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==Crystal structure of PMP-bound form of cysteine desulfurase SufS C361A from Bacillus subtilis== | ==Crystal structure of PMP-bound form of cysteine desulfurase SufS C361A from Bacillus subtilis== | ||
<StructureSection load='7e6b' size='340' side='right'caption='[[7e6b]]' scene=''> | <StructureSection load='7e6b' size='340' side='right'caption='[[7e6b]], [[Resolution|resolution]] 1.84Å' 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=7E6B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E6B FirstGlance]. <br> | <table><tr><td colspan='2'>[[7e6b]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7E6B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E6B 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=7e6b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e6b OCA], [https://pdbe.org/7e6b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e6b RCSB], [https://www.ebi.ac.uk/pdbsum/7e6b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e6b 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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PMP:4-DEOXY-4-AMINOPYRIDOXAL-5-PHOSPHATE'>PMP</scene></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=7e6b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e6b OCA], [https://pdbe.org/7e6b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e6b RCSB], [https://www.ebi.ac.uk/pdbsum/7e6b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e6b ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/SUFS_BACSU SUFS_BACSU]] Enzyme able to deliver sulfur to partners involved in Fe-S cluster assembly. Catalyzes the removal of elemental sulfur atoms from L-cysteine to produce L-alanine. Activity is stimulated 40-to 100-fold by SufU, which acts as a second substrate for this enzyme following release of Ala, and generating SufU.S. A mixture of SufS, SufU, Fra and L-cysteine is able to reconstitute Fe-S clusters on apo-aconitase (citB), reconstituting aconitase activity.<ref>PMID:20097860</ref> <ref>PMID:20822158</ref> <ref>PMID:21744456</ref> | |||
<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 7e6b" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[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 PMP-bound form of cysteine desulfurase SufS C361A from Bacillus subtilisCrystal structure of PMP-bound form of cysteine desulfurase SufS C361A from Bacillus subtilis
Structural highlights
Function[SUFS_BACSU] Enzyme able to deliver sulfur to partners involved in Fe-S cluster assembly. Catalyzes the removal of elemental sulfur atoms from L-cysteine to produce L-alanine. Activity is stimulated 40-to 100-fold by SufU, which acts as a second substrate for this enzyme following release of Ala, and generating SufU.S. A mixture of SufS, SufU, Fra and L-cysteine is able to reconstitute Fe-S clusters on apo-aconitase (citB), reconstituting aconitase activity.[1] [2] [3] 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[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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