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Protein

5-aminolevulinate synthase, erythroid-specific, mitochondrial

Gene

ALAS2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Miscellaneous

There are two delta-ALA synthases in vertebrates: an erythroid- specific form and one (housekeeping) which is expressed in all tissues.

Catalytic activityi

Succinyl-CoA + glycine = 5-aminolevulinate + CoA + CO2.1 Publication

Cofactori

Pathwayi: protoporphyrin-IX biosynthesis

This protein is involved in step 1 of the subpathway that synthesizes 5-aminolevulinate from glycine.
Proteins known to be involved in this subpathway in this organism are:
  1. 5-aminolevulinate synthase, nonspecific, mitochondrial (ALAS1), 5-aminolevulinate synthase (ALAS1), 5-aminolevulinate synthase, erythroid-specific, mitochondrial (ALAS2)
This subpathway is part of the pathway protoporphyrin-IX biosynthesis, which is itself part of Porphyrin-containing compound metabolism.
View all proteins of this organism that are known to be involved in the subpathway that synthesizes 5-aminolevulinate from glycine, the pathway protoporphyrin-IX biosynthesis and in Porphyrin-containing compound metabolism.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei163SubstrateBy similarity1
Binding sitei280SubstrateBy similarity1
Binding sitei299SubstrateBy similarity1
Binding sitei332Pyridoxal phosphateBy similarity1
Binding sitei360Pyridoxal phosphateBy similarity1
Binding sitei388Pyridoxal phosphateBy similarity1
Active sitei391By similarity1
Binding sitei420Pyridoxal phosphate; shared with dimeric partnerBy similarity1
Binding sitei421Pyridoxal phosphate; shared with dimeric partnerBy similarity1
Binding sitei508SubstrateBy similarity1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionAcyltransferase, Transferase
Biological processHeme biosynthesis
LigandPyridoxal phosphate

Enzyme and pathway databases

BioCyciMetaCyc:HS08311-MONOMER.
BRENDAi2.3.1.37. 2681.
ReactomeiR-HSA-189451. Heme biosynthesis.
UniPathwayiUPA00251; UER00375.

Names & Taxonomyi

Protein namesi
Recommended name:
5-aminolevulinate synthase, erythroid-specific, mitochondrial (EC:2.3.1.37)
Short name:
ALAS-E
Alternative name(s):
5-aminolevulinic acid synthase 2
Delta-ALA synthase 2
Delta-aminolevulinate synthase 2
Gene namesi
Name:ALAS2
Synonyms:ALASE, ASB
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome X

Organism-specific databases

EuPathDBiHostDB:ENSG00000158578.18.
HGNCiHGNC:397. ALAS2.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Mitochondrion

Pathology & Biotechi

Involvement in diseasei

Anemia, sideroblastic, 1 (SIDBA1)10 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of sideroblastic anemia that shows a variable hematologic response to pharmacologic doses of pyridoxine. 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.
See also OMIM:300751
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_066232156K → E in SIDBA1; significantly reduced activity. 1 Publication1
Natural variantiVAR_018604159D → Y in SIDBA1. 1 PublicationCorresponds to variant dbSNP:rs137852308Ensembl.1
Natural variantiVAR_072328165F → L in SIDBA1. 1 PublicationCorresponds to variant dbSNP:rs137852301Ensembl.1
Natural variantiVAR_072329170R → C in SIDBA1. 1 Publication1
Natural variantiVAR_066233170R → H in SIDBA1; significantly increased thermosensitivity. 1 Publication1
Natural variantiVAR_012334199Y → H in SIDBA1. 1 PublicationCorresponds to variant dbSNP:rs137852310Ensembl.1
Natural variantiVAR_012335204R → Q in SIDBA1; 15% to 35% activity of wild-type. 1 Publication1
Natural variantiVAR_066234218R → H in SIDBA1; significantly increased thermosensitivity. 1 PublicationCorresponds to variant dbSNP:rs185504937Ensembl.1
Natural variantiVAR_066235242E → K in SIDBA1; significantly reduced activity. 1 Publication1
Natural variantiVAR_066236263D → N in SIDBA1; significantly reduced activity. 1 Publication1
Natural variantiVAR_072330301V → A in SIDBA1. 1 Publication1
Natural variantiVAR_066237339P → L in SIDBA1; significantly reduced activity. 1 Publication1
Natural variantiVAR_066238375R → C in SIDBA1; significantly reduced activity. 1 Publication1
Natural variantiVAR_000562388T → S in SIDBA1. 1 PublicationCorresponds to variant dbSNP:rs137852300Ensembl.1
Natural variantiVAR_000563411R → C in SIDBA1; 12% to 25% activity of wild-type. 3 PublicationsCorresponds to variant dbSNP:rs137852305Ensembl.1
Natural variantiVAR_066239411R → H in SIDBA1; significantly reduced activity. 1 Publication1
Natural variantiVAR_012336448R → Q in SIDBA1. 1 Publication1
Natural variantiVAR_012337452R → C in SIDBA1. 2 PublicationsCorresponds to variant dbSNP:rs137852311Ensembl.1
Natural variantiVAR_066240452R → G in SIDBA1; does not affect activity. 2 Publications1
Natural variantiVAR_066241452R → H in SIDBA1. 1 PublicationCorresponds to variant dbSNP:rs863223904Ensembl.1
Natural variantiVAR_000564476I → N in SIDBA1. 1 PublicationCorresponds to variant dbSNP:rs137852299Ensembl.1
Natural variantiVAR_072331517R → G in SIDBA1. 1 Publication1
Natural variantiVAR_066242520P → L in SIDBA1. 2 PublicationsCorresponds to variant dbSNP:rs201062903Ensembl.1
Natural variantiVAR_018605560R → H in SIDBA1. 1 Publication1
Natural variantiVAR_066243572R → H in SIDBA1; does not affect activity. 1 Publication1
Erythropoietic protoporphyria, X-linked dominant (XLDPT)1 Publication
The disease is caused by mutations affecting the gene represented in this entry. 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 (PubMed:21309041).1 Publication
Disease descriptionA form of porphyria. 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 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.
See also OMIM:300752

