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Literature summary extracted from

  • Fratz, E.J.; Clayton, J.; Hunter, G.A.; Ducamp, S.; Breydo, L.; Uversky, V.N.; Deybach, J.C.; Gouya, L.; Puy, H.; Ferreira, G.C.
    Human erythroid 5-aminolevulinate synthase mutations associated with X-linked protoporphyria disrupt the conformational equilibrium and enhance product release (2015), Biochemistry, 54, 5617-5631.
    View publication on PubMedView publication on EuropePMC

Cloned(Commentary)

EC Number Cloned (Comment) Organism
2.3.1.37 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 Homo sapiens

Protein Variants

EC Number Protein Variants Comment Organism
2.3.1.37 additional information generation of X-linked protoporphyria-related deletion mutants delAT and delAGTG, the mutant delAGTG has a significantly increased affinity for the glycine substrate Homo sapiens
2.3.1.37 Q548X site-directed mutagenesis, an X-linked protoporphyria-related mutant Homo sapiens

KM Value [mM]

EC Number KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
2.3.1.37 additional information
-
 additional information Michaelis-Menten steady-state kinetics, two-step sequential kinetic mechanism , and thermodynamics. Both the reaction for wild-type hALAS2 and those for the X-linked protoporphyria variants comprised a single kinetic step associated with quinonoid intermediate formation followed by one decay step. Rates for the two steps range from 9.8-14.3/s and from 1.37-1.97 s for the reactions of the XLPP variants, whereas those for the wild-type hALAS2-catalyzed reaction are 6.6/s and 0.70/s Homo sapiens

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
2.3.1.37 mitochondrion
-
 Homo sapiens 5739
-

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.3.1.37 succinyl-CoA + glycine Homo sapiens
-
 5-aminolevulinate + CoA + CO2
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
2.3.1.37 Homo sapiens P22557 erythroid-specific gene ALAS2; erythroid-specific gene hALAS2
-

Source Tissue

EC Number Source Tissue Comment Organism Textmining
2.3.1.37 erythroid cell
-
 Homo sapiens
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.3.1.37 succinyl-CoA + glycine
-
 Homo sapiens 5-aminolevulinate + CoA + CO2
-
 ?

Subunits

EC Number Subunits Comment Organism
2.3.1.37 homodimer tertiary structures of wild-type and mutant enzymes, overview Homo sapiens

Synonyms

EC Number Synonyms Comment Organism
2.3.1.37 ALAS
-
 Homo sapiens

Temperature Stability [°C]

EC Number Temperature Stability Minimum [°C] Temperature Stability Maximum [°C] Comment Organism
2.3.1.37 additional information
-
 t1/2 is 48.6°C, 52.5°C, 49.9°C, and 51.4°C for wild-type hALAS2, delAT, delAGTG, and Q548X, respectively Homo sapiens

Cofactor

EC Number Cofactor Comment Organism Structure
2.3.1.37 pyridoxal 5'-phosphate dependent on, succinyl-CoA binding effects the cofactor-binding site of wild-type and mutant enzymes and induces distinct changes to the chiral environment of the cofactor, overview Homo sapiens

General Information

EC Number General Information Comment Organism
2.3.1.37 evolution vertebrate genomes encode two highly conserved, but differentially expressed, ALAS genes, a housekeeping gene (ALAS1)5,6 and an erythroid-specific gene (ALAS2) Homo sapiens
2.3.1.37 malfunction mutations in the C-terminal region of human erythroid-specific enzyme ALAS are associated with X-linked protoporphyria, a disease characterized by extreme photosensitivity, with elevated blood concentrations of free protoporphyrin IX and zinc protoporphyrin. The protein conformational transition step associated with product release is predominantly affected, because the mutations alter the microenvironment of the pyridoxal 5'-phosphate cofactor, which undergoes further and specific alterations upon succinyl-CoA binding. This results in enhanced activities of the XLPP mutant enzyme variants due to accelerations in the rate at which the product 5-aminolevulinate is released from the enzyme. The erythroid 5-aminolevulinate synthase mutations disrupt the conformational equilibrium. Molecular mechanism, overview Homo sapiens
2.3.1.37 metabolism the enzyme catalyzes the first and rate-limiting step of heme formation Homo sapiens
2.3.1.37 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 Homo sapiens
2.3.1.37 physiological function the extended C-terminus of wild-type mammalian ALAS2 provides a regulatory role that allows for allosteric modulation of activity, thereby controlling the rate of erythroid heme biosynthesis, regulation of 5-aminolevulinate synthase is at the origin of balanced heme production in mammals Homo sapiens