HEM2_HUMAN
ID HEM2_HUMAN Reviewed; 330 AA.
AC P13716; A8K375; B2R6F2; Q16870; Q16871; Q9BVQ9;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1990, sequence version 1.
DT 03-AUG-2022, entry version 222.
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 Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=3463993; DOI=10.1073/pnas.83.20.7703;
RA Wetmur J.G., Bishop D.F., Cantelmo C., Desnick R.J.;
RT "Human delta-aminolevulinate dehydratase: nucleotide sequence of a full-
RT length cDNA clone.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:7703-7707(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Liver;
RX PubMed=1678509; DOI=10.1093/nar/19.15.4307-a;
RA Wetmur J.G.;
RT "RsaI polymorphism in the human delta-aminolevulinate dehydratase gene at
RT 9q34.";
RL Nucleic Acids Res. 19:4307-4307(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS AHEPP TRP-240 AND
RP THR-274.
RX PubMed=1569184; DOI=10.1172/jci115732;
RA Ishida N., Fujita H., Fukuda Y., Noguchi T., Doss M., Kappas A., Sassa S.;
RT "Cloning and expression of the defective genes from a patient with delta-
RT aminolevulinate dehydratase porphyria.";
RL J. Clin. Invest. 89:1431-1437(1992).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, and Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ASN-59.
RG NIEHS SNPs program;
RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L.,
RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S.,
RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K.,
RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C.,
RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E.,
RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M.,
RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J.,
RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P.,
RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S.,
RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J.,
RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E.,
RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V.,
RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S.,
RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K.,
RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J.,
RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M.,
RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L.,
RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J.,
RA Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
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 [8]
RP PROTEIN SEQUENCE OF 1-17.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R.,
RA Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass spectrometric
RT identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [9]
RP ACTIVE SITE.
RX PubMed=3092810; DOI=10.1042/bj2360447;
RA Gibbs P.N.B., Jordan P.M.;
RT "Identification of lysine at the active site of human 5-aminolevulinate
RT dehydratase.";
RL Biochem. J. 236:447-451(1986).
RN [10]
RP POLYMORPHISM, AND VARIANT ASN-59.
RX PubMed=1769358; DOI=10.1016/s0013-9351(05)80001-5;
RA Wetmur J.G., Lehnert G., Desnick R.J.;
RT "The delta-aminolevulinate dehydratase polymorphism: higher blood lead
RT levels in lead workers and environmentally exposed children with the 1-2
RT and 2-2 isozymes.";
RL Environ. Res. 56:109-119(1991).
RN [11]
RP ACTIVITY REGULATION, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, COFACTOR, IDENTIFICATION BY MASS SPECTROMETRY, MUTAGENESIS OF
RP CYS-122; CYS-124; HIS-131; CYS-132 AND CYS-223, AND CHARACTERIZATION OF
RP VARIANT ASN-59.
RX PubMed=11032836; DOI=10.1074/jbc.m007663200;
RA Jaffe E.K., Martins J., Li J., Kervinen J., Dunbrack R.L. Jr.;
RT "The molecular mechanism of lead inhibition of human porphobilinogen
RT synthase.";
RL J. Biol. Chem. 276:1531-1537(2001).
RN [12]
RP POLYMORPHISM.
RX PubMed=17966070; DOI=10.1080/15287390701550946;
RA Zhao Y., Wang L., Shen H.B., Wang Z.X., Wei Q.Y., Chen F.;
RT "Association between delta-aminolevulinic acid dehydratase (ALAD)
RT polymorphism and blood lead levels: a meta-regression analysis.";
RL J. Toxicol. Environ. Health Part A 70:1986-1994(2007).
RN [13]
RP FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, AND ACTIVITY REGULATION.
RX PubMed=19812033; DOI=10.1074/jbc.m109.026294;
RA Lawrence S.H., Ramirez U.D., Selwood T., Stith L., Jaffe E.K.;
RT "Allosteric inhibition of human porphobilinogen synthase.";
RL J. Biol. Chem. 284:35807-35817(2009).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.83 ANGSTROMS) IN COMPLEX WITH PORPHOBILINOGEN AND
RP ZINC IONS.
