Reviewed, UniProtKB/Swiss-Prot P13716 (HEM2_HUMAN)

Names and origin

Protein names

Recommended name:
    Delta-aminolevulinic acid dehydratase
      Short name=ALADH
    EC=4.2.1.24
Alternative name(s):
    Porphobilinogen synthase

Gene names

Name:

ALAD

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	330 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Catalytic activity	2 5-aminolevulinate = porphobilinogen + 2 H2O.
Cofactor	Zinc.
Pathway	Porphyrin metabolism; protoporphyrin-IX biosynthesis; coproporphyrinogen-III from 5-aminolevulinate: step 1/4.
Subunit structure	Homooctamer.
Polymorphism	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.
Involvement in disease	Defects in ALAD are the cause of acute hepatic porphyria (AHP) [MIM:125270]. AHP is a form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme. AHP is characterized by attacks of gastrointestinal disturbances, abdominal colic, paralysis, and peripheral neuropathy. Most attacks are precipitated by drugs, alcohol, caloric deprivation, infections, or endocrine factors. Ref.3 Ref.13 Ref.15
Sequence similarities	Belongs to the ALADH family.

Ontologies

Keywords
Biological process	Heme biosynthesis Porphyrin biosynthesis
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Ligand	Metal-binding Zinc
Molecular function	Lyase
Technical term	3D-structure Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	heme biosynthetic process Traceable author statement. Source: ProtInc
Cellular component	cytosol Inferred from Experiment. Source: Reactome
Molecular function	porphobilinogen synthase activity Ref.1 Traceable author statement. Source: ProtInc zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P13716-1)

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.

Isoform 2 (identifier: P13716-2)

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

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 330

330

Delta-aminolevulinic acid dehydratase

PRO_0000140526

Sites

Active site

252

1

Ref.9

Metal binding

122

1

Zinc; catalytic

Metal binding

124

1

Zinc; catalytic

Metal binding

132

1

Zinc; catalytic

Natural variations

Alternative sequence

1 – 38

38

MQPQS…PIFVT → MPPTSSTPSLSRPGLGQAGK PDTGSHPPPTISTSIFLSCF PTIPLSRPRTTGPSHSYQSI SHPRSCR in isoform 2.

VSP_037866

Natural variant

12

1

F → L in an asymptomatic patient with ALAD deficiency; significant reduction of activity; also found in a hereditary coproporphyria patient carrying the R-279 mutation in CPOX. Ref.14 Ref.16

VAR_020973

Natural variant

59

1

K → N in allele ALAD*2; 10% of population. dbSNP rs1800435. Ref.5 Ref.12

VAR_003633

Natural variant

133

1

G → R in AHP. Ref.13

VAR_003634

Natural variant

153

1

V → M in AHP; reduction of activity. Ref.15

VAR_020974

Natural variant

240

1

R → W in AHP. Ref.3

VAR_003635

Natural variant

274

1

A → T in AHP. Ref.3

VAR_003636

Natural variant

275

1

V → M in AHP. Ref.13

VAR_003637

Secondary structure

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330

Helix Strand Turn

Details...

