ID   HEM2_RAT                Reviewed;         330 AA.
AC   P06214;
DT   01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
DT   01-JAN-1988, sequence version 1.
DT   27-MAR-2024, entry version 162.
DE   RecName: Full=Delta-aminolevulinic acid dehydratase;
DE            Short=ALADH;
DE            EC=4.2.1.24;
DE   AltName: Full=Porphobilinogen synthase;
GN   Name=Alad;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Liver;
RX   PubMed=3808948; DOI=10.1093/nar/14.24.10115;
RA   Bishop T.R., Frelin L.P., Boyer S.H.;
RT   "Nucleotide sequence of rat liver delta-aminolevulinic acid dehydratase
RT   cDNA.";
RL   Nucleic Acids Res. 14:10115-10115(1986).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Prostate;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 1-45.
RX   PubMed=3502704; DOI=10.1073/pnas.83.15.5568;
RA   Bishop T.R., Cohen P.J., Boyer S.H., Noyes A.N., Frelin L.P.;
RT   "Isolation of a rat liver delta-aminolevulinate dehydrase (ALAD) cDNA
RT   clone: evidence for unequal ALAD gene dosage among inbred mouse strains.";
RL   Proc. Natl. Acad. Sci. U.S.A. 83:5568-5572(1986).
RN   [4]
RP   PROTEIN SEQUENCE OF 56-84 AND 200-209, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY.
RC   STRAIN=Sprague-Dawley; TISSUE=Spinal cord;
RA   Lubec G., Afjehi-Sadat L.;
RL   Submitted (NOV-2006) to UniProtKB.
CC   -!- FUNCTION: Catalyzes an early step in the biosynthesis of tetrapyrroles.
CC       Binds two molecules of 5-aminolevulinate per subunit, each at a
CC       distinct site, and catalyzes their condensation to form porphobilinogen
CC       (By similarity). {ECO:0000250}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=2 5-aminolevulinate = H(+) + 2 H2O + porphobilinogen;
CC         Xref=Rhea:RHEA:24064, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:58126, ChEBI:CHEBI:356416; EC=4.2.1.24;
CC   -!- COFACTOR:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC       Note=Binds 8 zinc ions per octamer. Requires four zinc ions per octamer
CC       for full catalytic activity. Can bind up to 2 zinc ions per subunit.
CC       {ECO:0000250};
CC   -!- ACTIVITY REGULATION: Can alternate between a fully active homooctamer
CC       and a low-activity homohexamer. A bound magnesium ion may promote the
CC       assembly of the fully active homooctamer. The magnesium-binding site is
CC       absent in the low-activity homohexamer. Inhibited by compounds that
CC       favor the hexameric state. Inhibited by divalent lead ions. The lead
CC       ions partially displace the zinc cofactor (By similarity).
CC       {ECO:0000250}.
CC   -!- PATHWAY: Porphyrin-containing compound metabolism; protoporphyrin-IX
CC       biosynthesis; coproporphyrinogen-III from 5-aminolevulinate: step 1/4.
CC   -!- SUBUNIT: Homooctamer; active form. Homohexamer; low activity form (By
CC       similarity). {ECO:0000250}.
CC   -!- SIMILARITY: Belongs to the ALAD family. {ECO:0000305}.
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DR   EMBL; X04959; CAA28621.1; -; mRNA.
DR   EMBL; BC061806; AAH61806.1; -; mRNA.
DR   PIR; A24724; A24724.
DR   RefSeq; NP_037031.1; NM_012899.2.
DR   RefSeq; XP_006238296.1; XM_006238234.3.
DR   RefSeq; XP_006238297.1; XM_006238235.1.
DR   AlphaFoldDB; P06214; -.
DR   SMR; P06214; -.
DR   BioGRID; 247413; 1.
DR   STRING; 10116.ENSRNOP00000020625; -.
DR   iPTMnet; P06214; -.
DR   PhosphoSitePlus; P06214; -.
DR   jPOST; P06214; -.
DR   PaxDb; 10116-ENSRNOP00000020625; -.
DR   Ensembl; ENSRNOT00000020625.7; ENSRNOP00000020625.2; ENSRNOG00000015206.7.
DR   Ensembl; ENSRNOT00055030768; ENSRNOP00055024759; ENSRNOG00055018142.
