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Protein

Delta-aminolevulinic acid dehydratase

Gene

ALAD

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

Functioni

Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen.2 Publications

Catalytic activityi

2 5-aminolevulinate = porphobilinogen + 2 H2O.3 Publications

Cofactori

Zn2+1 PublicationNote: Binds 8 zinc ions per octamer. Requires four zinc ions per octamer for full catalytic activity. Can bind up to 2 zinc ions per subunit.1 Publication

Enzyme regulationi

Can alternate between a fully active homooctamer and a low-activity homohexamer. A bound magnesium ion may promote the assembly of the fully active homooctamer. The magnesium-binding site is absent in the low-activity homohexamer. Inhibited by compounds that favor the hexameric state. Inhibited by divalent lead ions. The lead ions partially displace the zinc cofactor.3 Publications

Kineticsi

  1. KM=0.09 mM for 5-aminolevulinate at pH 71 Publication
  1. Vmax=43 µmol/h/mg enzyme at pH 71 Publication

pH dependencei

Optimum pH is 6.8-7.3.1 Publication

Pathwayi: protoporphyrin-IX biosynthesis

This protein is involved in step 1 of the subpathway that synthesizes coproporphyrinogen-III from 5-aminolevulinate.
Proteins known to be involved in the 4 steps of the subpathway in this organism are:
  1. Delta-aminolevulinic acid dehydratase (ALAD)
  2. Porphobilinogen deaminase (HMBS)
  3. Uroporphyrinogen-III synthase (UROS)
  4. Uroporphyrinogen decarboxylase (UROD), Uroporphyrinogen decarboxylase (UROD)
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 coproporphyrinogen-III from 5-aminolevulinate, the pathway protoporphyrin-IX biosynthesis and in Porphyrin-containing compound metabolism.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi122Zinc 1; catalytic1
Metal bindingi124Zinc 1; catalytic1
Metal bindingi131Zinc 21
Metal bindingi132Zinc 1; catalytic1
Active sitei199Schiff-base intermediate with substrate1 Publication1
Binding sitei209Substrate 11
Binding sitei221Substrate 11
Metal bindingi223Zinc 21
Active sitei252Schiff-base intermediate with substrate1 Publication1
Binding sitei279Substrate 21
Binding sitei318Substrate 21

GO - Molecular functioni

  • catalytic activity Source: ProtInc
  • identical protein binding Source: UniProtKB
  • lead ion binding Source: UniProtKB
  • porphobilinogen synthase activity Source: UniProtKB
  • zinc ion binding Source: UniProtKB

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Lyase

Keywords - Biological processi

Heme biosynthesis, Porphyrin biosynthesis

Keywords - Ligandi

Metal-binding, Zinc

Enzyme and pathway databases

BioCyciMetaCyc:HS07501-MONOMER.
ZFISH:HS07501-MONOMER.
BRENDAi4.2.1.24. 2681.
ReactomeiR-HSA-189451. Heme biosynthesis.
R-HSA-6798695. Neutrophil degranulation.
UniPathwayiUPA00251; UER00318.

Names & Taxonomyi

Protein namesi
Recommended name:
Delta-aminolevulinic acid dehydratase (EC:4.2.1.24)
Short name:
ALADH
Alternative name(s):
Porphobilinogen synthase
Gene namesi
Name:ALAD
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 9

Organism-specific databases

HGNCiHGNC:395. ALAD.

Subcellular locationi

GO - Cellular componenti

  • cytosol Source: GO_Central
  • extracellular exosome Source: UniProtKB
  • extracellular space Source: Ensembl
  • nucleus Source: UniProtKB
Complete GO annotation...

