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==Crystal structure of D-cycloserine-bound form of cysteine desulfurase NifS from Helicobacter pylori== | ==Crystal structure of D-cycloserine-bound form of cysteine desulfurase NifS from Helicobacter pylori== | ||
<StructureSection load='7cet' size='340' side='right'caption='[[7cet]]' scene=''> | <StructureSection load='7cet' size='340' side='right'caption='[[7cet]], [[Resolution|resolution]] 2.64Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CET OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CET FirstGlance]. <br> | <table><tr><td colspan='2'>[[7cet]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Campylobacter_pylori Campylobacter pylori]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CET OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CET FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7cet FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cet OCA], [https://pdbe.org/7cet PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cet RCSB], [https://www.ebi.ac.uk/pdbsum/7cet PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cet ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7TS:(5-HYDROXY-6-METHYL-4-{[(3-OXO-2,3-DIHYDRO-1,2-OXAZOL-4-YL)AMINO]METHYL}PYRIDIN-3-YL)METHYL+DIHYDROGEN+PHOSPHATE'>7TS</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">iscS, HP_0220 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=85962 Campylobacter pylori])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Cysteine_desulfurase Cysteine desulfurase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.8.1.7 2.8.1.7] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7cet FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cet OCA], [https://pdbe.org/7cet PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cet RCSB], [https://www.ebi.ac.uk/pdbsum/7cet PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cet ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/ISCS_HELPY ISCS_HELPY]] Master enzyme that delivers sulfur to a number of partners involved in Fe-S cluster assembly, tRNA modification or cofactor biosynthesis. Catalyzes the removal of elemental sulfur atoms from cysteine to produce alanine. Functions as a sulfur delivery protein for Fe-S cluster synthesis onto IscU, an Fe-S scaffold assembly protein, as well as other S acceptor proteins. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The cysteine desulfurase SufS is a pyridoxal-5'-phosphate-dependent enzyme and is essential for the SUF system, which participates in iron-sulfur cluster biosynthesis. Inhibition of SufS in the SUF system by D-cycloserine (DCS) in Plasmodium falciparum apicoplast has recently been reported, indicating that SufS could be a target for malaria therapeutics. However, the mechanistic details underlying the inhibition of SufS by DCS have not yet been clarified. Moreover, inhibition of SufS by the other enantiomer, L-cycloserine (LCS), has not been investigated. Herein, we investigated the structure-based inhibition mechanisms of SufS by DCS and LCS using Bacillus subtilis SufS, whose catalytic mechanism has been well characterized in comparison to that of the P. falciparum SufS. Surprisingly, DCS- and LCS-mediated inhibitions of SufS occur via distinct mechanisms resulting in pyridoxamine-5'-phosphate (PMP) in DCS-mediated inhibition and PMP-3-hydroxyisoxazole adduct (PMP-isoxazole) in LCS-mediated inhibition. Biochemical and structural evaluation of SufS variants identified conserved His and Arg residues at the active site as the key determinants of the distinct inhibition mechanisms. The importance of structural elements involved in DCS and LCS-mediated inhibitions of SufS provides valuable insights for the structure-based design of new drugs targeting SufS. DATABASE: Structural data are available in PDB database under the accession numbers 6KFY, 7CEO, 7CEP, 7CEQ, 7CER, 7CES, 7CET, 7CEU, 7E6A, 7E6B, 7E6C, 7E6D, 7E6E, and 7E6F. | |||
Cycloserine enantiomers inhibit PLP-dependent cysteine desulfurase SufS via distinct mechanisms.,Nakamura R, Ogawa S, Takahashi Y, Fujishiro T FEBS J. 2022 Apr 8. doi: 10.1111/febs.16455. PMID:35395703<ref>PMID:35395703</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7cet" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Campylobacter pylori]] | |||
[[Category: Cysteine desulfurase]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Fujishiro T]] | [[Category: Fujishiro, T]] | ||
[[Category: Nakamura R]] | [[Category: Nakamura, R]] | ||
[[Category: Takahashi Y]] | [[Category: Takahashi, Y]] | ||
[[Category: Biosynthetic protein]] | |||
[[Category: Cycloserine]] | |||
[[Category: Cysteine metabolism]] | |||
[[Category: Fe-s cluster biosynthesis]] | |||
[[Category: Inhibitor]] | |||
[[Category: Plp-dependent enzyme]] | |||
Revision as of 14:47, 27 April 2022
Crystal structure of D-cycloserine-bound form of cysteine desulfurase NifS from Helicobacter pyloriCrystal structure of D-cycloserine-bound form of cysteine desulfurase NifS from Helicobacter pylori
Structural highlights
Function[ISCS_HELPY] Master enzyme that delivers sulfur to a number of partners involved in Fe-S cluster assembly, tRNA modification or cofactor biosynthesis. Catalyzes the removal of elemental sulfur atoms from cysteine to produce alanine. Functions as a sulfur delivery protein for Fe-S cluster synthesis onto IscU, an Fe-S scaffold assembly protein, as well as other S acceptor proteins. Publication Abstract from PubMedThe cysteine desulfurase SufS is a pyridoxal-5'-phosphate-dependent enzyme and is essential for the SUF system, which participates in iron-sulfur cluster biosynthesis. Inhibition of SufS in the SUF system by D-cycloserine (DCS) in Plasmodium falciparum apicoplast has recently been reported, indicating that SufS could be a target for malaria therapeutics. However, the mechanistic details underlying the inhibition of SufS by DCS have not yet been clarified. Moreover, inhibition of SufS by the other enantiomer, L-cycloserine (LCS), has not been investigated. Herein, we investigated the structure-based inhibition mechanisms of SufS by DCS and LCS using Bacillus subtilis SufS, whose catalytic mechanism has been well characterized in comparison to that of the P. falciparum SufS. Surprisingly, DCS- and LCS-mediated inhibitions of SufS occur via distinct mechanisms resulting in pyridoxamine-5'-phosphate (PMP) in DCS-mediated inhibition and PMP-3-hydroxyisoxazole adduct (PMP-isoxazole) in LCS-mediated inhibition. Biochemical and structural evaluation of SufS variants identified conserved His and Arg residues at the active site as the key determinants of the distinct inhibition mechanisms. The importance of structural elements involved in DCS and LCS-mediated inhibitions of SufS provides valuable insights for the structure-based design of new drugs targeting SufS. DATABASE: Structural data are available in PDB database under the accession numbers 6KFY, 7CEO, 7CEP, 7CEQ, 7CER, 7CES, 7CET, 7CEU, 7E6A, 7E6B, 7E6C, 7E6D, 7E6E, and 7E6F. Cycloserine enantiomers inhibit PLP-dependent cysteine desulfurase SufS via distinct mechanisms.,Nakamura R, Ogawa S, Takahashi Y, Fujishiro T FEBS J. 2022 Apr 8. doi: 10.1111/febs.16455. PMID:35395703[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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