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Delta-aminolevulinic acid dehydratase (ALADH) (EC 4.2.1.24) (Porphobilinogen synthase)

 HEM2_HUMAN              Reviewed;         330 AA.
P13716; A8K375; B2R6F2; Q16870; Q16871; Q9BVQ9;
01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
01-JAN-1990, sequence version 1.
30-AUG-2017, entry version 194.
RecName: Full=Delta-aminolevulinic acid dehydratase;
Short=ALADH;
EC=4.2.1.24;
AltName: Full=Porphobilinogen synthase;
Name=ALAD;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
PubMed=3463993; DOI=10.1073/pnas.83.20.7703;
Wetmur J.G., Bishop D.F., Cantelmo C., Desnick R.J.;
"Human delta-aminolevulinate dehydratase: nucleotide sequence of a
full-length cDNA clone.";
Proc. Natl. Acad. Sci. U.S.A. 83:7703-7707(1986).
[2]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
TISSUE=Liver;
PubMed=1678509; DOI=10.1093/nar/19.15.4307-a;
Wetmur J.G.;
"RsaI polymorphism in the human delta-aminolevulinate dehydratase gene
at 9q34.";
Nucleic Acids Res. 19:4307-4307(1991).
[3]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS AHEPP TRP-240 AND
THR-274.
PubMed=1569184; DOI=10.1172/JCI115732;
Ishida N., Fujita H., Fukuda Y., Noguchi T., Doss M., Kappas A.,
Sassa S.;
"Cloning and expression of the defective genes from a patient with
delta-aminolevulinate dehydratase porphyria.";
J. Clin. Invest. 89:1431-1437(1992).
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
TISSUE=Brain, and Tongue;
PubMed=14702039; DOI=10.1038/ng1285;
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[5]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ASN-59.
NIEHS SNPs program;
Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases.
[6]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=15164053; DOI=10.1038/nature02465;
Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
Rogers J., Dunham I.;
"DNA sequence and analysis of human chromosome 9.";
Nature 429:369-374(2004).
[7]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
TISSUE=Placenta;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[8]
PROTEIN SEQUENCE OF 1-17.
TISSUE=Platelet;
PubMed=12665801; DOI=10.1038/nbt810;
Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
Thomas G.R., Vandekerckhove J.;
"Exploring proteomes and analyzing protein processing by mass
spectrometric identification of sorted N-terminal peptides.";
Nat. Biotechnol. 21:566-569(2003).
[9]
ACTIVE SITE.
PubMed=3092810; DOI=10.1042/bj2360447;
Gibbs P.N.B., Jordan P.M.;
"Identification of lysine at the active site of human 5-
aminolevulinate dehydratase.";
Biochem. J. 236:447-451(1986).
[10]
POLYMORPHISM, AND VARIANT ASN-59.
PubMed=1769358; DOI=10.1016/S0013-9351(05)80001-5;
Wetmur J.G., Lehnert G., Desnick R.J.;
"The delta-aminolevulinate dehydratase polymorphism: higher blood lead
levels in lead workers and environmentally exposed children with the
1-2 and 2-2 isozymes.";
Environ. Res. 56:109-119(1991).
[11]
ENZYME REGULATION, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL
PROPERTIES, COFACTOR, IDENTIFICATION BY MASS SPECTROMETRY, MUTAGENESIS
OF CYS-122; CYS-124; HIS-131; CYS-132 AND CYS-223, AND
CHARACTERIZATION OF VARIANT ASN-59.
PubMed=11032836; DOI=10.1074/jbc.M007663200;
Jaffe E.K., Martins J., Li J., Kervinen J., Dunbrack R.L. Jr.;
"The molecular mechanism of lead inhibition of human porphobilinogen
synthase.";
J. Biol. Chem. 276:1531-1537(2001).
[12]
POLYMORPHISM.