RA Mills-Davies N.L., Thompson D., Cooper J.B., Shoolingin-Jordan P.M.;
RT "The crystal structure of human Ala-dehydratase.";
RL Submitted (OCT-1998) to the PDB data bank.
RN [17]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF MUTANT LEU-12 IN COMPLEX WITH
RP SUBSTRATE ANALOG, SUBUNIT, IDENTIFICATION BY MASS SPECTROMETRY, CATALYTIC
RP ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=12897770; DOI=10.1038/nsb963;
RA Breinig S., Kervinen J., Stith L., Wasson A.S., Fairman R., Wlodawer A.,
RA Zdanov A., Jaffe E.K.;
RT "Control of tetrapyrrole biosynthesis by alternate quaternary forms of
RT porphobilinogen synthase.";
RL Nat. Struct. Biol. 10:757-763(2003).
RN [18]
RP POLYMORPHISM, AND VARIANT ASN-59.
RX PubMed=1716854;
RA Wetmur J.G., Kaya A.H., Plewinska M., Desnick R.J.;
RT "Molecular characterization of the human delta-aminolevulinate dehydratase
RT 2 (ALAD2) allele: implications for molecular screening of individuals for
RT genetic susceptibility to lead poisoning.";
RL Am. J. Hum. Genet. 49:757-763(1991).
RN [19]
RP VARIANTS AHEPP ARG-133 AND MET-275.
RX PubMed=2063868;
RA Plewinska M., Thunell S., Holmberg L., Wetmur J.G., Desnick R.J.;
RT "Delta-aminolevulinate dehydratase deficient porphyria: identification of
RT the molecular lesions in a severely affected homozygote.";
RL Am. J. Hum. Genet. 49:167-174(1991).
RN [20]
RP VARIANTS AHEPP TRP-240 AND THR-274, AND CHARACTERIZATION OF VARIANTS AHEPP
RP TRP-240 AND THR-274.
RX PubMed=1309003;
RA Sassa S., Ishida N., Fujita H., Fukuda Y., Noguchi T., Doss M., Kappas A.;
RT "Cloning and expression of the defective genes in delta-aminolevulinate
RT dehydratase porphyria: compound heterozygosity in this hereditary liver
RT disease.";
RL Trans. Assoc. Am. Physicians 105:250-259(1992).
RN [21]
RP VARIANT LEU-12, AND CHARACTERIZATION OF VARIANT LEU-12.
RX PubMed=10519994; DOI=10.1046/j.1365-2141.1999.01647.x;
RA Akagi R., Yasui Y., Harper P., Sassa S.;
RT "A novel mutation of delta-aminolaevulinate dehydratase in a healthy child
RT with 12% erythrocyte enzyme activity.";
RL Br. J. Haematol. 106:931-937(1999).
RN [22]
RP VARIANT AHEPP MET-153, AND CHARACTERIZATION OF VARIANT AHEPP MET-153.
RX PubMed=10706561; DOI=10.1002/hep.510310321;
RA Akagi R., Shimizu R., Furuyama K., Doss M.O., Sassa S.;
RT "Novel molecular defects of the delta-aminolevulinate dehydratase gene in a
RT patient with inherited acute hepatic porphyria.";
RL Hepatology 31:704-708(2000).
RN [23]
RP VARIANT LEU-12.
RX PubMed=16398658; DOI=10.1111/j.1365-2141.2005.05852.x;
RA Akagi R., Inoue R., Muranaka S., Tahara T., Taketani S., Anderson K.E.,
RA Phillips J.D., Sassa S.;
RT "Dual gene defects involving delta-aminolaevulinate dehydratase and
RT coproporphyrinogen oxidase in a porphyria patient.";
RL Br. J. Haematol. 132:237-243(2006).
RN [24]
RP CHARACTERIZATION OF VARIANTS AHEPP ARG-133; MET-153; TRP-240; THR-274 AND
RP MET-275, AND CHARACTERIZATION OF VARIANTS LEU-12 AND ASN-59.
RX PubMed=17236137; DOI=10.1086/511444;
RA Jaffe E.K., Stith L.;
RT "ALAD porphyria is a conformational disease.";
RL Am. J. Hum. Genet. 80:329-337(2007).
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
CC porphobilinogen. {ECO:0000269|PubMed:11032836,
CC ECO:0000269|PubMed:19812033}.
