P22557 (HEM0_HUMAN) Reviewed, UniProtKB/Swiss-Prot
Last modified
January 25, 2012.
Version 134.
History...
Names·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order
Names·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize orderNames and origin
| Protein names | Recommended name: 5-aminolevulinate synthase, erythroid-specific, mitochondrial Short name=ALAS-E EC=2.3.1.37 Alternative name(s): 5-aminolevulinic acid synthase 2 Delta-ALA synthase 2 Delta-aminolevulinate synthase 2 | ||||
| Gene names |
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| Organism | Homo sapiens (Human) | ||||
| Taxonomic identifier | 9606 [NCBI] | ||||
| Taxonomic lineage | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Protein attributes
| Sequence length | 587 AA. |
| Sequence status | Complete. |
| Sequence processing | The displayed sequence is further processed into a mature form. |
| Protein existence | Evidence at protein level |
General annotation (Comments)
| Catalytic activity | Succinyl-CoA + glycine = 5-aminolevulinate + CoA + CO2. |
| Cofactor | Pyridoxal phosphate. |
| Pathway | Porphyrin metabolism; protoporphyrin-IX biosynthesis; 5-aminolevulinate from glycine: step 1/1. |
| Subunit structure | Homodimer. |
| Subcellular location | |
| Tissue specificity | Erythroid specific. |
| Involvement in disease | Defects in ALAS2 are a cause of anemia sideroblastic X-linked (XLSA) [MIM:300751]. Sideroblastic anemia is characterized by anemia of varying severity, hypochromic peripheral erythrocytes, systemic iron overload secondary to chronic ineffective erythropoiesis, and the presence of bone marrow ringed sideroblasts. Sideroblasts are characterized by iron-loaded mitochondria clustered around the nucleus. XLSA shows a variable hematologic response to pharmacologic doses of pyridoxine. Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.13 Ref.15 Defects in ALAS2 are the cause of erythropoietic protoporphyria X-linked dominant (XLDPT) [MIM:300752]. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. XLDPT is a form of porphyria characterized biochemically by a high proportion of zinc-protoporphyrin in erythrocytes, in which a mismatch between protoporphyrin production and the heme requirement of differentiating erythroid cells leads to overproduction of protoporphyrin in amounts sufficient to cause photosensitivity and liver disease. Note=Gain of function mutations in ALS2 are responsible for XLDPT, but they can also be a possible aggravating factor in congenital erythropoietic porphyria and other erythropoietic disorders caused by mutations in other genes (Ref.15). Ref.12 |
| Miscellaneous | There are two delta-ALA synthases in vertebrates: an erythroid- specific form and one (housekeeping) which is expressed in all tissues. |
| Sequence similarities | Belongs to the class-II pyridoxal-phosphate-dependent aminotransferase family. |
| Sequence caution | The sequence CAA39795.1 differs from that shown. Reason: Erroneous initiation. |
Ontologies
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | ||||
Molecule processing | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Transit peptide | 1 – ?49 | 49 | Mitochondrion | ||||||
| Chain | ?50 – 587 | 538 | 5-aminolevulinate synthase, erythroid-specific, mitochondrial | PRO_0000001223 | |||||
Amino acid modifications | |||||||||
| Modified residue | 391 | 1 | N6-(pyridoxal phosphate)lysine Probable | ||||||
Natural variations | |||||||||
| Natural variant | 156 | 1 | K → E in XLSA; significantly reduced activity. Ref.13 | VAR_066232 | |||||
| Natural variant | 159 | 1 | D → Y in XLSA. Ref.11 | VAR_018604 | |||||