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi212.
GeneReviewsiALAS2.
MalaCardsiALAS2.
MIMi300751. phenotype.
300752. phenotype.
OpenTargetsiENSG00000158578.
Orphaneti79278. Erythropoietic protoporphyria.
75563. X-linked sideroblastic anemia.
PharmGKBiPA24689.

Chemistry databases

DrugBankiDB00145. Glycine.
DB00114. Pyridoxal Phosphate.

Polymorphism and mutation databases

BioMutaiALAS2.
DMDMi20141346.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transit peptidei1 – 49Mitochondrion1 PublicationAdd BLAST49
ChainiPRO_000000122350 – 5875-aminolevulinate synthase, erythroid-specific, mitochondrialAdd BLAST538

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei391N6-(pyridoxal phosphate)lysineBy similarity1

Proteomic databases

MaxQBiP22557.
PaxDbiP22557.
PeptideAtlasiP22557.
PRIDEiP22557.

PTM databases

iPTMnetiP22557.
PhosphoSitePlusiP22557.

Expressioni

Tissue specificityi

Erythroid specific.

Gene expression databases

BgeeiENSG00000158578.
CleanExiHS_ALAS2.
ExpressionAtlasiP22557. baseline and differential.
GenevisibleiP22557. HS.

Organism-specific databases

HPAiHPA001638.

Interactioni

Subunit structurei

Homodimer. Interacts with SUCLA2.1 Publication

Binary interactionsi

Show more details

Protein-protein interaction databases

BioGridi106714. 3 interactors.
IntActiP22557. 2 interactors.
STRINGi9606.ENSP00000332369.

Structurei

3D structure databases

ProteinModelPortaliP22557.
SMRiP22557.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Keywords - Domaini

Transit peptide

Phylogenomic databases

eggNOGiKOG1360. Eukaryota.
COG0156. LUCA.
GeneTreeiENSGT00530000063111.
HOGENOMiHOG000221020.
HOVERGENiHBG005954.
InParanoidiP22557.
KOiK00643.
OMAiKQDHTYR.
OrthoDBiEOG091G043U.
PhylomeDBiP22557.
TreeFamiTF300724.

Family and domain databases

Gene3Di3.40.640.10. 1 hit.
3.90.1150.10. 1 hit.
InterProiView protein in InterPro
IPR010961. 4pyrrol_synth_NH2levulA_synth.
IPR015118. 5aminolev_synth_preseq.
IPR001917. Aminotrans_II_pyridoxalP_BS.
IPR004839. Aminotransferase_I/II.
IPR015424. PyrdxlP-dep_Trfase.
IPR015421. PyrdxlP-dep_Trfase_major_sub1.
IPR015422. PyrdxlP-dep_Trfase_sub2.
PfamiView protein in Pfam
PF00155. Aminotran_1_2. 1 hit.
PF09029. Preseq_ALAS. 1 hit.
SUPFAMiSSF53383. SSF53383. 1 hit.
TIGRFAMsiTIGR01821. 5aminolev_synth. 1 hit.
PROSITEiView protein in PROSITE
PS00599. AA_TRANSFER_CLASS_2. 1 hit.