Helix

14 – 20

7

Turn

21 – 24

4

Helix

28 – 30

3

Beta strand

31 – 37

7

Beta strand

44 – 46

3

Beta strand

48 – 50

3

Beta strand

54 – 56

3

Helix

58 – 71

14

Beta strand

75 – 80

6

Helix

100 – 111

12

Beta strand

115 – 121

7

Helix

141 – 160

20

Beta strand

163 – 167

5

Helix

174 – 184

11

Turn

188 – 190

3

Beta strand

192 – 194

3

Helix

203 – 205

3

Helix

206 – 210

5

Helix

231 – 243

13

Beta strand

247 – 253

7

Helix

255 – 257

3

Helix

258 – 267

10

Beta strand

273 – 277

5

Helix

279 – 290

12

Helix

296 – 310

15

Beta strand

313 – 317

5

Helix

320 – 326

7

Turn

327 – 329

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified January 1, 1990. Version 1. Checksum: E005F3055F6D9403	FASTA	330	36,295
	10 20 30 40 50 60 MQPQSVLHSG YFHPLLRAWQ TATTTLNASN LIYPIFVTDV PDDIQPITSL PGVARYGVKR 70 80 90 100 110 120 LEEMLRPLVE EGLRCVLIFG VPSRVPKDER GSAADSEESP AIEAIHLLRK TFPNLLVACD 130 140 150 160 170 180 VCLCPYTSHG HCGLLSENGA FRAEESRQRL AEVALAYAKA GCQVVAPSDM MDGRVEAIKE 190 200 210 220 230 240 ALMAHGLGNR VSVMSYSAKF ASCFYGPFRD AAKSSPAFGD RRCYQLPPGA RGLALRAVDR 250 260 270 280 290 300 DVREGADMLM VKPGMPYLDI VREVKDKHPD LPLAVYHVSG EFAMLWHGAQ AGAFDLKAAV 310 320 330 LEAMTAFRRA GADIIITYYT PQLLQWLKEE
	Isoform 2. Checksum: 4AD5F3B2570ACD81	FASTA	359	39,034
	10 20 30 40 50 60 MPPTSSTPSL SRPGLGQAGK PDTGSHPPPT ISTSIFLSCF PTIPLSRPRT TGPSHSYQSI 70 80 90 100 110 120 SHPRSCRDVP DDIQPITSLP GVARYGVKRL EEMLRPLVEE GLRCVLIFGV PSRVPKDERG 130 140 150 160 170 180 SAADSEESPA IEAIHLLRKT FPNLLVACDV CLCPYTSHGH CGLLSENGAF RAEESRQRLA 190 200 210 220 230 240 EVALAYAKAG CQVVAPSDMM DGRVEAIKEA LMAHGLGNRV SVMSYSAKFA SCFYGPFRDA 250 260 270 280 290 300 AKSSPAFGDR RCYQLPPGAR GLALRAVDRD VREGADMLMV KPGMPYLDIV REVKDKHPDL 310 320 330 340 350 PLAVYHVSGE FAMLWHGAQA GAFDLKAAVL EAMTAFRRAG ADIIITYYTP QLLQWLKEE

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human delta-aminolevulinate dehydratase: nucleotide sequence of a full-length cDNA clone." Wetmur J.G., Bishop D.F., Cantelmo C., Desnick R.J. Proc. Natl. Acad. Sci. U.S.A. 83:7703-7707(1986) [PubMed: 3463993] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"RsaI polymorphism in the human delta-aminolevulinate dehydratase gene at 9q34." Wetmur J.G. Nucleic Acids Res. 19:4307-4307(1991) [PubMed: 1678509] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Liver.
[3]	"Cloning and expression of the defective genes from a patient with delta-aminolevulinate dehydratase porphyria." Ishida N., Fujita H., Fukuda Y., Noguchi T., Doss M., Kappas A., Sassa S. J. Clin. Invest. 89:1431-1437(1992) [PubMed: 1569184] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS AHP TRP-240 AND THR-274.
[4]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." 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. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). Tissue: Brain and Tongue.
[5]	NIEHS SNPs program Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT ASN-59.
[6]	"DNA sequence and analysis of human chromosome 9." 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. Nature 429:369-374(2004) [PubMed: 15164053] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Placenta.
[8]	"Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides." Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R., Vandekerckhove J. Nat. Biotechnol. 21:566-569(2003) [PubMed: 12665801] [Abstract] Cited for: PROTEIN SEQUENCE OF 1-17. Tissue: Platelet.
[9]	"Identification of lysine at the active site of human 5-aminolaevulinate dehydratase." Gibbs P.N.B., Jordan P.M. Biochem. J. 236:447-451(1986) [PubMed: 3092810] [Abstract] Cited for: ACTIVE SITE.
[10]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[11]	Mills-Davies N.L., Thompson D., Cooper J.B., Shoolingin-Jordan P.M. Submitted (OCT-1998) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.83 ANGSTROMS).
[12]	"Molecular characterization of the human delta-aminolevulinate dehydratase 2 (ALAD2) allele: implications for molecular screening of individuals for genetic susceptibility to lead poisoning." Wetmur J.G., Kaya A.H., Plewinska M., Desnick R.J. Am. J. Hum. Genet. 49:757-763(1991) [PubMed: 1716854] [Abstract] Cited for: VARIANT ASN-59.
[13]	"Delta-aminolevulinate dehydratase deficient porphyria: identification of the molecular lesions in a severely affected homozygote." Plewinska M., Thunell S., Holmberg L., Wetmur J.G., Desnick R.J. Am. J. Hum. Genet. 49:167-174(1991) [PubMed: 2063868] [Abstract] Cited for: VARIANTS AHP ARG-133 AND MET-275.
[14]	"A novel mutation of delta-aminolaevulinate dehydratase in a healthy child with 12% erythrocyte enzyme activity." Akagi R., Yasui Y., Harper P., Sassa S. Br. J. Haematol. 106:931-937(1999) [PubMed: 10519994] [Abstract] Cited for: VARIANT LEU-12, CHARACTERIZATION OF VARIANT LEU-12.
[15]	"Novel molecular defects of the delta-aminolevulinate dehydratase gene in a patient with inherited acute hepatic porphyria." Akagi R., Shimizu R., Furuyama K., Doss M.O., Sassa S. Hepatology 31:704-708(2000) [PubMed: 10706561] [Abstract] Cited for: VARIANT AHP MET-153, CHARACTERIZATION OF VARIANT AHP MET-153.
[16]	"Dual gene defects involving delta-aminolaevulinate dehydratase and coproporphyrinogen oxidase in a porphyria patient." Akagi R., Inoue R., Muranaka S., Tahara T., Taketani S., Anderson K.E., Phillips J.D., Sassa S. Br. J. Haematol. 132:237-243(2006) [PubMed: 16398658] [Abstract] Cited for: VARIANT LEU-12.
+	Additional computationally mapped references.

