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delta-aminolevulinic acid dehydratase; ALADH; porphobilinogen synthase (ALAD)

Function: - catalyzes an early step in the biosynthesis of tetrapyrroles - binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, & catalyzes their condensation to form porphobilinogen 2 5-aminolevulinate = porphobilinogen + 2 H2O - can alternate between a fully active homooctamer & a low-activity homohexamer - a bound Mg+2 may promote the assembly of the fully active homooctamer - the Mg+2-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 Zn+2 cofactor - porphyrin metabolism; protoporphyrin-IX biosynthesis - coproporphyrinogen-III from 5-aminolevulinate: step 1/4 Cofactor: - binds 8 Zn+2 per octamer - only 4 Zn+2 per octamer are required for full catalytic activity - only 4 Zn+2 per octamer are tightly bound - can bind 2 Zn+2 per subunit - the 1st Zn+2 is important for catalysis Kinetic parameters: - KM=0.09 mM for 5-aminolevulinate at pH 7 - Vmax=43 umol/h/mg enzyme at pH 7 - pH dependence: Optimum pH is 6.8-7.3 Structure: belongs to the ALADH family Alternative splicing: named isoforms=2 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 Pathology: - defects in ALAD are the cause of acute hepatic porphyria

Interactions

molecular events

Related

heme synthesis

General

hydro-lyase, hydratase or dehydratase metalloprotein oligomerizing protein

Properties

SIZE: entity length = 330 aa MW = 36 kD MOTIF: Zn+2-binding site SITE: 122-122 Zn+2-binding site SITE: 124-124 Zn+2-binding site SITE: 131-131 Zn+2-binding site SITE: 132-132 active site lysine residue {K199} binding site SITE: 209-209 FOR-BINDING-OF: Substrate 1 binding site SITE: 221-221 FOR-BINDING-OF: Substrate 1 Zn+2-binding site SITE: 223-223 lysine residue {K252} binding site SITE: 279-279 FOR-BINDING-OF: Substrate 2 binding site SITE: 318-318 FOR-BINDING-OF: Substrate 2

Database Correlations

OMIM correlations UniProt P13716 Pfam PF00490 Entrez Gene 210 Kegg hsa:210 ENZYME 4.2.1.24

References

  1. UniProt :accession P13716
  2. GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/ALAD
  3. NIEHS-SNPs http://egp.gs.washington.edu/data/alad/
  4. Textbook of Biochemistry with Clinical Correlations, 3rd ed., TM Devlin (ed), Wiley-Liss, NY 1992 pg 1013