| Natural variant | 170 | 1 | R → H in XLSA; significantly increased thermosensitivity. Ref.15 | VAR_066233 | |||||
| Natural variant | 199 | 1 | Y → H in XLSA. Ref.9 | VAR_012334 | |||||
| Natural variant | 204 | 1 | R → Q in XLSA; 15% to 35% activity of wild-type. Ref.8 | VAR_012335 | |||||
| Natural variant | 218 | 1 | R → H in XLSA; significantly increased thermosensitivity. Ref.15 | VAR_066234 | |||||
| Natural variant | 242 | 1 | E → K in XLSA; significantly reduced activity. Ref.15 | VAR_066235 | |||||
| Natural variant | 263 | 1 | D → N in XLSA; significantly reduced activity. Ref.15 | VAR_066236 | |||||
| Natural variant | 339 | 1 | P → L in XLSA; significantly reduced activity. Ref.15 | VAR_066237 | |||||
| Natural variant | 375 | 1 | R → C in XLSA; significantly reduced activity. Ref.15 | VAR_066238 | |||||
| Natural variant | 388 | 1 | T → S in XLSA. Ref.5 | VAR_000562 | |||||
| Natural variant | 411 | 1 | R → C in XLSA; 12% to 25% activity of wild-type. Ref.7 Ref.9 | VAR_000563 | |||||
| Natural variant | 411 | 1 | R → H in XLSA; significantly reduced activity. Ref.15 | VAR_066239 | |||||
| Natural variant | 448 | 1 | R → Q in XLSA. Ref.9 | VAR_012336 | |||||
| Natural variant | 452 | 1 | R → C in XLSA. Ref.9 Ref.13 | VAR_012337 | |||||
| Natural variant | 452 | 1 | R → G in XLSA; does not affect activity. Ref.15 | VAR_066240 | |||||
| Natural variant | 452 | 1 | R → H in XLSA. Ref.13 | VAR_066241 | |||||
| Natural variant | 476 | 1 | I → N in XLSA. Ref.6 | VAR_000564 | |||||
| Natural variant | 520 | 1 | P → L. Ref.15 | VAR_066242 | |||||
| Natural variant | 560 | 1 | R → H in XLSA. Ref.10 | VAR_018605 | |||||
| Natural variant | 572 | 1 | R → H in XLSA; does not affect activity. Ref.15 | VAR_066243 | |||||
| Natural variant | 586 | 1 | Y → F Rare variant found in a congenital erythropoietic porphyria patient that also carries UROS mutations R-73R and Q-248; increased enzyme activity. Ref.14 | VAR_066244 | |||||
Experimental info | |||||||||
| Sequence conflict | 182 | 1 | S → F in CAA39795. Ref.1 | ||||||
Sequences
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References
| « Hide 'large scale' references | |
| [1] | "Two different genes encode delta-aminolevulinate synthase in humans: nucleotide sequences of cDNAs for the housekeeping and erythroid genes." Bishop D.F. Nucleic Acids Res. 18:7187-7188(1990) [PubMed: 2263504] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Liver. |
| [2] | "Human erythroid 5-aminolevulinate synthase: promoter analysis and identification of an iron-responsive element in the mRNA." Cox T.C., Bawden M.J., Martin A., May B.K. EMBO J. 10:1891-1902(1991) [PubMed: 2050125] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Liver. |
| [3] | "Identification and characterization of a conserved erythroid-specific enhancer located in intron 8 of the human 5-aminolevulinate synthase 2 gene." Surinya K.H., Cox T.C., May B.K. J. Biol. Chem. 273:16798-16809(1998) [PubMed: 9642238] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. |
| [4] | "The DNA sequence of the human X chromosome." Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C. Bentley D.R.Nature 434:325-337(2005) [PubMed: 15772651] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. |
| [5] | "X-linked pyridoxine-responsive sideroblastic anemia due to a Thr388-to-Ser substitution in erythroid 5-aminolevulinate synthase." Cox T.C., Bottomley S.S., Wiley J.S., Bawden M.J., Matthews C.S., May B.K. N. Engl. J. Med. 330:675-679(1994) [PubMed: 8107717] [Abstract] Cited for: VARIANT XLSA SER-388. |