PubMed=17966070; DOI=10.1080/15287390701550946;
Zhao Y., Wang L., Shen H.B., Wang Z.X., Wei Q.Y., Chen F.;
"Association between delta-aminolevulinic acid dehydratase (ALAD)
polymorphism and blood lead levels: a meta-regression analysis.";
J. Toxicol. Environ. Health Part A 70:1986-1994(2007).
[13]
FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, AND ENZYME REGULATION.
PubMed=19812033; DOI=10.1074/jbc.M109.026294;
Lawrence S.H., Ramirez U.D., Selwood T., Stith L., Jaffe E.K.;
"Allosteric inhibition of human porphobilinogen synthase.";
J. Biol. Chem. 284:35807-35817(2009).
[14]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21269460; DOI=10.1186/1752-0509-5-17;
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
"Initial characterization of the human central proteome.";
BMC Syst. Biol. 5:17-17(2011).
[15]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Liver;
PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D.,
Wang L., Ye M., Zou H.;
"An enzyme assisted RP-RPLC approach for in-depth analysis of human
liver phosphoproteome.";
J. Proteomics 96:253-262(2014).
[16]
X-RAY CRYSTALLOGRAPHY (2.83 ANGSTROMS) IN COMPLEX WITH PORPHOBILINOGEN
AND ZINC IONS.
Mills-Davies N.L., Thompson D., Cooper J.B., Shoolingin-Jordan P.M.;
"The crystal structure of human Ala-dehydratase.";
Submitted (OCT-1998) to the PDB data bank.
[17]
X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF MUTANT LEU-12 IN COMPLEX WITH
SUBSTRATE ANALOG, SUBUNIT, IDENTIFICATION BY MASS SPECTROMETRY,
CATALYTIC ACTIVITY, AND ENZYME REGULATION.
PubMed=12897770; DOI=10.1038/nsb963;
Breinig S., Kervinen J., Stith L., Wasson A.S., Fairman R.,
Wlodawer A., Zdanov A., Jaffe E.K.;
"Control of tetrapyrrole biosynthesis by alternate quaternary forms of
porphobilinogen synthase.";
Nat. Struct. Biol. 10:757-763(2003).
[18]
POLYMORPHISM, AND VARIANT ASN-59.
PubMed=1716854;
Wetmur J.G., Kaya A.H., Plewinska M., Desnick R.J.;
"Molecular characterization of the human delta-aminolevulinate
dehydratase 2 (ALAD2) allele: implications for molecular screening of
individuals for genetic susceptibility to lead poisoning.";
Am. J. Hum. Genet. 49:757-763(1991).
[19]
VARIANTS AHEPP ARG-133 AND MET-275.
PubMed=2063868;
Plewinska M., Thunell S., Holmberg L., Wetmur J.G., Desnick R.J.;
"Delta-aminolevulinate dehydratase deficient porphyria: identification
of the molecular lesions in a severely affected homozygote.";
Am. J. Hum. Genet. 49:167-174(1991).
[20]
VARIANTS AHEPP TRP-240 AND THR-274, AND CHARACTERIZATION OF VARIANTS
AHEPP TRP-240 AND THR-274.
PubMed=1309003;
Sassa S., Ishida N., Fujita H., Fukuda Y., Noguchi T., Doss M.,
Kappas A.;
"Cloning and expression of the defective genes in delta-
aminolevulinate dehydratase porphyria: compound heterozygosity in this
hereditary liver disease.";
Trans. Assoc. Am. Physicians 105:250-259(1992).
[21]
VARIANT LEU-12, AND CHARACTERIZATION OF VARIANT LEU-12.
PubMed=10519994; DOI=10.1046/j.1365-2141.1999.01647.x;
Akagi R., Yasui Y., Harper P., Sassa S.;
"A novel mutation of delta-aminolaevulinate dehydratase in a healthy
child with 12% erythrocyte enzyme activity.";
Br. J. Haematol. 106:931-937(1999).
[22]
VARIANT AHEPP MET-153, AND CHARACTERIZATION OF VARIANT AHEPP MET-153.
PubMed=10706561; DOI=10.1002/hep.510310321;
Akagi R., Shimizu R., Furuyama K., Doss M.O., Sassa S.;
"Novel molecular defects of the delta-aminolevulinate dehydratase gene
in a patient with inherited acute hepatic porphyria.";
Hepatology 31:704-708(2000).