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 Evidence={ECO:0000269|PubMed:11032836, ECO:0000269|PubMed:12897770,
CC ECO:0000269|PubMed:19812033};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:11032836};
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:0000269|PubMed:11032836};
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.
CC {ECO:0000269|PubMed:11032836, ECO:0000269|PubMed:12897770,
CC ECO:0000269|PubMed:19812033}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.09 mM for 5-aminolevulinate at pH 7
CC {ECO:0000269|PubMed:11032836};
CC Vmax=43 umol/h/mg enzyme at pH 7 {ECO:0000269|PubMed:11032836};
CC pH dependence:
CC Optimum pH is 6.8-7.3. {ECO:0000269|PubMed:11032836};
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.
CC {ECO:0000269|PubMed:12897770, ECO:0000269|PubMed:19812033,
CC ECO:0000269|Ref.16}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P13716-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P13716-2; Sequence=VSP_037866;
CC -!- POLYMORPHISM: Genetic variation in ALAD influences susceptibility to
CC lead poisoning in individuals exposed to high amount of environmental
CC lead. There are two common alleles: allele ALAD*1 and allele ALAD*2
CC resulting in 3 isozymes: ALAD 1-1, ALAD 1-2, and ALAD 2-2. Individuals
CC with ALAD 1-2 or ALAD 2-2 isozymes have levels of blood lead higher
CC than those in individuals with ALAD 1-1 isozyme. The sequence shown
CC corresponds to allele ALAD*1. {ECO:0000269|PubMed:1716854,
CC ECO:0000269|PubMed:1769358, ECO:0000305|PubMed:17966070}.
CC -!- DISEASE: Acute hepatic porphyria (AHEPP) [MIM:612740]: A form of
CC porphyria. Porphyrias are inherited defects in the biosynthesis of
CC heme, resulting in the accumulation and increased excretion of
CC porphyrins or porphyrin precursors. They are classified as
CC erythropoietic or hepatic, depending on whether the enzyme deficiency
CC occurs in red blood cells or in the liver. AHP is characterized by
CC attacks of gastrointestinal disturbances, abdominal colic, paralyses
CC and peripheral neuropathy. Most attacks are precipitated by drugs,
CC alcohol, caloric deprivation, infections, or endocrine factors.
CC {ECO:0000269|PubMed:10706561, ECO:0000269|PubMed:1309003,
CC ECO:0000269|PubMed:1569184, ECO:0000269|PubMed:17236137,
CC ECO:0000269|PubMed:2063868}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the ALAD family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH00977.3; Type=Erroneous initiation; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/alad/";
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DR EMBL; M13928; AAA51687.1; -; mRNA.
DR EMBL; X64467; CAA45796.1; -; Genomic_DNA.
DR EMBL; S99468; AAC60581.1; -; mRNA.
DR EMBL; S99471; AAC60582.1; -; mRNA.
DR EMBL; AK290490; BAF83179.1; -; mRNA.
DR EMBL; AK312552; BAG35449.1; -; mRNA.
DR EMBL; AY319481; AAP72012.1; -; Genomic_DNA.
DR EMBL; AL137066; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC000977; AAH00977.3; ALT_INIT; mRNA.
DR CCDS; CCDS6794.2; -. [P13716-1]
DR PIR; A26478; A26478.
DR RefSeq; NP_000022.3; NM_000031.5. [P13716-1]
DR RefSeq; NP_001003945.1; NM_001003945.2. [P13716-2]
DR RefSeq; XP_011516666.1; XM_011518364.2.
DR PDB; 1E51; X-ray; 2.83 A; A/B=1-330.
DR PDB; 1PV8; X-ray; 2.20 A; A/B=1-330.
DR PDB; 5HMS; X-ray; 2.80 A; A/B=1-330.
DR PDB; 5HNR; X-ray; 2.83 A; A/B=1-330.
DR PDBsum; 1E51; -.
DR PDBsum; 1PV8; -.
DR PDBsum; 5HMS; -.
DR PDBsum; 5HNR; -.
DR AlphaFoldDB; P13716; -.
DR SMR; P13716; -.
DR BioGRID; 106712; 43.
DR IntAct; P13716; 7.
