Argininosuccinate lyase
Crystallographic structure of the human ASL monomer with labeled domains.
Identifiers
Symbol	ASL
Entrez	435
HUGO	746
OMIM	608310
RefSeq	NM_000048
UniProt	P04424
Other data
EC number	4.3.2.1
Locus	Chr. 7 pter-q22

ASL (argininosuccinate lyase, also known as argininosuccinase) is an enzyme that catalyzes the reversible breakdown of argininosuccinate (ASA) producing the amino acid arginine and dicarboxylic acid fumarate. Located in liver cytosol, ASL is the fourth enzyme of the urea cycle and involved in the biosynthesis of arginine in all species and the production of urea in ureotelic species. Mutations in ASL, resulting low activity of the enzyme, increase levels of urea in the body and result in various side effects.

The ASL gene is located on chromosome 7 between the centromere (junction of the long and short arm) and the long (q) arm at position 11.2, from base pair 64,984,963 to base pair 65,002,090.

ASL is related to intragenic complementation.

ASL is composed of four identical monomers; each monomer consisting of a single polypeptide chain between 49 and 52 kDa, between 196 and 208 kDa for the entire tetrameric enzyme. Each monomer has three highly conserved regions remote from one another, but these regions cluster together in the tetramer to form four active sites. Therefore, each ASL homotetramer has four active sites to catalyze the breakdown of argininosuccinate.

Each monomer in the ASL homotetramer is composed of three structural domains; all three are primarily alpha helical. Domains 1 and 3 are similar in structure as they both consist of helix-turn-helix motifs. Domain 1 of the monomer contains the amino terminus. Domain 2 contains one small beta sheet, nine alpha helices, and the carboxyl terminus. Three of the nine alpha helices on one monomer are engaged mainly in hydrophobic interactions with another monomer to form a dimer. Two dimers then associate by way of alpha helix, one from each monomer, to form a central 20-helix core. The association of all four monomers allows for the catalytic activity at each possible active site.

The enzyme's cleavage of the argininosuccinate, to form fumarate and arginine, occurs through an E1cb elimination reaction. The base initiates the reaction by deprotonating the carbon adjacent to the arginine, or leaving group. Recent mutagenic studies of ASL homologues have shown that Histidine 162 or Threonine 161 of ASL is responsible for the proton abstraction of the Cβ, either directly or indirectly through a water molecule. Lysine 289 is thought to stabilize the negatively charged carbanion intermediate. Although there is no consensus of the catalytic acid that donates the proton to the imine functional group of the arginine product, some mutagenesis studies show serine 283 may be involved.

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