The crystal structure of adenylosuccinate lyase from Pyrobaculum aerophilum reveals an intracellular protein with three disulfide bonds

Adenylosuccinate lyase catalyzes two separate reactions in the de novo puri ne biosynthetic pathway. Through its dual action in this pathway, adenylosu ccinate lyase plays an integral part in cellular replication and metabolism . Mutations in the human enzyme can result in severe neurological disorders , including mental retardation with autistic features. The crystal structur e of adenylosuccinate lyase from the hyperthermophilic archaebacterium Pyro baculum aerophilum has been determined to 2.1 Angstrom resolution. Although both the fold of the monomer and the architecture of the tetrameric asssem bly are similar to adenylosuccinate lyase from the thermophilic eubacterium Thermotoga maritima, the archaebacterial lyase contains unique features. S urprisingly, the structure of adenylosuccinate lyase from P. aerophilum rev eals that this intracellular protein contains three disulfide bonds that co ntribute significantly to its stability against thermal and chemical denatu ration. The observation of multiple disulfide bonds in the recombinant form of the enzyme suggests the need for further investigations into whether th e intracellular environment of P. aerophilum, and possibly other hypertherm ophiles, may be compatible with protein disulfide bond formation. In additi on, the protein is shorter in P. aerophilum than it is in other organisms. This abbreviation results from an internal excision of a cluster of helices that may be involved in protein-protein interactions in other organisms an d may relate to the observed clinical effects of human mutations in that re gion. (C) 2000 Academic Press.