DR STRING; 9606.ENSP00000386284; -.
DR BindingDB; P13716; -.
DR ChEMBL; CHEMBL3126; -.
DR DrugBank; DB02878; 3-(2-Aminoethyl)-4-(Aminomethyl)Heptanedioic Acid.
DR DrugBank; DB04560; 4,7-Dioxosebacic Acid.
DR DrugBank; DB02260; 4-Oxosebacic Acid.
DR DrugBank; DB04781; 5-hydroxyvaleric acid.
DR DrugBank; DB00855; Aminolevulinic acid.
DR DrugBank; DB02068; Delta-Amino Valeric Acid.
DR DrugBank; DB02239; Laevulinic Acid.
DR DrugBank; DB02272; Porphobilinogen.
DR MoonDB; P13716; Curated.
DR MoonProt; P13716; -.
DR GlyGen; P13716; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P13716; -.
DR MetOSite; P13716; -.
DR PhosphoSitePlus; P13716; -.
DR SwissPalm; P13716; -.
DR BioMuta; ALAD; -.
DR DMDM; 122833; -.
DR OGP; P13716; -.
DR REPRODUCTION-2DPAGE; P13716; -.
DR SWISS-2DPAGE; P13716; -.
DR EPD; P13716; -.
DR jPOST; P13716; -.
DR MassIVE; P13716; -.
DR MaxQB; P13716; -.
DR PaxDb; P13716; -.
DR PeptideAtlas; P13716; -.
DR PRIDE; P13716; -.
DR ProteomicsDB; 52973; -. [P13716-1]
DR ProteomicsDB; 52974; -. [P13716-2]
DR Antibodypedia; 15306; 236 antibodies from 26 providers.
DR DNASU; 210; -.
DR Ensembl; ENST00000409155.8; ENSP00000386284.3; ENSG00000148218.16. [P13716-1]
DR GeneID; 210; -.
DR KEGG; hsa:210; -.
DR MANE-Select; ENST00000409155.8; ENSP00000386284.3; NM_000031.6; NP_000022.3.
DR UCSC; uc011lxf.3; human. [P13716-1]
DR CTD; 210; -.
DR DisGeNET; 210; -.
DR GeneCards; ALAD; -.
DR HGNC; HGNC:395; ALAD.
DR HPA; ENSG00000148218; Tissue enhanced (liver).
DR MalaCards; ALAD; -.
DR MIM; 125270; gene.
DR MIM; 612740; phenotype.
DR neXtProt; NX_P13716; -.
DR OpenTargets; ENSG00000148218; -.
DR Orphanet; 100924; Porphyria due to ALA dehydratase deficiency.
DR PharmGKB; PA24687; -.
DR VEuPathDB; HostDB:ENSG00000148218; -.
DR eggNOG; KOG2794; Eukaryota.
DR GeneTree; ENSGT00390000006998; -.
DR HOGENOM; CLU_035731_0_1_1; -.
DR InParanoid; P13716; -.
DR OMA; YQMDYAN; -.
DR OrthoDB; 918089at2759; -.
DR PhylomeDB; P13716; -.
DR TreeFam; TF300665; -.
DR BioCyc; MetaCyc:HS07501-MON; -.
DR BRENDA; 4.2.1.24; 2681.
DR PathwayCommons; P13716; -.
DR Reactome; R-HSA-189451; Heme biosynthesis.
DR Reactome; R-HSA-6798695; Neutrophil degranulation.
DR SignaLink; P13716; -.
DR UniPathway; UPA00251; UER00318.
DR BioGRID-ORCS; 210; 60 hits in 1085 CRISPR screens.
DR ChiTaRS; ALAD; human.
DR EvolutionaryTrace; P13716; -.
DR GeneWiki; ALAD; -.
DR GenomeRNAi; 210; -.
DR Pharos; P13716; Tbio.
DR PRO; PR:P13716; -.
DR Proteomes; UP000005640; Chromosome 9.
DR RNAct; P13716; protein.
DR Bgee; ENSG00000148218; Expressed in right adrenal gland and 199 other tissues.
DR ExpressionAtlas; P13716; baseline and differential.
DR Genevisible; P13716; HS.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:1904813; C:ficolin-1-rich granule lumen; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; HDA:UniProtKB.