[23]
VARIANT LEU-12.
PubMed=16398658; DOI=10.1111/j.1365-2141.2005.05852.x;
Akagi R., Inoue R., Muranaka S., Tahara T., Taketani S.,
Anderson K.E., Phillips J.D., Sassa S.;
"Dual gene defects involving delta-aminolaevulinate dehydratase and
coproporphyrinogen oxidase in a porphyria patient.";
Br. J. Haematol. 132:237-243(2006).
[24]
CHARACTERIZATION OF VARIANTS AHEPP ARG-133; MET-153; TRP-240; THR-274
AND MET-275, AND CHARACTERIZATION OF VARIANTS LEU-12 AND ASN-59.
PubMed=17236137; DOI=10.1086/511444;
Jaffe E.K., Stith L.;
"ALAD porphyria is a conformational disease.";
Am. J. Hum. Genet. 80:329-337(2007).
-!- FUNCTION: 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. {ECO:0000269|PubMed:11032836,
ECO:0000269|PubMed:19812033}.
-!- CATALYTIC ACTIVITY: 2 5-aminolevulinate = porphobilinogen + 2
H(2)O. {ECO:0000269|PubMed:11032836, ECO:0000269|PubMed:12897770,
ECO:0000269|PubMed:19812033}.
-!- COFACTOR:
Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
Evidence={ECO:0000269|PubMed:11032836};
Note=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. {ECO:0000269|PubMed:11032836};
-!- ENZYME REGULATION: 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. {ECO:0000269|PubMed:11032836,
ECO:0000269|PubMed:12897770, ECO:0000269|PubMed:19812033}.
-!- BIOPHYSICOCHEMICAL PROPERTIES:
Kinetic parameters:
KM=0.09 mM for 5-aminolevulinate at pH 7
{ECO:0000269|PubMed:11032836};
Vmax=43 umol/h/mg enzyme at pH 7 {ECO:0000269|PubMed:11032836};
pH dependence:
Optimum pH is 6.8-7.3. {ECO:0000269|PubMed:11032836};
-!- PATHWAY: Porphyrin-containing compound metabolism; protoporphyrin-
IX biosynthesis; coproporphyrinogen-III from 5-aminolevulinate:
step 1/4.
-!- SUBUNIT: Homooctamer; active form. Homohexamer; low activity form.
{ECO:0000269|PubMed:12897770, ECO:0000269|PubMed:19812033,
ECO:0000269|Ref.16}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=2;
Name=1;
IsoId=P13716-1; Sequence=Displayed;
Name=2;
IsoId=P13716-2; Sequence=VSP_037866;
-!- POLYMORPHISM: Genetic variation in ALAD influences susceptibility
to lead poisoning in individuals exposed to high amount of
environmental lead. There are two common alleles: allele ALAD*1
and allele ALAD*2 resulting in 3 isozymes: ALAD 1-1, ALAD 1-2, and
ALAD 2-2. Individuals with ALAD 1-2 or ALAD 2-2 isozymes have
levels of blood lead higher than those in individuals with ALAD 1-
1 isozyme. The sequence shown corresponds to allele ALAD*1.
{ECO:0000269|PubMed:1716854, ECO:0000269|PubMed:1769358,
ECO:0000305|PubMed:17966070}.
-!- DISEASE: Acute hepatic porphyria (AHEPP) [MIM:612740]: A 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. {ECO:0000269|PubMed:10706561,
ECO:0000269|PubMed:1309003, ECO:0000269|PubMed:1569184,
ECO:0000269|PubMed:17236137, ECO:0000269|PubMed:2063868}. Note=The
disease is caused by mutations affecting the gene represented in
this entry.
-!- SIMILARITY: Belongs to the ALAD family. {ECO:0000305}.
