High impact information on HEM1

• Interestingly, heme also potentiates binding of the yeast transcriptional activator HAP1 to DNA and inhibits mitochondrial import of the mammalian delta-aminolevulinate synthase (ALAS) and the catalytic activity of the reticulocyte kinase, HRI [1].
• First is a second activation system acting at a site close to the HAP2-HAP3 target sequence that keeps HEM1 turned on under conditions of heme deficiency [2].
• Oxygen appeared to act at the level of transcription through heme, since the addition of heme restored an aerobic pattern of transcription to anaerobically grown cells and the effect of anaerobiosis on COX5 transcription was reproduced in strains containing a mutation in the heme-biosynthetic pathway (hem1) [3].
• The amino acid sequence deduced from the DNA sequence of HEM1 showed that the amino-terminal region of delta-aminolevulinate synthase was largely hydrophobic, with a few basic residues interspersed [4].
• We found that the absence of heme, due to a deletion in the gene that encodes delta-aminolevulinic acid synthase (HEM1), resulted in decreased transcription of genes belonging to both the iron and copper regulons, but not the zinc regulon [5].

Biological context of HEM1

• An important element required for expression of HEM3 has been localized to a small region that contains a sequence homologous to the HAP2-3-4 binding sites of several genes including HEM1 [6].
• Transformation of an rhm1 strain with a multicopy plasmid containing the cloned HEM1 gene restored normal levels of 5-aminolevulinate synthase activity, but intracellular 5-aminolevulinate was increased to only 9 to 10% of normal [7].
• Using double mutants in the HEM1 gene and individual ARE genes we demonstrated that the relative contribution of these two enzymes to sterol esterification was dependent on cellular heme status [8].
• Yeast cells almost completely deficient in all cytochromes were obtained by introducing two defective nuclear genes, cyd1 and cyc4, into the same haploid strain [9].
• Mutant strain DA3-RS3/68 contained mutant gene rhm1, which segregated independently of hem1 and cyc4 during meiosis [7].

Anatomical context of HEM1

• The presence of subunit V, the iron-sulfur protein, of complex III has been demonstrated in mitochondria from a mutant of Saccharomyces cerevisiae which lacks 5-aminolevulinic acid synthase and, hence, is devoid of heme [10].

Associations of HEM1 with chemical compounds

• Mutants in hem1, hem2, and hem3 had an additional requirement for methionine on synthetic medium supplemented with either heme or ergosterol and Tween 80, owing to a lack of sulfite reductase which contains siroheme, a modified uroporphyrin III [11].
• We show that HEM1 (encoding 5-aminolevulinate synthase) expression, while constitutive under all steady-state growth conditions tested, is activated by the HAP2-HAP3 global activation system that controls expression of apocytochromes [2].
• The addition of delta-aminolevulinic acid to the medium allowed the sparking of FY3 (hem1 erg7 ura) on bulk cholestanol due to the derepression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and the production of endogenous ergosterol [12].
• A Saccharomyces cerevisiae sterol auxotroph, SPK14 (a hem1 erg6 erg7 ura), was constructed to test the ability of selected C-5,6 unsaturated sterols at growth-limiting concentrations to spark growth on bulk cholestanol [12].
• delta-aminolaevulinic acid modulates the resistance to fluconazole in a hem1 mutant of Saccharomyces cerevisiae [13].

Regulatory relationships of HEM1

• These findings suggest that HEM3 expression is regulated in the same manner as that of HEM1 which encodes the first enzyme of the heme biosynthetic pathway [6].

Other interactions of HEM1

• We propose that the absence of functional Asc1p allows the growth of hap1-hem1- cells by reducing the efficiency of translation [14].
• We observed that sterol uptake was then comparable with that obtained with a sterol importing hem1 mutant, although the heme status of the strain was not modified in a process which still occurs when the cells are not growing [15].
• The effect of delta-aminolevulinate on catalase T-messenger RNA levels in delta-aminolevulinate synthase-defective mutants of Saccharomyces cerevisiae [16].

Analytical, diagnostic and therapeutic context of HEM1

• In vitro translation of mRNA hybrid-selected by the cloned HEM1 gene, or of total RNA followed by immunoprecipitation with anti-(ALA synthase) antibody yielded a single polypeptide of higher molecular mass than the purified ALA synthase [17].

References