HEM1/YDR232W Summary Help

Standard Name HEM1 1
Systematic Name YDR232W
Alias CYD1 , OLE3 1 , 2
Feature Type ORF, Verified
Description 5-aminolevulinate synthase; catalyzes the first step in the heme biosynthetic pathway; an N-terminal signal sequence is required for localization to the mitochondrial matrix; expression is regulated by Hap2p-Hap3p (1, 3, 4, 5, 6, 7 and see Summary Paragraph)
Name Description HEMe biosynthesis 1, 4
Chromosomal Location
ChrIV:927452 to 929098 | ORF Map | GBrowse
Gbrowse
Gene Ontology Annotations All HEM1 GO evidence and references
  View Computational GO annotations for HEM1
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
High-throughput
Regulators 6 genes
Resources
Pathways
Classical genetics
null
unspecified
Large-scale survey
null
reduction of function
repressible
Resources
39 total interaction(s) for 39 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 4
  • Affinity Capture-RNA: 4

Genetic Interactions
  • Dosage Rescue: 1
  • Negative Genetic: 13
  • Phenotypic Enhancement: 4
  • Phenotypic Suppression: 5
  • Positive Genetic: 2
  • Synthetic Growth Defect: 4
  • Synthetic Lethality: 1
  • Synthetic Rescue: 1

Resources
Expression Summary
histogram
Resources
Length (a.a.) 548
Molecular Weight (Da) 59,362
Isoelectric Point (pI) 7.52
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrIV:927452 to 929098 | ORF Map | GBrowse
SGD ORF map
Last Update Coordinates: 2011-02-03 | Sequence: 1996-07-31
Subfeature details
Relative
Coordinates
Chromosomal
Coordinates
Most Recent Updates
Coordinates Sequence
CDS 1..1647 927452..929098 2011-02-03 1996-07-31
Retrieve sequences
Analyze Sequence
S288C only
S288C vs. other species
S288C vs. other strains
Resources
External Links All Associated Seq | E.C. | Entrez Gene | Entrez RefSeq Protein | MIPS | Search all NCBI (Entrez) | UniProtKB
Primary SGDIDS000002640
SUMMARY PARAGRAPH for HEM1

HEM1 encodes the enzyme 5-aminolevulinate synthase, which catalyzes the first step in heme biosynthesis and is also involved in regulating the transcription of genes involved in iron and copper transport (1, 4, 8). Hem1p is translated as a 59 kDa cytoplasmic precursor protein and then processed into a mature form of ~56 kDa in the mitochondrial matrix (4). While the first nine amino acids are important for efficient targeting of Hem1p to mitochondria, targeting information is also contained in the protein's carboxy terminus (5, 6). Pyridoxal 5'-phosphate is an essential cofactor for Hem1p while hemin has been shown to inhibit enzyme activity (9).

Deletion of HEM1 results in the loss of heme and consequently cells become auxotrophic for unsaturated fatty acids, ergosterol, and methionine. These cells can be maintained through the addition of high concentrations of aminolevulinic acid or, in some strains, media supplemented with the products of the heme-dependent reactions (8 and references therein). Mutations in human ALAS2, the erythroid-specific homolog of yeast Hem1p, lead to the disease X-linked sideroblastic anemia (OMIM) (10).

About tetrapyrrole biosynthesis

Tetrapyrroles, such as heme, siroheme, chlorophyll, and cobalamin (vitamin B12) function as cofactors in a variety of essential biological processes. Tetrapyrroles are comprised of four pyrrole rings linked together by single-carbon bridges in a linear or cyclic fashion. The cyclic tetrapyrroles heme and siroheme contain an iron-atom coordinated in their central cavity and function in respiration and sulfur assimilation, respectively. Saccharomyces cerevisiae synthesize heme and siroheme de novo via a common pathway up to the intermediate uroporphyrinogen III; oxidative decarboxylation of uroporphyrinogen III leads to the synthesis of heme while its methylation leads to siroheme synthesis.

The first committed precursor in the biosynthesis of tetrapyrroles is the five-carbon compound 5-aminolevulinic acid (ALA) (11). Animals, fungi, apicomplexan protozoa (such as the malaria parasite Plasmodium falciparum) and photosynthetic bacteria synthesize ALA from succinyl CoA and glycine (12, 13), while higher plants and other bacteria (including Escherichia coli) synthesize ALA from glutamate (12, 11)