DR GO; GO:0034774; C:secretory granule lumen; TAS:Reactome.
DR GO; GO:0003824; F:catalytic activity; TAS:ProtInc.
DR GO; GO:0042802; F:identical protein binding; IPI:UniProtKB.
DR GO; GO:0004655; F:porphobilinogen synthase activity; IDA:UniProtKB.
DR GO; GO:1904854; F:proteasome core complex binding; IEA:Ensembl.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0071353; P:cellular response to interleukin-4; IEA:Ensembl.
DR GO; GO:0071284; P:cellular response to lead ion; IEA:Ensembl.
DR GO; GO:0006783; P:heme biosynthetic process; IDA:UniProtKB.
DR GO; GO:1901799; P:negative regulation of proteasomal protein catabolic process; IDA:CAFA.
DR GO; GO:0051260; P:protein homooligomerization; IPI:UniProtKB.
DR GO; GO:0006782; P:protoporphyrinogen IX biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0014823; P:response to activity; IEA:Ensembl.
DR GO; GO:0010044; P:response to aluminum ion; IEA:Ensembl.
DR GO; GO:0043200; P:response to amino acid; IEA:Ensembl.
DR GO; GO:0046685; P:response to arsenic-containing substance; IEA:Ensembl.
DR GO; GO:0046686; P:response to cadmium ion; IEA:Ensembl.
DR GO; GO:0032025; P:response to cobalt ion; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0070542; P:response to fatty acid; IEA:Ensembl.
DR GO; GO:0051384; P:response to glucocorticoid; IEA:Ensembl.
DR GO; GO:0009635; P:response to herbicide; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR GO; GO:0010212; P:response to ionizing radiation; IEA:Ensembl.
DR GO; GO:0010039; P:response to iron ion; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0046689; P:response to mercury ion; IEA:Ensembl.
DR GO; GO:0051597; P:response to methylmercury; IEA:Ensembl.
DR GO; GO:0006979; P:response to oxidative stress; IEA:Ensembl.
DR GO; GO:0070541; P:response to platinum ion; IEA:Ensembl.
DR GO; GO:0010269; P:response to selenium ion; IEA:Ensembl.
DR GO; GO:0010266; P:response to vitamin B1; IEA:Ensembl.
DR GO; GO:0033197; P:response to vitamin E; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0010043; P:response to zinc ion; IEA:Ensembl.
DR Gene3D; 3.20.20.70; -; 1.
DR InterPro; IPR001731; ALAD.
DR InterPro; IPR030656; ALAD_AS.
DR InterPro; IPR013785; Aldolase_TIM.
DR PANTHER; PTHR11458; PTHR11458; 1.
DR Pfam; PF00490; ALAD; 1.
DR PIRSF; PIRSF001415; Porphbilin_synth; 1.
DR PRINTS; PR00144; DALDHYDRTASE.
DR SMART; SM01004; ALAD; 1.
DR PROSITE; PS00169; D_ALA_DEHYDRATASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Allosteric enzyme; Alternative splicing;
KW Direct protein sequencing; Disease variant; 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_0000140526"
FT ACT_SITE 199
FT /note="Schiff-base intermediate with substrate"
FT /evidence="ECO:0000269|PubMed:3092810"
FT ACT_SITE 252
FT /note="Schiff-base intermediate with substrate"
FT /evidence="ECO:0000269|PubMed:3092810"
FT BINDING 122
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT BINDING 124
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT BINDING 131
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT BINDING 132
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT BINDING 209
FT /ligand="5-aminolevulinate"
FT /ligand_id="ChEBI:CHEBI:356416"
FT /ligand_label="1"
FT BINDING 221
FT /ligand="5-aminolevulinate"
