Dihydropteroate synthase: Difference between revisions
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<StructureSection load='' size='350' side='right' scene='' caption='Dihydropteroate synthase complex with sulfate (PDB code [[1tws]])'> | <StructureSection load='1tws' size='350' side='right' scene='' caption='Dihydropteroate synthase complex with sulfate (PDB code [[1tws]])'> | ||
=== Insights into the drug resistance induced by the BaDHPS mutations: molecular dynamic simulations and MM/GBSA studies <ref>doi 10.1080/07391102.2012.726529</ref> | __TOC__ | ||
==Function== | |||
'''Dihydropteroate synthase''' (DHPS) catalyzes the condensation of 6-hydroxymethyl-7,8-dihydropteridine pyrophosphate to para-aminobenzoic acid (PABA) to form 7,8-dihydropteroate. DHPs is a key enzyme in folate synthesis. Folate is necessary for nucleic acid synthesis. DHPS is found in bacteria and not in eukaryotes. Hence, it makes a target to sulfonamide antibiotics<ref>PMID:10329458</ref> | |||
*'''7,8-dihydro-6-hydroxymethylpterin pyrophsphokinase-DHPS''' contains a dihydro-6-hydroxymethylpterin pyrophosphokinase domain at the N terminal and is named '''HPPK-DHPS'''. | |||
== Insights into the drug resistance induced by the BaDHPS mutations: molecular dynamic simulations and MM/GBSA studies <ref>doi 10.1080/07391102.2012.726529</ref>== | |||
Drug resistance has been an urgent problem that severely limits the therapy of current clinical microbial diseases. Sometimes, it generally correlates with mutations to the dihydropteroate synthase (DHPS) gene. | Drug resistance has been an urgent problem that severely limits the therapy of current clinical microbial diseases. Sometimes, it generally correlates with mutations to the dihydropteroate synthase (DHPS) gene. | ||
In the current study, we focus on the molecular dynamic behaviors and binding free energy calculations of <scene name='50/509381/Cv/10'>wild-type (wt)</scene> form and <scene name='50/509381/Cv/11'>mutated forms</scene> ''B. anthracis'' dihydropteroate synthase (BaDHPS) to search for the relationship between mutation and drug resistance. <span style="color:khaki;background-color:black;font-weight:bold;">Wt-BaDHPS is colored in khaki</span>, mutated <span style="color:lime;background-color:black;font-weight:bold;">D184N complex is in green</span> and <span style="color:cyan;background-color:black;font-weight:bold;">K220Q complex is in cyan</span>. | In the current study, we focus on the molecular dynamic behaviors and binding free energy calculations of <scene name='50/509381/Cv/10'>wild-type (wt)</scene> form and <scene name='50/509381/Cv/11'>mutated forms</scene> ''B. anthracis'' dihydropteroate synthase (BaDHPS) to search for the relationship between mutation and drug resistance. <span style="color:khaki;background-color:black;font-weight:bold;">Wt-BaDHPS is colored in khaki</span>, mutated <span style="color:lime;background-color:black;font-weight:bold;">D184N complex is in green</span> and <span style="color:cyan;background-color:black;font-weight:bold;">K220Q complex is in cyan</span>. | ||
After 20ns MD simulations on the <scene name='50/509381/Cv/12'>wt form and mutated form enzymes</scene>, it is obvious that <scene name='50/509381/8/1'>mutation D184N and K220Q have much lower binding affinity to the inhibitor DHP-STZ than the wt form enzyme</scene>. Only Loop 1, Loop 2 and Loop 7 are colored, ligand DHP-STZ is colored in the same color as the corresponding protein: for <span style="color:khaki;background-color:black;font-weight:bold;">Wt-BaDHPS is colored in khaki</span>, for mutated <span style="color:lime;background-color:black;font-weight:bold;">D184N complex is in green</span> and for <span style="color:cyan;background-color:black;font-weight:bold;">K220Q complex is in cyan</span>. Mutation will cause conformational change, which mainly locate on some loop region around the binding site (Loop 1, Loop 2 and Loop 7). These results may be helpful for further drug resistance and de novo drug design investigations. | After 20ns MD simulations on the <scene name='50/509381/Cv/12'>wt form and mutated form enzymes</scene>, it is obvious that <scene name='50/509381/8/1'>mutation D184N and K220Q have much lower binding affinity to the inhibitor DHP-STZ than the wt form enzyme</scene>. Only Loop 1, Loop 2 and Loop 7 are colored, ligand DHP-STZ is colored in the same color as the corresponding protein: for <span style="color:khaki;background-color:black;font-weight:bold;">Wt-BaDHPS is colored in khaki</span>, for mutated <span style="color:lime;background-color:black;font-weight:bold;">D184N complex is in green</span> and for <span style="color:cyan;background-color:black;font-weight:bold;">K220Q complex is in cyan</span>. Mutation will cause conformational change, which mainly locate on some loop region around the binding site (Loop 1, Loop 2 and Loop 7). These results may be helpful for further drug resistance and de novo drug design investigations. | ||
==3D structures of dihydropteroate synthase== | ==3D structures of dihydropteroate synthase== | ||
[[Dihydropteroate synthase 3D structures]] | |||
</StructureSection> | |||
==References== | |||
<references/> | <references/> | ||
[[Category:Topic Page]] | [[Category:Topic Page]] | ||