Mechanism of 5-aminolevulinate synthase and the role of the protein environment in controlling the cofactor chemistry.
5-Aminolevulinate synthase, a pyridoxal 5'-phosphate-dependent enzyme of the alpha-oxoamine synthase family, catalyzes the first step of the heme biosynthetic pathway in mammalian cells. This reaction entails the condensation of glycine with succinyl-coenzyme A to yield 5-aminolevulinate, carbon dioxide and CoA. Mutations in the erythroid aminolevulinate synthase gene lead to a defective enzyme and are associated with the erythropoietic disorder X-linked sideroblastic anemia. In the past few years, rapid scanning-stopped-flow spectroscopy and chemical quenched-flow studies of the ALAS reaction, under single- and multi-turnover conditions, have provided important results for the interpretation of the catalytic mechanism. In particular, the role of the protein scaffold in modulating the chemical reactivity of the pyridoxal 5'-phosphate cofactor and, thus, the catalytic pathway of ALAS has been investigated in our laboratory using transient kinetics and global analysis of the kinetic data.
Ferreira
G C
GC
Department of Biochemistry and Molecular Biology, College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, Florida 33612-4799, USA. gferreir@hsc.usf.edu
Zhang
J S
JS
D000624:5-Aminolevulinate Synthetase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D006801:Humans; D007700:Kinetics; D051379:Mice; D008956:Models, Chemical; D009154:Mutation; D013057:Spectrum Analysis
D000214:Acyl Coenzyme A; C012046:succinyl-coenzyme A; D000624:5-Aminolevulinate Synthetase