-!- SEQUENCE CAUTION:
Sequence=AAH00977.3; Type=Erroneous initiation; Evidence={ECO:0000305};
-!- WEB RESOURCE: Name=NIEHS-SNPs;
URL="http://egp.gs.washington.edu/data/alad/";
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EMBL; M13928; AAA51687.1; -; mRNA.
EMBL; X64467; CAA45796.1; -; Genomic_DNA.
EMBL; S99468; AAC60581.1; -; mRNA.
EMBL; S99471; AAC60582.1; -; mRNA.
EMBL; AK290490; BAF83179.1; -; mRNA.
EMBL; AK312552; BAG35449.1; -; mRNA.
EMBL; AY319481; AAP72012.1; -; Genomic_DNA.
EMBL; AL137066; CAH70099.3; -; Genomic_DNA.
EMBL; BC000977; AAH00977.3; ALT_INIT; mRNA.
CCDS; CCDS6794.2; -. [P13716-1]
PIR; A26478; A26478.
RefSeq; NP_000022.3; NM_000031.5. [P13716-1]
RefSeq; NP_001003945.1; NM_001003945.2. [P13716-2]
RefSeq; XP_011516666.1; XM_011518364.2.
UniGene; Hs.1227; -.
PDB; 1E51; X-ray; 2.83 A; A/B=1-330.
PDB; 1PV8; X-ray; 2.20 A; A/B=1-330.
PDB; 5HMS; X-ray; 2.80 A; A/B=1-330.
PDB; 5HNR; X-ray; 2.83 A; A/B=1-330.
PDBsum; 1E51; -.
PDBsum; 1PV8; -.
PDBsum; 5HMS; -.
PDBsum; 5HNR; -.
ProteinModelPortal; P13716; -.
SMR; P13716; -.
BioGrid; 106712; 24.
IntAct; P13716; 1.
STRING; 9606.ENSP00000386284; -.
BindingDB; P13716; -.
ChEMBL; CHEMBL3126; -.
DrugBank; DB02878; 3-(2-Aminoethyl)-4-(Aminomethyl)Heptanedioic Acid.
DrugBank; DB02260; 4-Oxosebacic Acid.
DrugBank; DB04781; 5-hydroxyvaleric acid.
DrugBank; DB00855; Aminolevulinic acid.
DrugBank; DB02068; Delta-Amino Valeric Acid.
DrugBank; DB02239; Laevulinic Acid.
DrugBank; DB02272; Porphobilinogen.
iPTMnet; P13716; -.
PhosphoSitePlus; P13716; -.
SwissPalm; P13716; -.
BioMuta; ALAD; -.
DMDM; 122833; -.
OGP; P13716; -.
REPRODUCTION-2DPAGE; P13716; -.
SWISS-2DPAGE; P13716; -.
EPD; P13716; -.
MaxQB; P13716; -.
PaxDb; P13716; -.
PeptideAtlas; P13716; -.
PRIDE; P13716; -.
Ensembl; ENST00000409155; ENSP00000386284; ENSG00000148218. [P13716-1]
GeneID; 210; -.
KEGG; hsa:210; -.
UCSC; uc011lxf.3; human. [P13716-1]
CTD; 210; -.
DisGeNET; 210; -.
GeneCards; ALAD; -.
HGNC; HGNC:395; ALAD.
HPA; HPA021023; -.
HPA; HPA022124; -.
MalaCards; ALAD; -.
MIM; 125270; gene.
MIM; 612740; phenotype.
neXtProt; NX_P13716; -.
OpenTargets; ENSG00000148218; -.
Orphanet; 100924; Porphyria due to ALA dehydratase deficiency.
PharmGKB; PA24687; -.
eggNOG; KOG2794; Eukaryota.
eggNOG; COG0113; LUCA.
GeneTree; ENSGT00390000006998; -.
HOGENOM; HOG000020323; -.
HOVERGEN; HBG001222; -.
InParanoid; P13716; -.
KO; K01698; -.
OMA; YQMDYAN; -.
OrthoDB; EOG091G0FMX; -.
PhylomeDB; P13716; -.
TreeFam; TF300665; -.
BioCyc; MetaCyc:HS07501-MONOMER; -.