| [6] | "Enzymatic defect in 'X-linked' sideroblastic anemia: molecular evidence for erythroid delta-aminolevulinate synthase deficiency." Cotter P.D., Baumann M., Bishop D.F. Proc. Natl. Acad. Sci. U.S.A. 89:4028-4032(1992) [PubMed: 1570328] [Abstract] Cited for: VARIANT XLSA ASN-476. |
| [7] | "R411C mutation of the ALAS2 gene encodes a pyridoxine-responsive enzyme with low activity." Furuyama K., Uno R., Urabe A., Hayashi N., Fujita H., Kondo M., Sassa S., Yamamoto M. Br. J. Haematol. 103:839-841(1998) [PubMed: 9858242] [Abstract] Cited for: VARIANT XLSA CYS-411. |
| [8] | "A novel mutation of the erythroid-specific gamma-aminolevulinate synthase gene in a patient with non-inherited pyridoxine-responsive sideroblastic anemia." Harigae H., Furuyama K., Kudo K., Hayashi N., Yamamoto M., Sassa S., Sasaki T. Am. J. Hematol. 62:112-114(1999) [PubMed: 10577279] [Abstract] Cited for: VARIANT XLSA GLN-204. |
| [9] | "Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis." Cotter P.D., May A., Li L., Al-Sabah A.I., Fitzsimons E.J., Cazzola M., Bishop D.F. Blood 93:1757-1769(1999) [PubMed: 10029606] [Abstract] Cited for: VARIANTS XLSA HIS-199; CYS-411; GLN-448 AND CYS-452. |
| [10] | "Absent phenotypic expression of X-linked sideroblastic anemia in one of 2 brothers with a novel ALAS2 mutation." Cazzola M., May A., Bergamaschi G., Cerani P., Ferrillo S., Bishop D.F. Blood 100:4236-4238(2002) [PubMed: 12393718] [Abstract] Cited for: VARIANT XLSA HIS-560. |
| [11] | "A novel mutation in exon 5 of the ALAS2 gene results in X-linked sideroblastic anemia." Hurford M.T., Marshall-Taylor C., Vicki S.L., Zhou J.Z., Silverman L.M., Rezuke W.N., Altman A., Tsongalis G.J. Clin. Chim. Acta 321:49-53(2002) [PubMed: 12031592] [Abstract] Cited for: VARIANT XLSA TYR-159. |
| [12] | "C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload." Whatley S.D., Ducamp S., Gouya L., Grandchamp B., Beaumont C., Badminton M.N., Elder G.H., Holme S.A., Anstey A.V., Parker M., Corrigall A.V., Meissner P.N., Hift R.J., Marsden J.T., Ma Y., Mieli-Vergani G., Deybach J.C., Puy H. Am. J. Hum. Genet. 83:408-414(2008) [PubMed: 18760763] [Abstract] Cited for: INVOLVEMENT IN XLDPT. |
| [13] | "New mutation in erythroid-specific delta-aminolevulinate synthase as the cause of X-linked sideroblastic anemia responsive to pyridoxine." Kucerova J., Horvathova M., Mojzikova R., Belohlavkova P., Cermak J., Divoky V. Acta Haematol. 125:193-197(2011) [PubMed: 21252495] [Abstract] Cited for: VARIANTS XLSA GLU-156; CYS-452 AND HIS-452, CHARACTERIZATION OF VARIANT XLSA GLU-156. |
| [14] | "ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria." To-Figueras J., Ducamp S., Clayton J., Badenas C., Delaby C., Ged C., Lyoumi S., Gouya L., de Verneuil H., Beaumont C., Ferreira G.C., Deybach J.C., Herrero C., Puy H. Blood 118:1443-1451(2011) [PubMed: 21653323] [Abstract] Cited for: VARIANT PHE-586, CHARACTERIZATION OF VARIANT PHE-586, POSSIBLE ROLE AS MODIFIER GENE IN ERYTHROPOIETIC DISORDERS. |
| [15] | "Sideroblastic anemia: molecular analysis of the ALAS2 gene in a series of 29 probands and functional studies of 10 missense mutations." Ducamp S., Kannengiesser C., Touati M., Garcon L., Guerci-Bresler A., Guichard J.F., Vermylen C., Dochir J., Poirel H.A., Fouyssac F., Mansuy L., Leroux G., Tertian G., Girot R., Heimpel H., Matthes T., Talbi N., Deybach J.C. Grandchamp B.Hum. Mutat. 32:590-597(2011) [PubMed: 21309041] [Abstract] Cited for: VARIANTS XLSA HIS-170; HIS-218; LYS-242; ASN-263; LEU-339; CYS-375; HIS-411; GLY-452 AND HIS-572, VARIANT LEU-520, CHARACTERIZATION OF VARIANTS XLSA HIS-170; HIS-218; LYS-242; ASN-263; LEU-339; CYS-375; HIS-411; GLY-452 AND HIS-572. |
| + | Additional computationally mapped references. |
Web resources
Cross-references
Sequence databases | |
|---|---|