FT /ligand_id="ChEBI:CHEBI:356416"
FT /ligand_label="1"
FT BINDING 223
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT BINDING 279
FT /ligand="5-aminolevulinate"
FT /ligand_id="ChEBI:CHEBI:356416"
FT /ligand_label="2"
FT BINDING 318
FT /ligand="5-aminolevulinate"
FT /ligand_id="ChEBI:CHEBI:356416"
FT /ligand_label="2"
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"
FT VAR_SEQ 1..38
FT /note="MQPQSVLHSGYFHPLLRAWQTATTTLNASNLIYPIFVT -> MPPTSSTPSL
FT SRPGLGQAGKPDTGSHPPPTISTSIFLSCFPTIPLSRPRTTGPSHSYQSISHPRSCR
FT (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_037866"
FT VARIANT 12
FT /note="F -> L (in an asymptomatic patient with ALAD
FT deficiency; also found in a hereditary coproporphyria
FT patient carrying the R-279 mutation in CPOX; hexamer with
FT almost no residual activity; dbSNP:rs121912984)"
FT /evidence="ECO:0000269|PubMed:10519994,
FT ECO:0000269|PubMed:16398658, ECO:0000269|PubMed:17236137"
FT /id="VAR_020973"
FT VARIANT 59
FT /note="K -> N (allele ALAD*2; ALAD*2 heterozygous or
FT homozygous carriers have significantly higher blood lead
FT levels than ALAD*1 homozygotes when exposed to
FT environmental lead; fully active octamer; dbSNP:rs1800435)"
FT /evidence="ECO:0000269|PubMed:11032836,
FT ECO:0000269|PubMed:1716854, ECO:0000269|PubMed:17236137,
FT ECO:0000269|PubMed:1769358, ECO:0000269|Ref.5"
FT /id="VAR_003633"
FT VARIANT 133
FT /note="G -> R (in AHEPP; mixture of about 50% hexamer and
FT 50% octamer; about 10% residual activity;
FT dbSNP:rs121912980)"
FT /evidence="ECO:0000269|PubMed:17236137,
FT ECO:0000269|PubMed:2063868"
FT /id="VAR_003634"
FT VARIANT 153
FT /note="V -> M (in AHEPP; about 95% octamer; about 40%
FT residual activity; dbSNP:rs1554740221)"
FT /evidence="ECO:0000269|PubMed:10706561,
FT ECO:0000269|PubMed:17236137"
FT /id="VAR_020974"
FT VARIANT 240
FT /note="R -> W (in AHEPP; mixture of about 80% hexamer and
FT 20% octamer; about 4% residual activity;
FT dbSNP:rs121912982)"
FT /evidence="ECO:0000269|PubMed:1309003,
FT ECO:0000269|PubMed:1569184, ECO:0000269|PubMed:17236137"
FT /id="VAR_003635"
FT VARIANT 274
FT /note="A -> T (in AHEPP; mixture of about 14% hexamer and
FT 86% octamer; about 20% enzyme residual activity;
FT dbSNP:rs121912983)"
FT /evidence="ECO:0000269|PubMed:1309003,
FT ECO:0000269|PubMed:1569184, ECO:0000269|PubMed:17236137"
FT /id="VAR_003636"
FT VARIANT 275
FT /note="V -> M (in AHEPP; mainly octamer; reduced activity;
FT dbSNP:rs121912981)"
FT /evidence="ECO:0000269|PubMed:17236137,
FT ECO:0000269|PubMed:2063868"
FT /id="VAR_003637"
FT MUTAGEN 122
FT /note="C->A: Reduces enzyme activity about 1000000-fold;
FT when associated with A-124 and A-132."
FT /evidence="ECO:0000269|PubMed:11032836"
FT MUTAGEN 124
FT /note="C->A: Reduces enzyme activity about 1000000-fold;
FT when associated with A-122 and A-132."
FT /evidence="ECO:0000269|PubMed:11032836"
FT MUTAGEN 131
FT /note="H->A: No effect on catalytic activity; when
FT associated with A-223."
FT /evidence="ECO:0000269|PubMed:11032836"
FT MUTAGEN 132
FT /note="C->A: Reduces enzyme activity about 1000000-fold;
FT when associated with A-122 and A-124."
FT /evidence="ECO:0000269|PubMed:11032836"
FT MUTAGEN 223
FT /note="C->A: No effect on catalytic activity; when
FT associated with A-131."