Pathology & Biotechi

Involvement in diseasei

Acute hepatic porphyria (AHEPP)4 Publications
The disease is caused by mutations affecting the gene represented in this entry.
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. AHP is characterized by attacks of gastrointestinal disturbances, abdominal colic, paralyses and peripheral neuropathy. Most attacks are precipitated by drugs, alcohol, caloric deprivation, infections, or endocrine factors.
See also OMIM:612740
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_003634133G → R in AHEPP; mixture of about 50% hexamer and 50% octamer; about 10% residual activity. 2 PublicationsCorresponds to variant rs121912980dbSNPEnsembl.1
Natural variantiVAR_020974153V → M in AHEPP; about 95% octamer; about 40% residual activity. 2 Publications1
Natural variantiVAR_003635240R → W in AHEPP; mixture of about 80% hexamer and 20% octamer; about 4% residual activity. 3 PublicationsCorresponds to variant rs121912982dbSNPEnsembl.1
Natural variantiVAR_003636274A → T in AHEPP; mixture of about 14% hexamer and 86% octamer; about 20% enzyme residual activity. 3 PublicationsCorresponds to variant rs121912983dbSNPEnsembl.1
Natural variantiVAR_003637275V → M in AHEPP; mainly octamer; reduced activity. 2 PublicationsCorresponds to variant rs121912981dbSNPEnsembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi122C → A: Reduces enzyme activity about 1000000-fold; when associated with A-124 and A-132. 1 Publication1
Mutagenesisi124C → A: Reduces enzyme activity about 1000000-fold; when associated with A-122 and A-132. 1 Publication1
Mutagenesisi131H → A: No effect on catalytic activity; when associated with A-223. 1 Publication1
Mutagenesisi132C → A: Reduces enzyme activity about 1000000-fold; when associated with A-122 and A-124. 1 Publication1
Mutagenesisi223C → A: No effect on catalytic activity; when associated with A-131. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi210.
MalaCardsiALAD.
MIMi612740. phenotype.
OpenTargetsiENSG00000148218.
Orphaneti100924. Porphyria due to ALA dehydratase deficiency.
PharmGKBiPA24687.

Chemistry databases

ChEMBLiCHEMBL3126.
DrugBankiDB00855. Aminolevulinic acid.

Polymorphism and mutation databases

BioMutaiALAD.
DMDMi122833.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001405261 – 330Delta-aminolevulinic acid dehydrataseAdd BLAST330

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei199N6-succinyllysineBy similarity1
Modified residuei215PhosphoserineBy similarity1
Modified residuei252N6-succinyllysineBy similarity1

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiP13716.
MaxQBiP13716.
PaxDbiP13716.
PeptideAtlasiP13716.
PRIDEiP13716.

2D gel databases

OGPiP13716.
REPRODUCTION-2DPAGEP13716.
SWISS-2DPAGEP13716.

PTM databases

iPTMnetiP13716.
PhosphoSitePlusiP13716.
SwissPalmiP13716.

Expressioni

Gene expression databases

BgeeiENSG00000148218.
CleanExiHS_ALAD.
ExpressionAtlasiP13716. baseline and differential.
GenevisibleiP13716. HS.

Organism-specific databases

HPAiHPA021023.
HPA022124.

Interactioni

Subunit structurei

Homooctamer; active form. Homohexamer; low activity form.3 Publications

GO - Molecular functioni

  • identical protein binding Source: UniProtKB

Protein-protein interaction databases

BioGridi106712. 22 interactors.
IntActiP13716. 1 interactor.
STRINGi9606.ENSP00000386284.

Chemistry databases

BindingDBiP13716.

