The three-dimensional structure of the bifunctional 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase/dihydropteroate synthase of Saccharomyces cerevisiae
| Autor: | Michael C. Lawrence, Ian Macreadie, Ross Fernley, Peter Iliades, Patricia A. Pilling, Janette Berglez |
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| Rok vydání: | 2004 |
| Předmět: |
Models
Molecular Saccharomyces cerevisiae Proteins Stereochemistry Saccharomyces cerevisiae Molecular Sequence Data DHPS Dihydroneopterin aldolase Crystallography X-Ray Ligands chemistry.chemical_compound Structural Biology parasitic diseases Dihydrofolate reductase Transferase Amino Acid Sequence Pterin Protein Structure Quaternary Molecular Biology chemistry.chemical_classification Dihydropteroate Synthase Binding Sites biology biology.organism_classification Protein Structure Tertiary Enzyme chemistry Biochemistry biology.protein Diphosphotransferases Dihydropteroate synthase Sequence Alignment |
| Zdroj: | Journal of molecular biology. 348(3) |
| ISSN: | 0022-2836 |
| Popis: | In Saccharomyces cerevisiae and other fungi, the enzymes dihydroneopterin aldolase, 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) and dihydropteroate synthase (DHPS) are encoded by a polycistronic gene that is translated into a single polypeptide having all three functions. These enzymatic functions are essential to both prokaryotes and lower eukaryotes, and catalyse sequential reactions in folate biosynthesis. Deletion or disruption of either function leads to cell death. These enzymes are absent from mammals and thus make ideal antimicrobial targets. DHPS is currently the target of antifolate therapy for a number of infectious diseases, and its activity is inhibited by sulfonamides and sulfones. These drugs are typically used as part of a synergistic cocktail with the 2,4-diaminopyrimidines that inhibit dihydrofolate reductase. A gene encoding the S.cerevisiae HPPK and DHPS enzymes has been cloned and expressed in Escherichia coli. A complex of the purified bifunctional polypeptide with a pterin monophosphate substrate analogue has been crystallized, and its structure solved by molecular replacement and refined to 2.3A resolution. The polypeptide consists of two structural domains, each of which closely resembles its respective monofunctional bacterial HPPK and DHPS counterpart. The mode of ligand binding is similar to that observed in the bacterial enzymes. The association between the domains within the polypeptide as well as the quaternary association of the polypeptide via its constituent DHPS domains provide insight into the assembly of the trifunctional enzyme in S.cerevisiae and probably other fungal species. |
| Databáze: | OpenAIRE |
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