Evolution and Analysis of the Functional Domains of the Chimeric Proteins That Initiate Pyrimidine Biosynthesis.
Final rept. 1 Dec 86-31 Jul 90,
WAYNE STATE UNIV DETROIT MI DEPT OF BIOCHEMISTRY
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The objective of this project is to test the hypothesis that the complex proteins with novel functions arose in the course of evolution by combining structural domains having partial functions. The research focuses on the enzymes that catalyze de novo pyrimidine biosynthesis. While the reactions are the same in most organisms, there are striking differences in the structure and regulation of these enzymes. This year we completed the sequence of the mammalian protein CAD, a 243 kDa polypeptide which carries glutamine dependent GLN carbamyl phosphate synthetase CPS, aspartate transcarbamylase ATC and dihydroorotase DHO activities. Phylogenetic analysis suggests that the mammalian chimeric protein was formed by stepwise translocation and fusion of ancestral genes that occurred prior to the major radiation that lead to fungi, plants and animals. The sequence divergence suggests that the fused and monofunctional DHO domains have a different evolutionary history. In contrast, sequence studies and molecular modeling of the mammalian ATC domain and a reexamination of the subunit structure of a class A ATCase, thought to have a radically different structure, showed that the ATCase catalytic domain is a trimer of identical 34 kDa polypeptides that has been highly conserved throughout the course of evolution. Chimeric or multifunctional proteins, protein domains, pyrimidine biosynthesis, carbamyl phosphate synthetase, aspartate transcarbamylase, dihydroorotase, molecular evolution.
- Organic Chemistry