Sequences (4)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P22557-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MVTAAMLLQC CPVLARGPTS LLGKVVKTHQ FLFGIGRCPI LATQGPNCSQ
60 70 80 90 100
IHLKATKAGG DSPSWAKGHC PFMLSELQDG KSKIVQKAAP EVQEDVKAFK
110 120 130 140 150
TDLPSSLVSV SLRKPFSGPQ EQEQISGKVT HLIQNNMPGN YVFSYDQFFR
160 170 180 190 200
DKIMEKKQDH TYRVFKTVNR WADAYPFAQH FSEASVASKD VSVWCSNDYL
210 220 230 240 250
GMSRHPQVLQ ATQETLQRHG AGAGGTRNIS GTSKFHVELE QELAELHQKD
260 270 280 290 300
SALLFSSCFV ANDSTLFTLA KILPGCEIYS DAGNHASMIQ GIRNSGAAKF
310 320 330 340 350
VFRHNDPDHL KKLLEKSNPK IPKIVAFETV HSMDGAICPL EELCDVSHQY
360 370 380 390 400
GALTFVDEVH AVGLYGSRGA GIGERDGIMH KIDIISGTLG KAFGCVGGYI
410 420 430 440 450
ASTRDLVDMV RSYAAGFIFT TSLPPMVLSG ALESVRLLKG EEGQALRRAH
460 470 480 490 500
QRNVKHMRQL LMDRGLPVIP CPSHIIPIRV GNAALNSKLC DLLLSKHGIY
510 520 530 540 550
VQAINYPTVP RGEELLRLAP SPHHSPQMME DFVEKLLLAW TAVGLPLQDV
560 570 580
SVAACNFCRR PVHFELMSEW ERSYFGNMGP QYVTTYA
Length:587
Mass (Da):64,633
Last modified:January 23, 2002 - v2
Checksum:iFD821BE245C440B5
GO
Isoform 2 (identifier: P22557-2) [UniParc]FASTAAdd to basket
Also known as: Delta4

The sequence of this isoform differs from the canonical sequence as follows:
     102-138: Missing.

Note: Constitutes 35-45% of erythrocytes ALAS2 mRNAs. Catalytic activity is 70% of isoform 1 activity.
Show »
Length:550
Mass (Da):60,589
Checksum:iBB28A593D343264F
GO
Isoform 3 (identifier: P22557-3) [UniParc]FASTAAdd to basket
Also known as: F143M

The sequence of this isoform differs from the canonical sequence as follows:
     1-142: Missing.
     143-143: F → M

Note: Catalytic activity is 80% of isoform 1 activity.
Show »
Length:445
Mass (Da):49,395
Checksum:i3304747E4DE0CC2E
GO
Isoform 4 (identifier: P22557-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MRGGEVALGWNKKKRLFCEDFRFKM
     102-138: Missing.

