7mya: Difference between revisions
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==Structure of proline utilization A with the FAD covalently-modified by 1,3-dithiolane== | ==Structure of proline utilization A with the FAD covalently-modified by 1,3-dithiolane== | ||
<StructureSection load='7mya' size='340' side='right'caption='[[7mya]]' scene=''> | <StructureSection load='7mya' size='340' side='right'caption='[[7mya]], [[Resolution|resolution]] 1.56Å' 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=7MYA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MYA FirstGlance]. <br> | <table><tr><td colspan='2'>[[7mya]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Sinorhizobium_meliloti_SM11 Sinorhizobium meliloti SM11]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MYA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MYA 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=7mya FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mya OCA], [https://pdbe.org/7mya PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mya RCSB], [https://www.ebi.ac.uk/pdbsum/7mya PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mya ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.56Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UJJ:[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl+(2R,3S,4S)-5-[5-(1,3-dithiolan-2-yl)-7,8-dimethyl-2,4-dioxo-1,3,4,5-tetrahydrobenzo[g]pteridin-10(2H)-yl]-2,3,4-trihydroxypentyl+dihydrogen+diphosphate'>UJJ</scene></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=7mya FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mya OCA], [https://pdbe.org/7mya PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mya RCSB], [https://www.ebi.ac.uk/pdbsum/7mya PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mya ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/F7X6I3_SINMM F7X6I3_SINMM] Oxidizes proline to glutamate for use as a carbon and nitrogen source.[PIRNR:PIRNR000197] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Proline dehydrogenase (PRODH) is a flavoenzyme that catalyzes the first step of proline catabolism, the oxidation of l-proline to Delta(1)-pyrroline-5-carboxylate. PRODH has emerged as a cancer therapy target because of its involvement in the metabolic reprogramming of cancer cells. Here, we report the discovery of a new class of PRODH inactivator, which covalently and irreversibly modifies the FAD in a light-dependent manner. Two examples, 1,3-dithiolane-2-carboxylate and tetrahydrothiophene-2-carboxylate, have been characterized using X-ray crystallography (1.52-1.85 A resolution), absorbance spectroscopy, and enzyme kinetics. The structures reveal that in the dark, these compounds function as classical reversible, proline analogue inhibitors. However, exposure of enzyme-inhibitor cocrystals to bright white light induces decarboxylation of the inhibitor and covalent attachment of the residual S-heterocycle to the FAD N5 atom, locking the cofactor into a reduced, inactive state. Spectroscopic measurements of the inactivation process in solution confirm the requirement for light and show that blue light is preferred. Enzyme activity assays show that the rate of inactivation is enhanced by light and that the inactivation is irreversible. We also demonstrate the photosensitivity of cancer cells to one of these compounds. A possible mechanism is proposed involving photoexcitation of the FAD, while the inhibitor is noncovalently bound in the active site, followed by electron transfer, decarboxylation, and radical combination steps. Our results could lead to the development of photopharmacological drugs targeting PRODH. | |||
Photoinduced Covalent Irreversible Inactivation of Proline Dehydrogenase by S-Heterocycles.,Campbell AC, Prater AR, Bogner AN, Quinn TP, Gates KS, Becker DF, Tanner JJ ACS Chem Biol. 2021 Sep 20. doi: 10.1021/acschembio.1c00427. PMID:34542291<ref>PMID:34542291</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7mya" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Proline utilization A|Proline utilization A]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Sinorhizobium meliloti SM11]] | |||
[[Category: Campbell AC]] | [[Category: Campbell AC]] | ||
[[Category: Tanner JJ]] | [[Category: Tanner JJ]] | ||
Latest revision as of 19:21, 18 October 2023
Structure of proline utilization A with the FAD covalently-modified by 1,3-dithiolaneStructure of proline utilization A with the FAD covalently-modified by 1,3-dithiolane
Structural highlights
FunctionF7X6I3_SINMM Oxidizes proline to glutamate for use as a carbon and nitrogen source.[PIRNR:PIRNR000197] Publication Abstract from PubMedProline dehydrogenase (PRODH) is a flavoenzyme that catalyzes the first step of proline catabolism, the oxidation of l-proline to Delta(1)-pyrroline-5-carboxylate. PRODH has emerged as a cancer therapy target because of its involvement in the metabolic reprogramming of cancer cells. Here, we report the discovery of a new class of PRODH inactivator, which covalently and irreversibly modifies the FAD in a light-dependent manner. Two examples, 1,3-dithiolane-2-carboxylate and tetrahydrothiophene-2-carboxylate, have been characterized using X-ray crystallography (1.52-1.85 A resolution), absorbance spectroscopy, and enzyme kinetics. The structures reveal that in the dark, these compounds function as classical reversible, proline analogue inhibitors. However, exposure of enzyme-inhibitor cocrystals to bright white light induces decarboxylation of the inhibitor and covalent attachment of the residual S-heterocycle to the FAD N5 atom, locking the cofactor into a reduced, inactive state. Spectroscopic measurements of the inactivation process in solution confirm the requirement for light and show that blue light is preferred. Enzyme activity assays show that the rate of inactivation is enhanced by light and that the inactivation is irreversible. We also demonstrate the photosensitivity of cancer cells to one of these compounds. A possible mechanism is proposed involving photoexcitation of the FAD, while the inhibitor is noncovalently bound in the active site, followed by electron transfer, decarboxylation, and radical combination steps. Our results could lead to the development of photopharmacological drugs targeting PRODH. Photoinduced Covalent Irreversible Inactivation of Proline Dehydrogenase by S-Heterocycles.,Campbell AC, Prater AR, Bogner AN, Quinn TP, Gates KS, Becker DF, Tanner JJ ACS Chem Biol. 2021 Sep 20. doi: 10.1021/acschembio.1c00427. PMID:34542291[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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