Dihydropteroate synthase

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Line 1: Line 1:
-
{{STRUCTURE_1aj0| PDB=1aj0 | SIZE=400| SCENE= |right|CAPTION=E. coli dihydropteroate synthase complex with pterin derivative and sulfanilamide, [[1aj0]] }}
+
<StructureSection load='' size='450' side='right' scene='Journal:JBSD:24/Cv/1' caption=''>
-
<!--
+
-
Please use the "3D" button above this box to insert a Jmol applet (molecule) on this page.
+
-
Or use the four-green-boxes-button to insert scrollable text adjacent
+
-
to a Jmol applet. Check out the other buttons as well!
+
-
-->
+
'''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.
'''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>===
 +
 +
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='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>
 +
__NOTOC__
==3S structures of dihydropteroate synthase==
==3S structures of dihydropteroate synthase==

Revision as of 11:12, 13 November 2013

Drag the structure with the mouse to rotate

3S structures of dihydropteroate synthase

Updated on 13-November-2013

1ad1 – SaDHPS - Staphylococcus aureus
1ajz – EcDHPS – Escherichia coli
1tws, 3v5o – BaDHPS – Bacillus anthracis
2dqw - TtDHPS – Thermus thermophilus
2vef - SpDHPS – Streptococcus pneumonia
2vp8 – MtDHPS – Mycobacterium tuberculosis
2y5j – BcDHPS – Burkholderia cenocepacia
3tzn – YpDHPS – Yersinia pestis

DHPS binary comlexes

1ad4 – SaDHPS + pterin-pyrophosphate
1aj2 – EcDHPS + dihydro-pterin-methanyl-phosphonophosphate
1eye - MtDHPS + pterin-methyl-phosphate
1tww - BaDHPS + hydroxymethylpterin-diphosphate
1twz - BaDHPS + pterin-methyl-phosphate
1tx0 - BaDHPS + pteroic acid
1tx2, 3h21, 3h22, 3h23, 3h24, 3h26, 3h2a, 3h2c, 3h2e, 3h2f, 3h2m, 3h2n, 3h2o, 4d8z, 4d9p, 4dai, 4db7, 4d8a, 4daf - BaDHPS + inhibitor
2dza - TtDHPS + PABA
2dzb - TtDHPS + hydroxymethylpterin-diphosphate
2veg - SpDHPS + pterin-methyl-phosphate
2y5s - BcDHPS + dihydro-pteroate
3tya - BaDHPS + dihydro-pteroate
3tyc - BaDHPS + amino-hydroxymethyl-dihydro-pteridinone
3tr9 - DHPS + pteroic acid – Coxiella burnetii
3tyu – YpDHPS + pteroic acid

DHPS ternary complexes

1aj0 – EcDHPS + sulfanilamide + amino-methyldiene-dihydro-pteridinone
3tyb - BaDHPS + hydroxybenzoic acid + amino-hydroxymethyl-dihydro-pteridinone
3tyd - BaDHPS + pyrophosphate+ amino-hydroxymethyl-dihydro-pteridinone
3tye - BaDHPS + sulfa derivative + amino-hydroxymethyl-dihydro-pteridinone
3tyz - YpDHPS + pyrophosphate + PABA + amino-hydroxymethyl-dihydro-pteridinone
3tzf - YpDHPS + sulfa derivative + hydroxymethylpterin-diphosphate

Bifunctional 6-hydroxymethyl-7,8-dihydropterin pyrophsphokinase-DHPS

3mcm, 3mcn – FtPPPK-DHPS – Francisella tulerensis
3mco - FtPPPK-DHPS + amino-hydroxymethyl-dihydro-pteridinone + methyladenosine triphosphate
2bmb - PPPK-DHPS + pterin-methyl-phosphate - yeast

Proteopedia Page Contributors and Editors (what is this?)

Michal Harel, Alexander Berchansky, Joel L. Sussman

Personal tools