In Saccharomyces cerevisiae, HEM1 encodes for ALA synthase, the enzyme catalyzing the first committed step in the biosynthesis of tetrapyrroles (9). Pyridoxal 5'-phosphate is an essential factor for Hem1p (9). The second step, the condensation of two molecules of ALA to form the pyrrole porphobilinogen, is catalyzed by ALA dehydratase (also known as porphobilinogen synthase; EC 4.2.1.24), a homo-octameric enzyme encoded by HEM2 (14). Hem3p and Hem4p catalyze the third and fourth steps of tetrapyrrole biosynthesis, respectively. HEM3 encodes for porphobilinogen deaminase (also known as hydroxymethylbilane synthase; EC 2.5.1.61), which catalyzes the condensation of four molecules of 4-porphobilinogen to form the linear tetrapyrrole hydroxymethylbilane (15), and HEM4 encodes for uroporphyrinogen III synthase (UROS; EC 4.2.1.75), the enzyme catalyzing the cyclization of hydroxymethylbilane and rearrangement of the fourth pyrrole to form the important intermediate uroporphyrinogen III (16). In the absence of UROS, the linear tetrapole hydroxymethylbilane undergoes non-enzymatic cyclization without rearrangement of the fourth pyrrole ring to form uroporphyrinogen I, which is not an intermediate in the synthesis of biological tetrapyrroles. Uroporphyrinogen III is a major branch point intermediate leading to biosynthesis of different tetrapyrrole-derived compounds, such as siroheme, heme, cobalamin (vitamin B12), and the methanogenic coenzyme F430 (11). S. cerevisiae is not believed to synthesize cobalamin de novo (17, 18).

Last updated: 2006-09-28 Contact SGD

References cited on this page View Complete Literature Guide for HEM1
1) Gollub EG, et al.  (1977) Yeast mutants deficient in heme biosynthesis and a heme mutant additionally blocked in cyclization of 2,3-oxidosqualene. J Biol Chem 252(9):2846-54
2) Bard M  (1972) Biochemical and genetic aspects of nystatin resistance in saccharomyces cerevisiae. J Bacteriol 111(3):649-57
3) Keng T and Guarente L  (1987) Constitutive expression of the yeast HEM1 gene is actually a composite of activation and repression. Proc Natl Acad Sci U S A 84(24):9113-7
4) Urban-Grimal D, et al.  (1986) The nucleotide sequence of the HEM1 gene and evidence for a precursor form of the mitochondrial 5-aminolevulinate synthase in Saccharomyces cerevisiae. Eur J Biochem 156(3):511-9
5) Keng T, et al.  (1986) The nine amino-terminal residues of delta-aminolevulinate synthase direct beta-galactosidase into the mitochondrial matrix. Mol Cell Biol 6(2):355-64
6) Haldi M and Guarente L  (1989) N-terminal deletions of a mitochondrial signal sequence in yeast. Targeting information of delta-aminolevulinate synthase is encoded in non-overlapping regions. J Biol Chem 264(29):17107-12
7) Urban-Grimal D and Labbe-Bois R  (1981) Genetic and biochemical characterization of mutants of Saccharomyces cerevisiae blocked in six different steps of heme biosynthesis. Mol Gen Genet 183(1):85-92
8) Crisp RJ, et al.  (2003) Inhibition of heme biosynthesis prevents transcription of iron uptake genes in yeast. J Biol Chem 278(46):45499-506
9) Volland C and Felix F  (1984) Isolation and properties of 5-aminolevulinate synthase from the yeast Saccharomyces cerevisiae. Eur J Biochem 142(3):551-7
10) Cotter PD, et al.  (1992) Enzymatic defect in "X-linked" sideroblastic anemia: molecular evidence for erythroid delta-aminolevulinate synthase deficiency. Proc Natl Acad Sci U S A 89(9):4028-32
11) Warren MJ and Scott AI  (1990) Tetrapyrrole assembly and modification into the ligands of biologically functional cofactors. Trends Biochem Sci 15(12):486-91
12) Avissar YJ, et al.  (1989) Distribution of delta-aminolevulinic acid biosynthetic pathways among phototrophic bacterial groups. Arch Microbiol 151(6):513-9
13) Sato S, et al.  (2004) Enzymes for heme biosynthesis are found in both the mitochondrion and plastid of the malaria parasite Plasmodium falciparum. Protist 155(1):117-25
14) Borralho LM, et al.  (1990) Purification of delta-aminolevulinate dehydratase from genetically engineered yeast. Yeast 6(4):319-30
15) Keng T, et al.  (1992) Structure and regulation of yeast HEM3, the gene for porphobilinogen deaminase. Mol Gen Genet 234(2):233-43
16) Amillet JM and Labbe-Bois R  (1995) Isolation of the gene HEM4 encoding uroporphyrinogen III synthase in Saccharomyces cerevisiae. Yeast 11(5):419-24
17) Hansen J, et al.  (1997) Siroheme biosynthesis in Saccharomyces cerevisiae requires the products of both the MET1 and MET8 genes. FEBS Lett 401(1):20-4
18) Raux E, et al.  (1999) The role of Saccharomyces cerevisiae Met1p and Met8p in sirohaem and cobalamin biosynthesis. Biochem J 338 ( Pt 3)():701-8