Information on EC 2.3.1.37 - 5-aminolevulinate synthase and Organism(s) Homo sapiens

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Homo sapiens


The expected taxonomic range for this enzyme is: Bacteria, Eukaryota


The taxonomic range for the selected organisms is: Homo sapiens

EC NUMBER
COMMENTARY hide
2.3.1.37
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RECOMMENDED NAME
GeneOntology No.
5-aminolevulinate synthase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
succinyl-CoA + glycine = 5-aminolevulinate + CoA + CO2
show the reaction diagram
mechanism
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Acyl group transfer
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-
-
-
condensation
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
2-amino-3-hydroxycyclopent-2-enone biosynthesis
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tetrapyrrole biosynthesis II (from glycine)
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heme metabolism
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Glycine, serine and threonine metabolism
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Porphyrin and chlorophyll metabolism
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Metabolic pathways
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Biosynthesis of secondary metabolites
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SYSTEMATIC NAME
IUBMB Comments
succinyl-CoA:glycine C-succinyltransferase (decarboxylating)
A pyridoxal-phosphate protein. The enzyme in erythrocytes is genetically distinct from that in other tissues.
CAS REGISTRY NUMBER
COMMENTARY hide
9037-14-3
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
vertebrate genomes encode two highly conserved, but differentially expressed, ALAS genes, a housekeeping gene (ALAS1)5,6 and an erythroid-specific gene (ALAS2)
malfunction
metabolism
the enzyme catalyzes the first and rate-limiting step of heme formation
physiological function
additional information
the N-terminal region, designated as region 2 and encoded by exons 3 and 4 of the human ALAS2 gene, is not required for activity and contains an heme-regulatory motif
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
acetyl-CoA + glycine
?
show the reaction diagram
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at 2% the rate of the reaction with succinyl-CoA
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-
?
alpha-glutamyl-CoA + glycine
6-amino-5-oxohexanoate + CoA + CO2
show the reaction diagram
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at 9% the rate of the reaction with succinyl-CoA
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-
?
succinyl-CoA + glycine
5-aminolevulinate + CoA + CO2
show the reaction diagram
succinyl-CoA-monomethyl ester + glycine
5-aminolevulinic acid methyl ester + CoA + CO2
show the reaction diagram
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at 80% the rate of the reaction with succinyl-CoA
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-
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additional information
?
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enzyme deficiency causes X-linked sideroblastic anemia
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
succinyl-CoA + glycine
5-aminolevulinate + CoA + CO2
show the reaction diagram
additional information
?
-
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enzyme deficiency causes X-linked sideroblastic anemia
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
pyridoxal 5'-phosphate
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Iron
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regulation of erythroid-specific isoform ALAS-2 via 5'-iron responsive element, i.e. IRE
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2-oxoglutarate
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Aminomethylphosphonate
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ferroheme
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Hemin
hemoglobin
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Metalloporphyrins
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containing Co2+, Zn2+ or Mg2+
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myoglobin
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protoheme
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feed-back inhibition, non-specific isoform ALAS-1
pyruvate
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
7.5 - 13.5
glycine
0.0357 - 52.4
succinyl-CoA
additional information
additional information
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
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various tissues, overview
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.4
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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sodium butyrate treatment activates ALAS2 gene transcription
Manually annotated by BRENDA team
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sodium butyrate treatment activates ALAS2 gene transcription
Manually annotated by BRENDA team
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rapid stimulation of ALA-s mRNA by ACTH which acts through cyclic AMP
Manually annotated by BRENDA team
additional information
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enzyme is synthezised in the cytosol as the precursor protein and then imported into the mitochondria matrix and cleaved to the mature enzyme, the targeting information is encoded in nonoverlapping regions of the presequence