FT /evidence="ECO:0000269|PubMed:11032836"
FT HELIX 8..10
FT /evidence="ECO:0007829|PDB:5HMS"
FT STRAND 11..13
FT /evidence="ECO:0007829|PDB:5HMS"
FT HELIX 14..20
FT /evidence="ECO:0007829|PDB:1PV8"
FT TURN 21..24
FT /evidence="ECO:0007829|PDB:1PV8"
FT HELIX 28..30
FT /evidence="ECO:0007829|PDB:1PV8"
FT STRAND 31..37
FT /evidence="ECO:0007829|PDB:1PV8"
FT STRAND 44..46
FT /evidence="ECO:0007829|PDB:1PV8"
FT STRAND 48..50
FT /evidence="ECO:0007829|PDB:1PV8"
FT STRAND 54..56
FT /evidence="ECO:0007829|PDB:1PV8"
FT HELIX 58..71
FT /evidence="ECO:0007829|PDB:1PV8"
FT STRAND 75..80
FT /evidence="ECO:0007829|PDB:1PV8"
FT STRAND 83..85
FT /evidence="ECO:0007829|PDB:5HMS"
FT STRAND 88..90
FT /evidence="ECO:0007829|PDB:5HMS"
FT HELIX 92..94
FT /evidence="ECO:0007829|PDB:5HMS"
FT HELIX 100..111
FT /evidence="ECO:0007829|PDB:1PV8"
FT STRAND 115..121
FT /evidence="ECO:0007829|PDB:1PV8"
FT HELIX 124..126
FT /evidence="ECO:0007829|PDB:5HMS"
FT STRAND 127..129
FT /evidence="ECO:0007829|PDB:5HMS"
FT STRAND 131..133
FT /evidence="ECO:0007829|PDB:5HNR"
FT STRAND 137..139
FT /evidence="ECO:0007829|PDB:5HMS"
FT HELIX 141..160
FT /evidence="ECO:0007829|PDB:1PV8"
FT STRAND 163..167
FT /evidence="ECO:0007829|PDB:1PV8"
FT HELIX 174..184
FT /evidence="ECO:0007829|PDB:1PV8"
FT TURN 188..190
FT /evidence="ECO:0007829|PDB:1PV8"
FT STRAND 192..194
FT /evidence="ECO:0007829|PDB:1PV8"
FT STRAND 198..200
FT /evidence="ECO:0007829|PDB:5HMS"
FT HELIX 203..205
FT /evidence="ECO:0007829|PDB:1PV8"
FT HELIX 206..210
FT /evidence="ECO:0007829|PDB:1PV8"
FT STRAND 217..219
FT /evidence="ECO:0007829|PDB:5HMS"
FT TURN 222..224
FT /evidence="ECO:0007829|PDB:5HMS"
FT HELIX 231..243
FT /evidence="ECO:0007829|PDB:1PV8"
FT STRAND 247..253
FT /evidence="ECO:0007829|PDB:1PV8"
FT HELIX 255..257
FT /evidence="ECO:0007829|PDB:1PV8"
FT HELIX 258..267
FT /evidence="ECO:0007829|PDB:1PV8"
FT STRAND 273..277
FT /evidence="ECO:0007829|PDB:1PV8"
FT HELIX 279..290
FT /evidence="ECO:0007829|PDB:1PV8"
FT HELIX 296..310
FT /evidence="ECO:0007829|PDB:1PV8"
FT STRAND 313..317
FT /evidence="ECO:0007829|PDB:1PV8"
FT HELIX 320..326
FT /evidence="ECO:0007829|PDB:1PV8"
FT TURN 327..329
FT /evidence="ECO:0007829|PDB:1PV8"
SQ SEQUENCE 330 AA; 36295 MW; E005F3055F6D9403 CRC64;
MQPQSVLHSG YFHPLLRAWQ TATTTLNASN LIYPIFVTDV PDDIQPITSL PGVARYGVKR
LEEMLRPLVE EGLRCVLIFG VPSRVPKDER GSAADSEESP AIEAIHLLRK TFPNLLVACD
VCLCPYTSHG HCGLLSENGA FRAEESRQRL AEVALAYAKA GCQVVAPSDM MDGRVEAIKE
ALMAHGLGNR VSVMSYSAKF ASCFYGPFRD AAKSSPAFGD RRCYQLPPGA RGLALRAVDR
DVREGADMLM VKPGMPYLDI VREVKDKHPD LPLAVYHVSG EFAMLWHGAQ AGAFDLKAAV
LEAMTAFRRA GADIIITYYT PQLLQWLKEE