BRENDA; 4.2.1.24; 2681.
Reactome; R-HSA-189451; Heme biosynthesis.
Reactome; R-HSA-6798695; Neutrophil degranulation.
UniPathway; UPA00251; UER00318.
ChiTaRS; ALAD; human.
EvolutionaryTrace; P13716; -.
GeneWiki; ALAD; -.
GenomeRNAi; 210; -.
PRO; PR:P13716; -.
Proteomes; UP000005640; Chromosome 9.
Bgee; ENSG00000148218; -.
CleanEx; HS_ALAD; -.
ExpressionAtlas; P13716; baseline and differential.
Genevisible; P13716; HS.
GO; GO:0005829; C:cytosol; IBA:GO_Central.
GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB.
GO; GO:0005576; C:extracellular region; TAS:Reactome.
GO; GO:1904813; C:ficolin-1-rich granule lumen; TAS:Reactome.
GO; GO:0005634; C:nucleus; IDA:UniProtKB.
GO; GO:0005839; C:proteasome core complex; IEA:Ensembl.
GO; GO:0034774; C:secretory granule lumen; TAS:Reactome.
GO; GO:0003824; F:catalytic activity; TAS:ProtInc.
GO; GO:0042802; F:identical protein binding; IPI:UniProtKB.
GO; GO:0004655; F:porphobilinogen synthase activity; IDA:UniProtKB.
GO; GO:1904854; F:proteasome core complex binding; IEA:Ensembl.
GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
GO; GO:0071353; P:cellular response to interleukin-4; IEA:Ensembl.
GO; GO:0071284; P:cellular response to lead ion; IEA:Ensembl.
GO; GO:0006783; P:heme biosynthetic process; IDA:UniProtKB.
GO; GO:1901799; P:negative regulation of proteasomal protein catabolic process; IDA:CAFA.
GO; GO:0043312; P:neutrophil degranulation; TAS:Reactome.
GO; GO:0051260; P:protein homooligomerization; IPI:UniProtKB.
GO; GO:0006782; P:protoporphyrinogen IX biosynthetic process; IEA:UniProtKB-UniPathway.
GO; GO:0014823; P:response to activity; IEA:Ensembl.
GO; GO:0010044; P:response to aluminum ion; IEA:Ensembl.
GO; GO:0043200; P:response to amino acid; IEA:Ensembl.
GO; GO:0046685; P:response to arsenic-containing substance; IEA:Ensembl.
GO; GO:0046686; P:response to cadmium ion; IEA:Ensembl.
GO; GO:0032025; P:response to cobalt ion; IEA:Ensembl.
GO; GO:0042493; P:response to drug; IEA:Ensembl.
GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
GO; GO:0070542; P:response to fatty acid; IEA:Ensembl.
GO; GO:0051384; P:response to glucocorticoid; IEA:Ensembl.
GO; GO:0009635; P:response to herbicide; IEA:Ensembl.
GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
GO; GO:0010212; P:response to ionizing radiation; IEA:Ensembl.
GO; GO:0010039; P:response to iron ion; IEA:Ensembl.
GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
GO; GO:0046689; P:response to mercury ion; IEA:Ensembl.
GO; GO:0051597; P:response to methylmercury; IEA:Ensembl.
GO; GO:0006979; P:response to oxidative stress; IEA:Ensembl.
GO; GO:0070541; P:response to platinum ion; IEA:Ensembl.
GO; GO:0010269; P:response to selenium ion; IEA:Ensembl.
GO; GO:0010266; P:response to vitamin B1; IEA:Ensembl.
GO; GO:0033197; P:response to vitamin E; IEA:Ensembl.
GO; GO:0010043; P:response to zinc ion; IEA:Ensembl.
Gene3D; 3.20.20.70; -; 1.
InterPro; IPR001731; ALAD.
InterPro; IPR030656; ALAD_AS.
InterPro; IPR013785; Aldolase_TIM.
PANTHER; PTHR11458; PTHR11458; 1.
Pfam; PF00490; ALAD; 1.