Show »
Length:574
Mass (Da):63,487
Checksum:i7F5E13D5F36738CD
GO

Sequence cautioni

The sequence CAA39795 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti182S → F in CAA39795 (PubMed:2263504).Curated1
Sequence conflicti221A → V in AAH30230 (PubMed:15489334).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_066232156K → E in SIDBA1; significantly reduced activity. 1 Publication1
Natural variantiVAR_018604159D → Y in SIDBA1. 1 PublicationCorresponds to variant dbSNP:rs137852308Ensembl.1
Natural variantiVAR_072328165F → L in SIDBA1. 1 PublicationCorresponds to variant dbSNP:rs137852301Ensembl.1
Natural variantiVAR_072329170R → C in SIDBA1. 1 Publication1
Natural variantiVAR_066233170R → H in SIDBA1; significantly increased thermosensitivity. 1 Publication1
Natural variantiVAR_012334199Y → H in SIDBA1. 1 PublicationCorresponds to variant dbSNP:rs137852310Ensembl.1
Natural variantiVAR_012335204R → Q in SIDBA1; 15% to 35% activity of wild-type. 1 Publication1
Natural variantiVAR_066234218R → H in SIDBA1; significantly increased thermosensitivity. 1 PublicationCorresponds to variant dbSNP:rs185504937Ensembl.1
Natural variantiVAR_066235242E → K in SIDBA1; significantly reduced activity. 1 Publication1
Natural variantiVAR_066236263D → N in SIDBA1; significantly reduced activity. 1 Publication1
Natural variantiVAR_072330301V → A in SIDBA1. 1 Publication1
Natural variantiVAR_066237339P → L in SIDBA1; significantly reduced activity. 1 Publication1
Natural variantiVAR_066238375R → C in SIDBA1; significantly reduced activity. 1 Publication1
Natural variantiVAR_000562388T → S in SIDBA1. 1 PublicationCorresponds to variant dbSNP:rs137852300Ensembl.1
Natural variantiVAR_000563411R → C in SIDBA1; 12% to 25% activity of wild-type. 3 PublicationsCorresponds to variant dbSNP:rs137852305Ensembl.1
Natural variantiVAR_066239411R → H in SIDBA1; significantly reduced activity. 1 Publication1
Natural variantiVAR_012336448R → Q in SIDBA1. 1 Publication1
Natural variantiVAR_012337452R → C in SIDBA1. 2 PublicationsCorresponds to variant dbSNP:rs137852311Ensembl.1
Natural variantiVAR_066240452R → G in SIDBA1; does not affect activity. 2 Publications1
Natural variantiVAR_066241452R → H in SIDBA1. 1 PublicationCorresponds to variant dbSNP:rs863223904Ensembl.1
Natural variantiVAR_000564476I → N in SIDBA1. 1 PublicationCorresponds to variant dbSNP:rs137852299Ensembl.1
Natural variantiVAR_072331517R → G in SIDBA1. 1 Publication1
Natural variantiVAR_066242520P → L in SIDBA1. 2 PublicationsCorresponds to variant dbSNP:rs201062903Ensembl.1
Natural variantiVAR_018605560R → H in SIDBA1. 1 Publication1
Natural variantiVAR_066243572R → H in SIDBA1; does not affect activity. 1 Publication1
Natural variantiVAR_066244586Y → F Rare variant found in a congenital erythropoietic porphyria patient that also carries UROS mutations R-73 and Q-248; increased enzyme activity. 1 PublicationCorresponds to variant dbSNP:rs139596860Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0428511 – 142Missing in isoform 3. CuratedAdd BLAST142
Alternative sequenceiVSP_0473301M → MRGGEVALGWNKKKRLFCED FRFKM in isoform 4. 1 Publication1
Alternative sequenceiVSP_042852102 – 138Missing in isoform 2 and isoform 4. 2 PublicationsAdd BLAST37
Alternative sequenceiVSP_042853143F → M in isoform 3. Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X56352 mRNA. Translation: CAA39795.1. Different initiation.
X60364 mRNA. Translation: CAA42916.1.
AF068624 Genomic DNA. Translation: AAC39838.1.
AK290565 mRNA. Translation: BAF83254.1.
AK291589 mRNA. Translation: BAF84278.1.
AK313118 mRNA. Translation: BAG35939.1.
Z83821 Genomic DNA. No translation available.
AL020991 Genomic DNA. Translation: CAA15886.1.
AL020991 Genomic DNA. Translation: CAX15017.1.
CH471154 Genomic DNA. Translation: EAW93211.1.
CH471154 Genomic DNA. Translation: EAW93213.1.
BC030230 mRNA. Translation: AAH30230.2.
CCDSiCCDS14366.1. [P22557-1]
CCDS35303.1. [P22557-2]
CCDS43960.1. [P22557-4]
PIRiS16347. SYHUAE.
RefSeqiNP_000023.2. NM_000032.4. [P22557-1]
NP_001033056.1. NM_001037967.3. [P22557-2]
NP_001033057.1. NM_001037968.3. [P22557-4]
UniGeneiHs.522666.
Hs.555936.

Genome annotation databases

EnsembliENST00000330807; ENSP00000332369; ENSG00000158578. [P22557-1]
ENST00000335854; ENSP00000337131; ENSG00000158578. [P22557-2]
ENST00000396198; ENSP00000379501; ENSG00000158578. [P22557-4]
GeneIDi212.
KEGGihsa:212.
UCSCiuc004dua.4. human. [P22557-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiHEM0_HUMAN
AccessioniPrimary (citable) accession number: P22557
Secondary accession number(s): A8K3F0
, A8K6C4, Q13735, Q5JZF5, Q8N6H3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 1, 1991
Last sequence update: January 23, 2002
Last modified: September 27, 2017
This is version 186 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome X
    Human chromosome X: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  6. SIMILARITY comments
    Index of protein domains and families