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
additional information
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synthesized in microsomes and then migrates to the mitochondria
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Manually annotated by BRENDA team
PDB
SCOP
CATH
UNIPROT
ORGANISM
P22557
Homo sapiens;
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
52000
x * 54000, recombinant wild-type enzyme, SDS-PAGE, x * 52000, recombinant mutant F557X, SDS-PAGE
54000
x * 54000, recombinant wild-type enzyme, SDS-PAGE, x * 52000, recombinant mutant F557X, SDS-PAGE
additional information
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
x * 54000, recombinant wild-type enzyme, SDS-PAGE, x * 52000, recombinant mutant F557X, SDS-PAGE
homodimer
tertiaryy strutcures of wild-type and mutant enzyes, overview
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
proteolytic modification
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first 49 amino acids of enzyme pre-protein are mitochondrial targeting sequence
ubiquitinylation
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ALAS2 appears to be ubiquitinated as rapidly as at is produced
additional information
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
45
t1/2 of the wild-type is 11.7 min, and t1/2 of mutant enzymes are between 3.8 and 12.8 min
additional information
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
short half-life
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OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
ALAS2 is broken down under normoxic conditions by the proteasome
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671812
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant MBP-fusion wild-type and mutant enzymes 29-114fold by amylose affinity chromatography and gel filtration
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in eukaryotic cells
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gene ALAS2, expression of N-terminally His-tagged wild-type enzyme, deletion mutants delAT and delAGTG, and mutant Q548X in Escherichia coli strain BL21(DE3), transient expression of the wild-type enzyme in HeLa cells
liver and erythroid enzyme
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recombinant expression of MBP-fusion wild-type and mutant enzymes
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
analysis of the 5' regulatory region of 5-aminolevulinate synthase gene in variegate porphyria patients heterozygous for the causative R59W mutation in the protoporphyrinogen oxidase gene. In the presence of estrogen and ERalpha, the wild-type -853C/-1253T allele induces a 47% increase in transcription, while the -853T/-1253A double mutant allele showed a 35% increase in transcription. The highest induction is observed for the mutant -853T/1253T allele generating an increase of 66%
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HIF1R knockdown by RNA interference decreased the level of ALAS2 expression. In silico analysis reveal three potential hypoxia-response elements (HREs) that are located 611, 621, and 741 bp downstream of the ALAS2 gene
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increased expression of erythroid specific 5-aminolevulinate synthase ALAS2 and gamma-globin mRNAs after 48 h of hypoxia. Exogenous TGF-beta1 induces hemoglobinization and the expression of ALAS2 mRNA in YN-1-0-A cells, but not of c-globin and mitoferrin mRNAs. A specific inhibitor of intracellular TGF-b signaling markedly reduces the degree of the hypoxia-mediated increase in the expression of ALAS2 mRNA in YN-1-0-A cells
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the relative expression of ALAS1 mRNA, the first and rate-limiting enzyme for heme biosynthesis under normal physiological conditions, is significantly reduced by nearly 90% in patients with Alzheimer's disease compared to control. The relative expression of porphobilinogen deaminase mRNA, the third enzyme in the heme synthesis pathway and a secondary rate-limiting enzyme in heme biosynthesis, is also significantly reduced by nearly 60% in brain of patients with Alzheimer's disease and significantly related to apolipoprotein E genotype. The relative expression of aminolevulinate dehydratase mRNA, the second and a non-rate-limiting enzyme for heme biosynthesis, is unchanged between the two groups
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under hypoxic conditions, significantly increased ALAS2 mRNA and protein levels are detected in K562 cells and erythroid induction cultures of CD34+ hematopoietic stem/progenitor cells
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
F557X
site-directed mutagenesis, a ALAS2 exon 11, c.1670-1671TC>GA mutation
M567I
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mutant shows 25% of wild-type activity, while its half-life is longer than that of wild-type
S568G
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mutant shows decreased catalytic activity in vitro (20% compared to wild-type), but a higher half-life compared to those of wild-type ALAS2
V562A
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mutant shows a higher catalytic activity in vitro, but a shorter half-life in vivo compared to those of wild-type ALAS2
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine