PORPHOBILINOGEN DEAMINASE AND UROPORPHYRINOGEN-III SYNTHASE - STRUCTURE, MOLECULAR-BIOLOGY, AND MECHANISM

Porphobilinogen deaminase (hydroxymethylbilane synthase) and uroporphy rinogen III synthase (uroporphyrinogen III cosynthase) catalyze the tr ansformation of four molecules of porphobilinogen, via the 1-hydroxyme thylbilane, preuroporphyrinogen, into uroporphyrinogen III. A combinat ion of studies involving protein chemistry, molecular biology, site-di rected mutagenesis, and the use of chemically synthesized substrate an alogs and inhibitors is helping to unravel the complex mechanisms by w hich the two enzymes function. The determination of the X-ray structur e of E. coli porphobilinogen deaminase at 1.76 Angstrom resolution has provided the springboard for the design of further experiments to elu cidate the precise mechanism for the assembly of both the dipyrrometha ne cofactor and the tetrapyrrole chain. The human deaminase structure has been modeled from the E. coli structure and has led to a molecular explanation for the disease acute intermittent porphyria. Molecular m odeling has also been employed to simulate the spiro-mechanism of urop orphyrinogen III synthase.