Web resources

GeneReviews

NIEHS-SNPs

Cross-references

Sequence databases

EMBLGenBankDDBJ

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.

IPI

IPI00442121.
IPI00937974.

PIR

A26478.

RefSeq

NP_000022.3.

UniGene

Hs.1227

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1E51	X-ray	2.83	A/B	1-330	[»]
1PV8	X-ray	2.20	A/B	1-330	[»]

ModBase

Search...

Protein-protein interaction databases

STRING

P13716.

PTM databases

PhosphoSite

P13716.

2-D gel databases

SWISS-2DPAGE

P13716.

OGP

P13716.

REPRODUCTION-2DPAGE

P13716.

Proteomic databases

PRIDE

P13716.

Genome annotation databases

Ensembl

ENST00000277315; ENSP00000277315; ENSG00000148218; Homo sapiens. [Genome view]
ENST00000374173; ENSP00000363288; ENSG00000148218; Homo sapiens. [Genome view]
ENST00000409155; ENSP00000386284; ENSG00000148218; Homo sapiens. [Genome view]
ENST00000445750; ENSP00000398438; ENSG00000148218; Homo sapiens. [Genome view]
ENST00000448137; ENSP00000392748; ENSG00000148218; Homo sapiens. [Genome view]
ENST00000452726; ENSP00000415737; ENSG00000148218; Homo sapiens. [Genome view]

GeneID

210.

KEGG

hsa:210.

NMPDR

fig|9606.3.peg.31768.

UCSC

uc004bhm.2. human.

Organism-specific databases

CTD

210.

GeneCards

GC09M115188.

HGNC

HGNC:395. ALAD.

HPA

HPA021023.
HPA022124.

MIM

125270. gene+phenotype.

Orphanet

95157. Porphyria, acute hepatic.

PharmGKB

PA24687.

GenAtlas

Search...

Phylogenomic databases

HOVERGEN

P13716.

Enzyme and pathway databases

BRENDA

4.2.1.24. 247.

Reactome

REACT_9431. Metabolism of porphyrins.

Gene expression databases

ArrayExpress

P13716.

Bgee

P13716.

CleanEx

HS_ALAD.

Genevestigator

P13716.

GermOnline

ENSG00000148218. Homo sapiens.

Family and domain databases

InterPro

IPR001731. 4pyrrol_synth_porphobiln_synth.
IPR013785. Aldolase_TIM.
[Graphical view]

Gene3D

G3DSA:3.20.20.70. Aldolase_TIM. 1 hit.

PANTHER

PTHR11458. AlaD_dehydratase. 1 hit.

Pfam

PF00490. ALAD. 1 hit.
[Graphical view]

PIRSF

PIRSF001415. Porphbilin_synth. 1 hit.

PRINTS

PR00144. DALDHYDRTASE.

ProDom

PD002304. AlaD_dehydratase. 1 hit.
[Graphical view] [Entries sharing at least one domain]

PROSITE

PS00169. D_ALA_DEHYDRATASE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB00855. Aminolevulinic acid.

NextBio

840.

SOURCE

Search...

Entry information

Entry name

HEM2_HUMAN

Accession

Primary (citable) accession number: P13716
Secondary accession number(s): A8K375 , B2R6F2, Q16870, Q16871, Q9BVQ9

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 1, 1990
Last sequence update:	January 1, 1990
Last modified:	November 3, 2009
This is version 116 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any 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.