Structurei

Secondary structure

1330
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi8 – 10Combined sources3
Beta strandi11 – 13Combined sources3
Helixi14 – 20Combined sources7
Turni21 – 24Combined sources4
Helixi28 – 30Combined sources3
Beta strandi31 – 37Combined sources7
Beta strandi44 – 46Combined sources3
Beta strandi48 – 50Combined sources3
Beta strandi54 – 56Combined sources3
Helixi58 – 71Combined sources14
Beta strandi75 – 80Combined sources6
Beta strandi83 – 85Combined sources3
Beta strandi88 – 90Combined sources3
Helixi92 – 94Combined sources3
Helixi100 – 111Combined sources12
Beta strandi115 – 121Combined sources7
Helixi124 – 126Combined sources3
Beta strandi127 – 129Combined sources3
Beta strandi131 – 133Combined sources3
Beta strandi137 – 139Combined sources3
Helixi141 – 160Combined sources20
Beta strandi163 – 167Combined sources5
Helixi174 – 184Combined sources11
Turni188 – 190Combined sources3
Beta strandi192 – 194Combined sources3
Beta strandi198 – 200Combined sources3
Helixi203 – 205Combined sources3
Helixi206 – 210Combined sources5
Beta strandi217 – 219Combined sources3
Turni222 – 224Combined sources3
Helixi231 – 243Combined sources13
Beta strandi247 – 253Combined sources7
Helixi255 – 257Combined sources3
Helixi258 – 267Combined sources10
Beta strandi273 – 277Combined sources5
Helixi279 – 290Combined sources12
Helixi296 – 310Combined sources15
Beta strandi313 – 317Combined sources5
Helixi320 – 326Combined sources7
Turni327 – 329Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1E51X-ray2.83A/B1-330[»]
1PV8X-ray2.20A/B1-330[»]
5HMSX-ray2.80A/B1-330[»]
5HNRX-ray2.83A/B1-330[»]
ProteinModelPortaliP13716.
SMRiP13716.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP13716.

Family & Domainsi

Sequence similaritiesi

Belongs to the ALAD family.Curated

Phylogenomic databases

eggNOGiKOG2794. Eukaryota.
COG0113. LUCA.
GeneTreeiENSGT00390000006998.
HOGENOMiHOG000020323.
HOVERGENiHBG001222.
InParanoidiP13716.
KOiK01698.
OMAiMHHATLR.
OrthoDBiEOG091G0FMX.
PhylomeDBiP13716.
TreeFamiTF300665.

Family and domain databases

Gene3Di3.20.20.70. 1 hit.
InterProiIPR001731. ALAD.
IPR030656. ALAD_AS.
IPR013785. Aldolase_TIM.
[Graphical view]
PANTHERiPTHR11458. PTHR11458. 1 hit.
PfamiPF00490. ALAD. 1 hit.
[Graphical view]
PIRSFiPIRSF001415. Porphbilin_synth. 1 hit.
PRINTSiPR00144. DALDHYDRTASE.
SMARTiSM01004. ALAD. 1 hit.
[Graphical view]
PROSITEiPS00169. D_ALA_DEHYDRATASE. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P13716-1) [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
MQPQSVLHSG YFHPLLRAWQ TATTTLNASN LIYPIFVTDV PDDIQPITSL
60 70 80 90 100
PGVARYGVKR LEEMLRPLVE EGLRCVLIFG VPSRVPKDER GSAADSEESP
110 120 130 140 150
AIEAIHLLRK TFPNLLVACD VCLCPYTSHG HCGLLSENGA FRAEESRQRL
160 170 180 190 200
AEVALAYAKA GCQVVAPSDM MDGRVEAIKE ALMAHGLGNR VSVMSYSAKF
210 220 230 240 250
ASCFYGPFRD AAKSSPAFGD RRCYQLPPGA RGLALRAVDR DVREGADMLM
260 270 280 290 300
VKPGMPYLDI VREVKDKHPD LPLAVYHVSG EFAMLWHGAQ AGAFDLKAAV
310 320 330
LEAMTAFRRA GADIIITYYT PQLLQWLKEE
Length:330
Mass (Da):36,295
Last modified:January 1, 1990 - v1
Checksum:iE005F3055F6D9403
GO
Isoform 2 (identifier: P13716-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-38: MQPQSVLHSG...SNLIYPIFVT → MPPTSSTPSL...QSISHPRSCR

Show »
Length:359
Mass (Da):39,034
Checksum:i4AD5F3B2570ACD81
GO

Sequence cautioni

The sequence AAH00977 differs from that shown. Reason: Erroneous initiation.Curated

Polymorphismi

There are two common alleles of ALAD. Individuals heterozygous or homozygous for ALAD*2 Asn-59 have significantly higher blood lead levels than do ALAD*1 Lys-59 homozygotes when exposed to environmental lead.

