Dihydropteroate synthase

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<StructureSection load='' size='450' side='right' scene='49/493691/Cv/1' caption='Dihydropteroate synthase (PDB code [[1tws]])'>
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<StructureSection load='1tws' size='350' side='right' scene='' caption='Dihydropteroate synthase complex with sulfate (PDB code [[1tws]])'>
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'''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.
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=== 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>===
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__TOC__
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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.
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==Function==
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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>.
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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.
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</StructureSection>
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'''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>
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*'''7,8-dihydro-6-hydroxymethylpterin pyrophsphokinase-DHPS''' contains a dihydro-6-hydroxymethylpterin pyrophosphokinase domain at the N terminal and is named '''HPPK-DHPS'''.
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==3D structures of dihydropteroate synthase==
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== 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>==
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Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
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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.
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{{#tree:id=OrganizedByTopic|openlevels=0|
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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>.
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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.
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*DHPS
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==3D structures of dihydropteroate synthase==
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[[Dihydropteroate synthase 3D structures]]
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**[[1ad1]], [[4hb7]] – SaDHPS - ''Staphylococcus aureus'' <br />
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</StructureSection>
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**[[1ajz]] – EcDHPS – ''Escherichia coli''<br />
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**[[1tws]], [[3v5o]] – BaDHPS – ''Bacillus anthracis''<br />
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**[[2dqw]] - TtDHPS – ''Thermus thermophilus''<br />
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**[[2vef]] - SpDHPS – ''Streptococcus pneumonia''<br />
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**[[2vp8]] – MtDHPS – ''Mycobacterium tuberculosis''<br />
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**[[2y5j]] – BcDHPS – ''Burkholderia cenocepacia''<br />
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**[[3tzn]] – YpDHPS – ''Yersinia pestis''
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*DHPS binary complexes
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**[[1ad4]] – SaDHPS + pterin-pyrophosphate<br />
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**[[1aj2]] – EcDHPS + dihydro-pterin-methanyl-phosphonophosphate<br />
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**[[1eye]] - MtDHPS + pterin-methyl-phosphate<br />
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**[[1tww]] - BaDHPS + hydroxymethylpterin-diphosphate<br />
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**[[1twz]] - BaDHPS + pterin-methyl-phosphate<br />
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**[[1tx0]] - BaDHPS + pteroic acid<br />
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**[[1tx2]], [[3h21]], [[3h22]], [[3h23]], [[3h24]], [[3h26]], [[3h2a]], [[3h2c]], [[3h2e]], [[3h2f]], [[3h2m]], [[3h2n]], [[3h2o]], [[4d8z]], [[4d9p]], [[4dai]], [[4db7]], [[4d8a]], [[4daf]] - BaDHPS + inhibitor<br />
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**[[2dza]] - TtDHPS + PABA<br />
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**[[2dzb]] - TtDHPS + hydroxymethylpterin-diphosphate<br />
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**[[2veg]] - SpDHPS + pterin-methyl-phosphate<br />
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**[[2y5s]] - BcDHPS + dihydro-pteroate<br />
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**[[3tya]] - BaDHPS + dihydro-pteroate<br />
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**[[3tyc]] - BaDHPS + amino-hydroxymethyl-dihydro-pteridinone<br />
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**[[3tr9]] - DHPS + pteroic acid – ''Coxiella burnetii''<br />
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**[[3tyu]] – YpDHPS + pteroic acid
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*DHPS ternary complexes
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**[[1aj0]] – EcDHPS + sulfanilamide + amino-methyldiene-dihydro-pteridinone<br />
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**[[3tyb]] - BaDHPS + hydroxybenzoic acid + amino-hydroxymethyl-dihydro-pteridinone<br />
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**[[3tyd]] - BaDHPS + pyrophosphate+ amino-hydroxymethyl-dihydro-pteridinone<br />
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**[[3tye]] - BaDHPS + sulfa derivative + amino-hydroxymethyl-dihydro-pteridinone<br />
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**[[3tyz]] - YpDHPS + pyrophosphate + PABA + amino-hydroxymethyl-dihydro-pteridinone<br />
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**[[3tzf]] - YpDHPS + sulfa derivative + hydroxymethylpterin-diphosphate<br />
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*Bifunctional 6-hydroxymethyl-7,8-dihydropterin pyrophsphokinase-DHPS
 
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**[[3mcm]], [[3mcn]] – FtPPPK-DHPS – ''Francisella tulerensis''<br />
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==References==
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**[[3mco]] - FtPPPK-DHPS + amino-hydroxymethyl-dihydro-pteridinone + methyladenosine triphosphate<br />
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**[[2bmb]] - PPPK-DHPS + pterin-methyl-phosphate - yeast
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}}
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'''References'''
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<references/>
<references/>
[[Category:Topic Page]]
[[Category:Topic Page]]

Current revision

Dihydropteroate synthase complex with sulfate (PDB code 1tws)

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References

  1. ↑ Vinnicombe HG, Derrick JP. Dihydropteroate synthase from Streptococcus pneumoniae: characterization of substrate binding order and sulfonamide inhibition. Biochem Biophys Res Commun. 1999 May 19;258(3):752-7. doi:, 10.1006/bbrc.1999.0695. PMID:10329458 doi:http://dx.doi.org/10.1006/bbrc.1999.0695
  2. ↑ Chu WT, Zhang JL, Zheng QC, Chen L, Xue Q, Zhang HX. Insights into the drug resistance induced by the BaDHPS mutations: molecular dynamic simulations and MM/GBSA studies. J Biomol Struct Dyn. 2012 Oct 2. PMID:23030549 doi:10.1080/07391102.2012.726529

Proteopedia Page Contributors and Editors (what is this?)

Michal Harel, Alexander Berchansky, Joel L. Sussman

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