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

Pathology

• defects in ALAD are the cause of acute hepatic porphyria

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

More general terms

• hydro-lyase, hydratase or dehydratase
• metalloprotein
• oligomerizing protein

Additional terms

• heme synthesis

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=210
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:210
• OMIM: https://mirror.omim.org/entry/125270
• OMIM: https://mirror.omim.org/entry/612740
• UniProt: http://www.uniprot.org/uniprot/P13716.html