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_02097312F → L in an asymptomatic patient with ALAD deficiency; also found in a hereditary coproporphyria patient carrying the R-279 mutation in CPOX; hexamer with almost no residual activity. 3 PublicationsCorresponds to variant rs121912984dbSNPEnsembl.1
Natural variantiVAR_00363359K → N in allele ALAD*2; 10% of population; fully active octamer. 3 PublicationsCorresponds to variant rs1800435dbSNPEnsembl.1
Natural variantiVAR_003634133G → R in AHEPP; mixture of about 50% hexamer and 50% octamer; about 10% residual activity. 2 PublicationsCorresponds to variant rs121912980dbSNPEnsembl.1
Natural variantiVAR_020974153V → M in AHEPP; about 95% octamer; about 40% residual activity. 2 Publications1
Natural variantiVAR_003635240R → W in AHEPP; mixture of about 80% hexamer and 20% octamer; about 4% residual activity. 3 PublicationsCorresponds to variant rs121912982dbSNPEnsembl.1
Natural variantiVAR_003636274A → T in AHEPP; mixture of about 14% hexamer and 86% octamer; about 20% enzyme residual activity. 3 PublicationsCorresponds to variant rs121912983dbSNPEnsembl.1
Natural variantiVAR_003637275V → M in AHEPP; mainly octamer; reduced activity. 2 PublicationsCorresponds to variant rs121912981dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0378661 – 38MQPQS…PIFVT → MPPTSSTPSLSRPGLGQAGK PDTGSHPPPTISTSIFLSCF PTIPLSRPRTTGPSHSYQSI SHPRSCR in isoform 2. 1 PublicationAdd BLAST38

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M13928 mRNA. Translation: AAA51687.1.
X64467 Genomic DNA. Translation: CAA45796.1.
S99468 mRNA. Translation: AAC60581.1.
S99471 mRNA. Translation: AAC60582.1.
AK290490 mRNA. Translation: BAF83179.1.
AK312552 mRNA. Translation: BAG35449.1.
AY319481 Genomic DNA. Translation: AAP72012.1.
AL137066 Genomic DNA. Translation: CAH70099.3.
BC000977 mRNA. Translation: AAH00977.3. Different initiation.
CCDSiCCDS6794.2. [P13716-1]
PIRiA26478.
RefSeqiNP_000022.3. NM_000031.5. [P13716-1]
NP_001003945.1. NM_001003945.2. [P13716-2]
XP_011516666.1. XM_011518364.2.
UniGeneiHs.1227.

Genome annotation databases

EnsembliENST00000409155; ENSP00000386284; ENSG00000148218. [P13716-1]
GeneIDi210.
KEGGihsa:210.
UCSCiuc011lxf.3. human. [P13716-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Web resourcesi

NIEHS-SNPs

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M13928 mRNA. Translation: AAA51687.1.
X64467 Genomic DNA. Translation: CAA45796.1.
S99468 mRNA. Translation: AAC60581.1.
S99471 mRNA. Translation: AAC60582.1.
AK290490 mRNA. Translation: BAF83179.1.
AK312552 mRNA. Translation: BAG35449.1.
AY319481 Genomic DNA. Translation: AAP72012.1.
AL137066 Genomic DNA. Translation: CAH70099.3.
BC000977 mRNA. Translation: AAH00977.3. Different initiation.
CCDSiCCDS6794.2. [P13716-1]
PIRiA26478.
RefSeqiNP_000022.3. NM_000031.5. [P13716-1]
NP_001003945.1. NM_001003945.2. [P13716-2]
XP_011516666.1. XM_011518364.2.
UniGeneiHs.1227.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1E51X-ray2.83A/B1-330[»]
1PV8X-ray2.20A/B1-330[»]
5HMSX-ray2.80A/B1-330[»]
5HNRX-ray2.83A/B1-330[»]
ProteinModelPortaliP13716.
SMRiP13716.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi106712. 22 interactors.
IntActiP13716. 1 interactor.
STRINGi9606.ENSP00000386284.