| EMBL GenBank DDBJ | X56352 mRNA. Translation: CAA39795.1. Different initiation. X60364 mRNA. Translation: CAA42916.1. AF068624 Genomic DNA. Translation: AAC39838.1. Z83821 Genomic DNA. No translation available. AL020991 Genomic DNA. Translation: CAA15886.1. |
| IPI | IPI00304949. |
| PIR | SYHUAE. S16347. |
| RefSeq | NP_000023.2. NM_000032.4. |
| UniGene | Hs.522666. Hs.555936. |
3D structure databases | |
| ProteinModelPortal | P22557. |
| SMR | P22557. Positions 1-49, 144-542. |
| ModBase | Search... |
Protein-protein interaction databases | |
| IntAct | P22557. 1 interaction. |
| STRING | P22557. |
PTM databases | |
| PhosphoSite | P22557. |
Polymorphism databases | |
| DMDM | 20141346. |
Proteomic databases | |
| PRIDE | P22557. |
Protocols and materials databases | |
| StructuralBiologyKnowledgebase | Search... |
Genome annotation databases | |
| Ensembl | ENST00000330807; ENSP00000332369; ENSG00000158578. |
| GeneID | 212. |
| KEGG | hsa:212. |
| UCSC | uc004dua.2. human. |
Organism-specific databases | |
| CTD | 212. |
| GeneCards | GC0XM055053. |
| H-InvDB | HIX0016826. |
| HGNC | HGNC:397. ALAS2. |
| HPA | HPA001638. |
| MIM | 300751. phenotype. 300752. phenotype. 301300. gene. |
| neXtProt | NX_P22557. |
| Orphanet | 79278. Erythropoietic protoporphyria. 75563. X-linked sideroblastic anemia. |
| GenAtlas | Search... |
Phylogenomic databases | |
| eggNOG | prNOG08438. |
| HOGENOM | HBG649839. |
| HOVERGEN | HBG005954. |
| InParanoid | P22557. |
| OMA | HLKESNE. |
| OrthoDB | EOG4H19VB. |
| PhylomeDB | P22557. |
Enzyme and pathway databases | |
| Reactome | REACT_111217. Metabolism. |
Gene expression databases | |
| ArrayExpress | P22557. |
| Bgee | P22557. |
| CleanEx | HS_ALAS2. |
| Genevestigator | P22557. |
| GermOnline | ENSG00000158578. Homo sapiens. |
Family and domain databases | |
| InterPro | IPR010961. 4pyrrol_synth_NH2levulA_synth. IPR015118. 5aminolev_synth_preseq. IPR001917. Aminotrans_II_pyridoxalP_BS. IPR004839. Aminotransferase_I/II. IPR015424. PyrdxlP-dep_Trfase_major_dom. IPR015421. PyrdxlP-dep_Trfase_major_sub1. IPR015422. PyrdxlP-dep_Trfase_major_sub2. [Graphical view] |
| Gene3D | G3DSA:3.40.640.10. PyrdxlP-dep_Trfase_major_sub1. 1 hit. G3DSA:3.90.1150.10. PyrdxlP-dep_Trfase_major_sub2. 1 hit. |
| KO | K00643. |
| Pfam | PF00155. Aminotran_1_2. 1 hit. PF09029. Preseq_ALAS. 1 hit. [Graphical view] |
| SUPFAM | SSF53383. PyrdxlP-dep_Trfase_major. 1 hit. |
| TIGRFAMs | TIGR01821. 5aminolev_synth. 1 hit. |
| PROSITE | PS00599. AA_TRANSFER_CLASS_2. 1 hit. [Graphical view] |
| ProtoNet | Search... |
Other | |
| DrugBank | DB00145. Glycine. |
| NextBio | 852. |
| SOURCE | Search... |
Entry information
| Entry name | HEM0_HUMAN | ||||||||
| Accession | Primary (citable) accession number: P22557 Secondary accession number(s): Q13735 | ||||||||
| Entry history |
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| Entry status | Reviewed (UniProtKB/Swiss-Prot) | ||||||||
| Annotation program | Chordata Protein Annotation Program | ||||||||
| Disclaimer | Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. | ||||||||
Relevant documents
| Human chromosome X Human chromosome X: entries, gene names and cross-references to MIM |
| Human entries with polymorphisms or disease mutations List of human entries with polymorphisms or disease mutations |
| Human polymorphisms and disease mutations Index of human polymorphisms and disease mutations |
| MIM cross-references Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot |
| PATHWAY comments Index of metabolic and biosynthesis pathways |
| SIMILARITY comments Index of protein domains and families |

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