title: Catalytic mechanism of porphobilinogen synthase: the chemical step revisited by QM/MM calculations.
abstract: Porphobilinogen synthase (PBGS) catalyzes the asymmetric condensation and cyclization of two 5-aminolevulinic acid (5-ALA) substrate molecules to give porphobilinogen (PBG). The chemical step of PBGS is herein revisited using QM/MM (ONIOM) calculations. Two different protonation states and several different mechanisms are considered. Previous mechanisms based on DFT-only calculations are shown unlikely to occur. According to these new calculations, the deprotonation step rather than ring closure is rate-limiting. Both the C-C bond formation first mechanism and the C-N bond formation first mechanism are possible, depending on how the A-site ALA binds to the enzyme. We furthermore propose that future work should focus on the substrate binding step rather than the enzymatic mechanism.
authors.affiliation: School of Chemistry, National University of Ireland-Galway, Galway, Ireland.
authors.forename: Bo-Xue
authors.initials: BX
authors.lastname: Tian
authors.forename: Edvin
authors.initials: E
authors.lastname: Erdtman
authors.forename: Leif A
authors.initials: LA
authors.lastname: Eriksson
mesh_terms: D000622:Aminolevulinic Acid / Q000737:chemistry / Q000378:metabolism*; D055162:Biocatalysis; D003500:Cyclization; D015394:Molecular Structure; D000623:Porphobilinogen Synthase / Q000737:chemistry / Q000378:metabolism*; D011789:Quantum Theory
chemical_list: D000622:Aminolevulinic Acid; D000623:Porphobilinogen Synthase