PIRSF; PIRSF001415; Porphbilin_synth; 1.
PRINTS; PR00144; DALDHYDRTASE.
SMART; SM01004; ALAD; 1.
PROSITE; PS00169; D_ALA_DEHYDRATASE; 1.
1: Evidence at protein level;
3D-structure; Allosteric enzyme; Alternative splicing;
Complete proteome; Direct protein sequencing; Disease mutation;
Heme biosynthesis; Lyase; Metal-binding; Phosphoprotein; Polymorphism;
Porphyrin biosynthesis; Reference proteome; Zinc.
CHAIN 1 330 Delta-aminolevulinic acid dehydratase.
/FTId=PRO_0000140526.
ACT_SITE 199 199 Schiff-base intermediate with substrate.
{ECO:0000269|PubMed:3092810}.
ACT_SITE 252 252 Schiff-base intermediate with substrate.
{ECO:0000269|PubMed:3092810}.
METAL 122 122 Zinc 1; catalytic.
METAL 124 124 Zinc 1; catalytic.
METAL 131 131 Zinc 2.
METAL 132 132 Zinc 1; catalytic.
METAL 223 223 Zinc 2.
BINDING 209 209 Substrate 1.
BINDING 221 221 Substrate 1.
BINDING 279 279 Substrate 2.
BINDING 318 318 Substrate 2.
MOD_RES 199 199 N6-succinyllysine.
{ECO:0000250|UniProtKB:P10518}.
MOD_RES 215 215 Phosphoserine.
{ECO:0000250|UniProtKB:P10518}.
MOD_RES 252 252 N6-succinyllysine.
{ECO:0000250|UniProtKB:P10518}.
VAR_SEQ 1 38 MQPQSVLHSGYFHPLLRAWQTATTTLNASNLIYPIFVT ->
MPPTSSTPSLSRPGLGQAGKPDTGSHPPPTISTSIFLSCFP
TIPLSRPRTTGPSHSYQSISHPRSCR (in isoform
2). {ECO:0000303|PubMed:14702039}.
/FTId=VSP_037866.
VARIANT 12 12 F -> 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;
dbSNP:rs121912984).
{ECO:0000269|PubMed:10519994,
ECO:0000269|PubMed:16398658,
ECO:0000269|PubMed:17236137}.
/FTId=VAR_020973.
VARIANT 59 59 K -> N (common polymorphism; allele
ALAD*2; ALAD*2 heterozygous or homozygous
carriers have significantly higher blood
lead levels than ALAD*1 homozygotes when
exposed to environmental lead; fully
active octamer; dbSNP:rs1800435).
{ECO:0000269|PubMed:11032836,
ECO:0000269|PubMed:1716854,
ECO:0000269|PubMed:17236137,
ECO:0000269|PubMed:1769358,
ECO:0000269|Ref.5}.
/FTId=VAR_003633.
VARIANT 133 133 G -> R (in AHEPP; mixture of about 50%
hexamer and 50% octamer; about 10%
residual activity; dbSNP:rs121912980).
{ECO:0000269|PubMed:17236137,
ECO:0000269|PubMed:2063868}.
/FTId=VAR_003634.
VARIANT 153 153 V -> M (in AHEPP; about 95% octamer;
about 40% residual activity).
{ECO:0000269|PubMed:10706561,
ECO:0000269|PubMed:17236137}.
/FTId=VAR_020974.
VARIANT 240 240 R -> W (in AHEPP; mixture of about 80%
hexamer and 20% octamer; about 4%
residual activity; dbSNP:rs121912982).
{ECO:0000269|PubMed:1309003,
ECO:0000269|PubMed:1569184,
ECO:0000269|PubMed:17236137}.
/FTId=VAR_003635.
VARIANT 274 274 A -> T (in AHEPP; mixture of about 14%
hexamer and 86% octamer; about 20% enzyme
residual activity; dbSNP:rs121912983).
{ECO:0000269|PubMed:1309003,
ECO:0000269|PubMed:1569184,
ECO:0000269|PubMed:17236137}.