DR   Ensembl; ENSRNOT00060017404; ENSRNOP00060013521; ENSRNOG00060010276.
DR   Ensembl; ENSRNOT00065026678; ENSRNOP00065020925; ENSRNOG00065016023.
DR   GeneID; 25374; -.
DR   KEGG; rno:25374; -.
DR   UCSC; RGD:2083; rat.
DR   AGR; RGD:2083; -.
DR   CTD; 210; -.
DR   RGD; 2083; Alad.
DR   eggNOG; KOG2794; Eukaryota.
DR   GeneTree; ENSGT00390000006998; -.
DR   HOGENOM; CLU_035731_0_1_1; -.
DR   InParanoid; P06214; -.
DR   OMA; YQMDYAN; -.
DR   OrthoDB; 2782182at2759; -.
DR   PhylomeDB; P06214; -.
DR   TreeFam; TF300665; -.
DR   Reactome; R-RNO-189451; Heme biosynthesis.
DR   Reactome; R-RNO-6798695; Neutrophil degranulation.
DR   UniPathway; UPA00251; UER00318.
DR   PRO; PR:P06214; -.
DR   Proteomes; UP000002494; Chromosome 5.
DR   Bgee; ENSRNOG00000015206; Expressed in liver and 19 other cell types or tissues.
DR   ExpressionAtlas; P06214; baseline and differential.
DR   GO; GO:0005829; C:cytosol; ISO:RGD.
DR   GO; GO:0005615; C:extracellular space; IDA:RGD.
DR   GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR   GO; GO:0004655; F:porphobilinogen synthase activity; IDA:RGD.
DR   GO; GO:1904854; F:proteasome core complex binding; IDA:RGD.
DR   GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR   GO; GO:0071353; P:cellular response to interleukin-4; ISO:RGD.
DR   GO; GO:0071284; P:cellular response to lead ion; IEP:RGD.
DR   GO; GO:0006784; P:heme A biosynthetic process; ISO:RGD.
DR   GO; GO:0006785; P:heme B biosynthetic process; ISO:RGD.
DR   GO; GO:0006783; P:heme biosynthetic process; IDA:RGD.
DR   GO; GO:0048034; P:heme O biosynthetic process; ISO:RGD.
DR   GO; GO:1901799; P:negative regulation of proteasomal protein catabolic process; ISO:RGD.
DR   GO; GO:0051260; P:protein homooligomerization; ISO:RGD.
DR   GO; GO:0006782; P:protoporphyrinogen IX biosynthetic process; IEA:UniProtKB-UniPathway.
DR   GO; GO:0014823; P:response to activity; IEP:RGD.
DR   GO; GO:0010044; P:response to aluminum ion; IEP:RGD.
DR   GO; GO:0043200; P:response to amino acid; IEP:RGD.
DR   GO; GO:0046685; P:response to arsenic-containing substance; IDA:RGD.
DR   GO; GO:0046686; P:response to cadmium ion; IDA:RGD.
DR   GO; GO:0032025; P:response to cobalt ion; IEP:RGD.
DR   GO; GO:0045471; P:response to ethanol; IDA:RGD.
DR   GO; GO:0070542; P:response to fatty acid; IEP:RGD.
DR   GO; GO:0051384; P:response to glucocorticoid; IEP:RGD.
DR   GO; GO:0009635; P:response to herbicide; IEP:RGD.
DR   GO; GO:0009725; P:response to hormone; IEP:RGD.
DR   GO; GO:0001666; P:response to hypoxia; IEP:RGD.
DR   GO; GO:0010035; P:response to inorganic substance; IEP:RGD.
DR   GO; GO:0010212; P:response to ionizing radiation; IEP:RGD.
DR   GO; GO:0010039; P:response to iron ion; IEP:RGD.
DR   GO; GO:0010288; P:response to lead ion; IEP:RGD.
DR   GO; GO:0032496; P:response to lipopolysaccharide; IEP:RGD.
DR   GO; GO:0046689; P:response to mercury ion; IEP:RGD.
DR   GO; GO:0010038; P:response to metal ion; IDA:RGD.
DR   GO; GO:0051597; P:response to methylmercury; IEP:RGD.
DR   GO; GO:0007584; P:response to nutrient; IDA:RGD.
DR   GO; GO:0031667; P:response to nutrient levels; IEP:RGD.
