Probing the active site of rat porphobilinogen synthase using newly developed inhibitors.
The structurally related tetrapyrrolic pigments are a group of natural products that participate in many of the fundamental biosynthetic and catabolic processes of living organisms. Porphobilinogen synthase catalyzes a rate-limiting step for the biosyntheses of tetrapyrrolic natural products. In the present study, a variety of new substrate analogs and reaction intermediate analogs were synthesized, which were used as probes for studying the active site of rat porphobilinogen synthase. The compounds 1, 3, 6, 9, 14, 16, and 28 were found to be competitive inhibitors of rat porphobilinogen synthase with inhibition constants ranging from 0.96 to 73.04mM. Compounds 7, 10, 12, 13, 15, 17, 18, and 26 were found to be irreversible enzyme inhibitors. For irreversible inhibitors, loose-binding inhibitors were found to give stronger inactivation. The amino group and carboxyl group of the analogs were found to be important for their binding to the enzyme. This study increased our understanding of the active site of porphobilinogen synthase.
Li
Nan
N
Department of Biology and Chemistry, City University of Hong Kong, Kowloon, SAR, PR China.
Chu
Xiusheng
X
Liu
Xiaojun
X
Li
Ding
D
D000595:Amino Acid Sequence; D000818:Animals; D002384:Catalysis; D020134:Catalytic Domain; D003001:Cloning, Molecular; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology*; D007700:Kinetics; D008956:Models, Chemical; D008969:Molecular Sequence Data; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D000623:Porphobilinogen Synthase