When macrophage cell line RAW 264.7 cells were treated with interferon-gamma and lipopolysaccharide NO synthesis in the cells was stimulated, and a decrease in ferrochelatase activity was observed, with no change in the amount of ferrochelatase [19].
• In eukaryotic cells, ferrochelatase is a mitochondrial inner membrane-associated protein with the active site facing the matrix [20].

Associations of hemH with chemical compounds

• It encodes a water-soluble ferrochelatase which catalyzes the final step in protoheme IX synthesis, the insertion of ferrous iron into protoporphyrin IX [21].
• Moreover, ferrochelatase catalyses insertion of Cu(II) and Zn(II) into N-MeMP with a rate that is about 20 times faster than non-enzymatic metallation in solution, suggesting that the catalytic strategy of ferrochelatase includes a stage of acceleration of the rate of ligand exchange for the metal substrate [22].
• Human and Schizosaccharomyces pombe forms of ferrochelatase contain a [2Fe-2S] cluster with three of the four coordinating cysteine ligands located within the 30 carboxyl-terminal residues [23].
• When purified recombinant human ferrochelatase was treated with 3-morpholinosydnonimine, a NO-generating compound, ferrochelatase activity decreased with disappearance of characteristic absorbance spectra of the iron-sulphur cluster [19].
• Nitric oxide-mediated inactivation of mammalian ferrochelatase in vivo and in vitro: possible involvement of the iron-sulphur cluster of the enzyme [19].

Other interactions of hemH

• In contrast, expression of hemCD, hemH and hemA were shown to be mildly regulated in response to heme availability [24].
• According to their growth responses to haem precursors and their patterns of porphyrin accumulation, the 55 mutants fell into three groups which were judged to have defects in 5-aminolaevulinate dehydratase, ferrochelatase, and uroporphyrinogen III cosynthase or uroporphyrinogen decarboxylase [25].
• Thus the rfb gene cluster of YeO8 is located between the adk-hemH and gsk loci, and the order is adk-hemH-rfb-rfc-gsk in the chromosome [3].
• Strikingly, the malarial FC lacks a bipartite presequence at its N-terminus, unlike delta-aminolevulinic acid dehydratase of the same organism [14].
• Functional complementation of Escherichia coli mutant strains was used to isolate cDNAs encoding three heme biosynthetic enzymes, glutamate-1-semialdehyde aminotransferase, protoporphyrinogen IX oxidase, and ferrochelatase [26].

Analytical, diagnostic and therapeutic context of hemH

• Northern blot analysis also indicated that the hemH gene was expressed mainly in hypocotyls and roots, but little in cotyledons, and the level of the hemH transcripts was not light-responsive [17].
• This 35-kDa protein was identified as the ferrochelatase of E. coli by Western blotting and amino-terminal amino acid sequence analysis [15].
• Here, we present a study of metal insertion into the transition-state inhibitor of protoporphyrin IX ferrochelatase, N-methyl mesoporphyrin (N-MeMP), by time-resolved crystallography and mass spectrometry with and without the presence of ferrochelatase [22].
• Purification, crystallization, and preliminary X-ray analysis of Bacillus subtilis ferrochelatase [27].
• Here the use of imaged light to select bacterial colonies is explored, employing either photodynamic therapy agents or a ferrochelatase mutation in combination with porphyrin precursors to sensitize the bacteria to light and a computer-controlled light projection system to illuminate some bacterial colonies while leaving others in the dark [28].

References