DR   GO; GO:0014070; P:response to organic cyclic compound; IEP:RGD.
DR   GO; GO:0010033; P:response to organic substance; IDA:RGD.
DR   GO; GO:0006979; P:response to oxidative stress; IEP:RGD.
DR   GO; GO:0070541; P:response to platinum ion; IEP:RGD.
DR   GO; GO:0010269; P:response to selenium ion; IEP:RGD.
DR   GO; GO:0009636; P:response to toxic substance; IEP:RGD.
DR   GO; GO:0033273; P:response to vitamin; IEP:RGD.
DR   GO; GO:0010266; P:response to vitamin B1; IEP:RGD.
DR   GO; GO:0033197; P:response to vitamin E; IEP:RGD.
DR   GO; GO:0009410; P:response to xenobiotic stimulus; IDA:RGD.
DR   GO; GO:0010043; P:response to zinc ion; IDA:RGD.
DR   CDD; cd04824; eu_ALAD_PBGS_cysteine_rich; 1.
DR   Gene3D; 3.20.20.70; Aldolase class I; 1.
DR   InterPro; IPR001731; ALAD.
DR   InterPro; IPR030656; ALAD_AS.
DR   InterPro; IPR013785; Aldolase_TIM.
DR   PANTHER; PTHR11458; DELTA-AMINOLEVULINIC ACID DEHYDRATASE; 1.
DR   PANTHER; PTHR11458:SF0; DELTA-AMINOLEVULINIC ACID DEHYDRATASE; 1.
DR   Pfam; PF00490; ALAD; 1.
DR   PIRSF; PIRSF001415; Porphbilin_synth; 1.
DR   PRINTS; PR00144; DALDHYDRTASE.
DR   SMART; SM01004; ALAD; 1.
DR   SUPFAM; SSF51569; Aldolase; 1.
DR   PROSITE; PS00169; D_ALA_DEHYDRATASE; 1.
DR   Genevisible; P06214; RN.
PE   1: Evidence at protein level;
KW   Allosteric enzyme; Direct protein sequencing; Heme biosynthesis; Lyase;
KW   Metal-binding; Phosphoprotein; Porphyrin biosynthesis; Reference proteome;
KW   Zinc.
FT   CHAIN           1..330
FT                   /note="Delta-aminolevulinic acid dehydratase"
FT                   /id="PRO_0000140530"
FT   ACT_SITE        199
FT                   /note="Schiff-base intermediate with substrate"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        252
FT                   /note="Schiff-base intermediate with substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         122
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000250"
FT   BINDING         124
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000250"
FT   BINDING         131
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250"
FT   BINDING         132
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000250"
FT   BINDING         209
FT                   /ligand="5-aminolevulinate"
FT                   /ligand_id="ChEBI:CHEBI:356416"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   BINDING         221
FT                   /ligand="5-aminolevulinate"
FT                   /ligand_id="ChEBI:CHEBI:356416"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   BINDING         223
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250"
FT   BINDING         279
FT                   /ligand="5-aminolevulinate"
FT                   /ligand_id="ChEBI:CHEBI:356416"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250"
FT   BINDING         318
FT                   /ligand="5-aminolevulinate"
FT                   /ligand_id="ChEBI:CHEBI:356416"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         199
FT                   /note="N6-succinyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10518"
FT   MOD_RES         215
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P10518"
FT   MOD_RES         252
FT                   /note="N6-succinyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P10518"
SQ   SEQUENCE   330 AA;  36032 MW;  617F6E85B647AB25 CRC64;
     MHHQSVLHSG YFHPLLRAWQ TTPSTVSATN LIYPIFVTDV PDDVQPIASL PGVARYGVNQ
     LEEMLRPLVE AGLRCVLIFG VPSRVPKDEQ GSAADSEDSP TIEAVRLLRK TFPTLLVACD
     VCLCPYTSHG HCGLLSENGA FLAEESRQRL AEVALAYAKA GCQVVAPSDM MDGRVEAIKA
     ALLKHGLGNR VSVMSYSAKF ASCFYGPFRD AAQSSPAFGD RRCYQLPPGA RGLALRAVAR
     DIQEGADILM VKPGLPYLDM VQEVKDKHPE LPLAVYQVSG EFAMLWHGAK AGAFDLRTAV
     LESMTAFRRA GADIIITYFA PQLLKWLKEE
//