2bmb
From Proteopedia
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==Overview== | ==Overview== | ||
| - | In Saccharomyces cerevisiae and other fungi, the enzymes dihydroneopterin | + | 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. |
==About this Structure== | ==About this Structure== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Berglez, J.]] | [[Category: Berglez, J.]] | ||
| - | [[Category: Fernley, R | + | [[Category: Fernley, R T.]] |
[[Category: Iliades, P.]] | [[Category: Iliades, P.]] | ||
| - | [[Category: Lawrence, M | + | [[Category: Lawrence, M C.]] |
| - | [[Category: Macreadie, I | + | [[Category: Macreadie, I G.]] |
| - | [[Category: Pilling, P | + | [[Category: Pilling, P A.]] |
[[Category: PMM]] | [[Category: PMM]] | ||
[[Category: folate biosynthesis]] | [[Category: folate biosynthesis]] | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:39:18 2008'' |
Revision as of 14:39, 21 February 2008
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X-RAY STRUCTURE OF THE BIFUNCTIONAL 6-HYDROXYMETHYL-7,8-DIHYDROXYPTERIN PYROPHOSPHOKINASE DIHYDROPTEROATE SYNTHASE FROM SACCHAROMYCES CEREVISIAE
Overview
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.
About this Structure
2BMB is a Single protein structure of sequence from Saccharomyces cerevisiae with as ligand. Known structural/functional Site: . Full crystallographic information is available from OCA.
Reference
The three-dimensional structure of the bifunctional 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase/dihydropteroate synthase of Saccharomyces cerevisiae., Lawrence MC, Iliades P, Fernley RT, Berglez J, Pilling PA, Macreadie IG, J Mol Biol. 2005 May 6;348(3):655-70. PMID:15826662
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