/FTId=VAR_003636.
VARIANT 275 275 V -> M (in AHEPP; mainly octamer; reduced
activity; dbSNP:rs121912981).
{ECO:0000269|PubMed:17236137,
ECO:0000269|PubMed:2063868}.
/FTId=VAR_003637.
MUTAGEN 122 122 C->A: Reduces enzyme activity about
1000000-fold; when associated with A-124
and A-132. {ECO:0000269|PubMed:11032836}.
MUTAGEN 124 124 C->A: Reduces enzyme activity about
1000000-fold; when associated with A-122
and A-132. {ECO:0000269|PubMed:11032836}.
MUTAGEN 131 131 H->A: No effect on catalytic activity;
when associated with A-223.
{ECO:0000269|PubMed:11032836}.
MUTAGEN 132 132 C->A: Reduces enzyme activity about
1000000-fold; when associated with A-122
and A-124. {ECO:0000269|PubMed:11032836}.
MUTAGEN 223 223 C->A: No effect on catalytic activity;
when associated with A-131.
{ECO:0000269|PubMed:11032836}.
HELIX 8 10 {ECO:0000244|PDB:5HMS}.
STRAND 11 13 {ECO:0000244|PDB:5HMS}.
HELIX 14 20 {ECO:0000244|PDB:1PV8}.
TURN 21 24 {ECO:0000244|PDB:1PV8}.
HELIX 28 30 {ECO:0000244|PDB:1PV8}.
STRAND 31 37 {ECO:0000244|PDB:1PV8}.
STRAND 44 46 {ECO:0000244|PDB:1PV8}.
STRAND 48 50 {ECO:0000244|PDB:1PV8}.
STRAND 54 56 {ECO:0000244|PDB:1PV8}.
HELIX 58 71 {ECO:0000244|PDB:1PV8}.
STRAND 75 80 {ECO:0000244|PDB:1PV8}.
STRAND 83 85 {ECO:0000244|PDB:5HMS}.
STRAND 88 90 {ECO:0000244|PDB:5HMS}.
HELIX 92 94 {ECO:0000244|PDB:5HMS}.
HELIX 100 111 {ECO:0000244|PDB:1PV8}.
STRAND 115 121 {ECO:0000244|PDB:1PV8}.
HELIX 124 126 {ECO:0000244|PDB:5HMS}.
STRAND 127 129 {ECO:0000244|PDB:5HMS}.
STRAND 131 133 {ECO:0000244|PDB:5HNR}.
STRAND 137 139 {ECO:0000244|PDB:5HMS}.
HELIX 141 160 {ECO:0000244|PDB:1PV8}.
STRAND 163 167 {ECO:0000244|PDB:1PV8}.
HELIX 174 184 {ECO:0000244|PDB:1PV8}.
TURN 188 190 {ECO:0000244|PDB:1PV8}.
STRAND 192 194 {ECO:0000244|PDB:1PV8}.
STRAND 198 200 {ECO:0000244|PDB:5HMS}.
HELIX 203 205 {ECO:0000244|PDB:1PV8}.
HELIX 206 210 {ECO:0000244|PDB:1PV8}.
STRAND 217 219 {ECO:0000244|PDB:5HMS}.
TURN 222 224 {ECO:0000244|PDB:5HMS}.
HELIX 231 243 {ECO:0000244|PDB:1PV8}.
STRAND 247 253 {ECO:0000244|PDB:1PV8}.
HELIX 255 257 {ECO:0000244|PDB:1PV8}.
HELIX 258 267 {ECO:0000244|PDB:1PV8}.
STRAND 273 277 {ECO:0000244|PDB:1PV8}.
HELIX 279 290 {ECO:0000244|PDB:1PV8}.
HELIX 296 310 {ECO:0000244|PDB:1PV8}.
STRAND 313 317 {ECO:0000244|PDB:1PV8}.
HELIX 320 326 {ECO:0000244|PDB:1PV8}.
TURN 327 329 {ECO:0000244|PDB:1PV8}.
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


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