Chemistry databases

BindingDBiP13716.
ChEMBLiCHEMBL3126.
DrugBankiDB00855. Aminolevulinic acid.

PTM databases

iPTMnetiP13716.
PhosphoSitePlusiP13716.
SwissPalmiP13716.

Polymorphism and mutation databases

BioMutaiALAD.
DMDMi122833.

2D gel databases

OGPiP13716.
REPRODUCTION-2DPAGEP13716.
SWISS-2DPAGEP13716.

Proteomic databases

EPDiP13716.
MaxQBiP13716.
PaxDbiP13716.
PeptideAtlasiP13716.
PRIDEiP13716.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000409155; ENSP00000386284; ENSG00000148218. [P13716-1]
GeneIDi210.
KEGGihsa:210.
UCSCiuc011lxf.3. human. [P13716-1]

Organism-specific databases

CTDi210.
DisGeNETi210.
GeneCardsiALAD.
HGNCiHGNC:395. ALAD.
HPAiHPA021023.
HPA022124.
MalaCardsiALAD.
MIMi125270. gene.
612740. phenotype.
neXtProtiNX_P13716.
OpenTargetsiENSG00000148218.
Orphaneti100924. Porphyria due to ALA dehydratase deficiency.
PharmGKBiPA24687.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG2794. Eukaryota.
COG0113. LUCA.
GeneTreeiENSGT00390000006998.
HOGENOMiHOG000020323.
HOVERGENiHBG001222.
InParanoidiP13716.
KOiK01698.
OMAiMHHATLR.
OrthoDBiEOG091G0FMX.
PhylomeDBiP13716.
TreeFamiTF300665.

Enzyme and pathway databases

UniPathwayiUPA00251; UER00318.
BioCyciMetaCyc:HS07501-MONOMER.
ZFISH:HS07501-MONOMER.
BRENDAi4.2.1.24. 2681.
ReactomeiR-HSA-189451. Heme biosynthesis.
R-HSA-6798695. Neutrophil degranulation.

Miscellaneous databases

ChiTaRSiALAD. human.
EvolutionaryTraceiP13716.
GeneWikiiALAD.
GenomeRNAii210.
PROiP13716.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000148218.
CleanExiHS_ALAD.
ExpressionAtlasiP13716. baseline and differential.
GenevisibleiP13716. HS.

Family and domain databases

Gene3Di3.20.20.70. 1 hit.
InterProiIPR001731. ALAD.
IPR030656. ALAD_AS.
IPR013785. Aldolase_TIM.
[Graphical view]
PANTHERiPTHR11458. PTHR11458. 1 hit.
PfamiPF00490. ALAD. 1 hit.
[Graphical view]
PIRSFiPIRSF001415. Porphbilin_synth. 1 hit.
PRINTSiPR00144. DALDHYDRTASE.
SMARTiSM01004. ALAD. 1 hit.
[Graphical view]
PROSITEiPS00169. D_ALA_DEHYDRATASE. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiHEM2_HUMAN
AccessioniPrimary (citable) accession number: P13716
Secondary accession number(s): A8K375
, B2R6F2, Q16870, Q16871, Q9BVQ9
Entry historyi
Integrated into UniProtKB/Swiss-Prot: January 1, 1990
Last sequence update: January 1, 1990
Last modified: November 30, 2016
This is version 188 of the entry and version 1 of the sequence. [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

3D-structure, Allosteric enzyme, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 9
    Human chromosome 9: 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. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.