|
|
| (23 intermediate revisions by 3 users not shown) |
| Line 1: |
Line 1: |
| <StructureSection load='' size='450' side='right' scene='Journal:JBSD:24/Cv/1' caption=''> | | <StructureSection load='1tws' size='350' side='right' scene='' caption='Dihydropteroate synthase complex with sulfate (PDB code [[1tws]])'> |
| '''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. Some DHPS contain a dihydro-6-hydroxymethylpterin pyrophosphokinase domain at their N terminal and are named PPPK-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>===
| | __TOC__ |
|
| |
|
| 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.
| | ==Function== |
| In the current study, we focus on the molecular dynamic behaviors and binding free energy calculations of <scene name='Journal:JBSD:24/Cv/2'>wild-type (wt)</scene> form and <scene name='Journal:JBSD:24/Cv/3'>mutated forms</scene> ''B. anthracis'' dihydropteroate synthase (BaDHPS) to search for the relationship between mutation and drug resistance. <font color='darkmagenta'><b>Wt-BaDHPS is colored in darkmagenta</b></font>, 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='Journal:JBSD:24/Cv/5'>wt form and mutated form enzymes</scene>, it is obvious that <scene name='Journal:JBSD:24/Cv/8'>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 <font color='darkmagenta'><b>Wt-BaDHPS is in darkmagenta</b></font>, 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.
| |
|
| |
|
| </StructureSection> | | '''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> |
| __NOTOC__
| | *'''7,8-dihydro-6-hydroxymethylpterin pyrophsphokinase-DHPS''' contains a dihydro-6-hydroxymethylpterin pyrophosphokinase domain at the N terminal and is named '''HPPK-DHPS'''. |
| ==3S structures of dihydropteroate synthase==
| |
|
| |
|
| Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
| | == 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>== |
|
| |
|
| [[1ad1]] – SaDHPS - ''Staphylococcus aureus'' <br />
| | 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. |
| [[1ajz]] – EcDHPS – ''Escherichia coli''<br />
| | 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>. |
| [[1tws]], [[3v5o]] – BaDHPS – ''Bacillus anthracis''<br />
| | 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. |
| [[2dqw]] - TtDHPS – ''Thermus thermophilus''<br />
| |
| [[2vef]] - SpDHPS – ''Streptococcus pneumonia''<br />
| |
| [[2vp8]] – MtDHPS – ''Mycobacterium tuberculosis''<br />
| |
| [[2y5j]] – BcDHPS – ''Burkholderia cenocepacia''<br />
| |
| [[3tzn]] – YpDHPS – ''Yersinia pestis''
| |
|
| |
|
| '''DHPS binary comlexes'''
| | ==3D structures of dihydropteroate synthase== |
| | [[Dihydropteroate synthase 3D structures]] |
|
| |
|
| [[1ad4]] – SaDHPS + pterin-pyrophosphate<br />
| | </StructureSection> |
| [[1aj2]] – EcDHPS + dihydro-pterin-methanyl-phosphonophosphate<br />
| |
| [[1eye]] - MtDHPS + pterin-methyl-phosphate<br />
| |
| [[1tww]] - BaDHPS + hydroxymethylpterin-diphosphate<br />
| |
| [[1twz]] - BaDHPS + pterin-methyl-phosphate<br />
| |
| [[1tx0]] - BaDHPS + pteroic acid<br />
| |
| [[1tx2]], [[3h21]], [[3h22]], [[3h23]], [[3h24]], [[3h26]], [[3h2a]], [[3h2c]], [[3h2e]], [[3h2f]], [[3h2m]], [[3h2n]], [[3h2o]], [[4d8z]], [[4d9p]], [[4dai]], [[4db7]], [[4d8a]], [[4daf]] - BaDHPS + inhibitor<br />
| |
| [[2dza]] - TtDHPS + PABA<br />
| |
| [[2dzb]] - TtDHPS + hydroxymethylpterin-diphosphate<br />
| |
| [[2veg]] - SpDHPS + pterin-methyl-phosphate<br />
| |
| [[2y5s]] - BcDHPS + dihydro-pteroate<br />
| |
| [[3tya]] - BaDHPS + dihydro-pteroate<br />
| |
| [[3tyc]] - BaDHPS + amino-hydroxymethyl-dihydro-pteridinone<br />
| |
| [[3tr9]] - DHPS + pteroic acid – ''Coxiella burnetii''<br />
| |
| [[3tyu]] – YpDHPS + pteroic acid
| |
| | |
| '''DHPS ternary complexes'''
| |
| | |
| [[1aj0]] – EcDHPS + sulfanilamide + amino-methyldiene-dihydro-pteridinone<br />
| |
| [[3tyb]] - BaDHPS + hydroxybenzoic acid + amino-hydroxymethyl-dihydro-pteridinone<br />
| |
| [[3tyd]] - BaDHPS + pyrophosphate+ amino-hydroxymethyl-dihydro-pteridinone<br />
| |
| [[3tye]] - BaDHPS + sulfa derivative + amino-hydroxymethyl-dihydro-pteridinone<br />
| |
| [[3tyz]] - YpDHPS + pyrophosphate + PABA + amino-hydroxymethyl-dihydro-pteridinone<br />
| |
| [[3tzf]] - YpDHPS + sulfa derivative + hydroxymethylpterin-diphosphate<br />
| |
| | |
| '''Bifunctional 6-hydroxymethyl-7,8-dihydropterin pyrophsphokinase-DHPS'''
| |
|
| |
|
| [[3mcm]], [[3mcn]] – FtPPPK-DHPS – ''Francisella tulerensis''<br />
| |
| [[3mco]] - FtPPPK-DHPS + amino-hydroxymethyl-dihydro-pteridinone + methyladenosine triphosphate<br />
| |
| [[2bmb]] - PPPK-DHPS + pterin-methyl-phosphate - yeast
| |
|
| |
|
| '''References'''
| | ==References== |
| <references/> | | <references/> |
| [[Category:Topic Page]] | | [[Category:Topic Page]] |