|
|
| Line 1: |
Line 1: |
| | | | |
| | ==Human biliverdin IX beta reductase: NADP/Phloxine B ternary complex== | | ==Human biliverdin IX beta reductase: NADP/Phloxine B ternary complex== |
| - | <StructureSection load='5oog' size='340' side='right' caption='[[5oog]], [[Resolution|resolution]] 1.33Å' scene=''> | + | <StructureSection load='5oog' size='340' side='right'caption='[[5oog]], [[Resolution|resolution]] 1.33Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5oog]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OOG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OOG FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5oog]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OOG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OOG FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A0B:Phloxine+B'>A0B</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></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]] 1.33Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BLVRB, FLR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A0B:Phloxine+B'>A0B</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5oog FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5oog OCA], [http://pdbe.org/5oog PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5oog RCSB], [http://www.ebi.ac.uk/pdbsum/5oog PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5oog ProSAT]</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=5oog FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5oog OCA], [https://pdbe.org/5oog PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5oog RCSB], [https://www.ebi.ac.uk/pdbsum/5oog PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5oog ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/BLVRB_HUMAN BLVRB_HUMAN]] Broad specificity oxidoreductase that catalyzes the NADPH-dependent reduction of a variety of flavins, such as riboflavin, FAD or FMN, biliverdins, methemoglobin and PQQ (pyrroloquinoline quinone). Contributes to heme catabolism and metabolizes linear tetrapyrroles. Can also reduce the complexed Fe(3+) iron to Fe(2+) in the presence of FMN and NADPH. In the liver, converts biliverdin to bilirubin.<ref>PMID:10620517</ref> | + | [https://www.uniprot.org/uniprot/BLVRB_HUMAN BLVRB_HUMAN] Broad specificity oxidoreductase that catalyzes the NADPH-dependent reduction of a variety of flavins, such as riboflavin, FAD or FMN, biliverdins, methemoglobin and PQQ (pyrroloquinoline quinone). Contributes to heme catabolism and metabolizes linear tetrapyrroles. Can also reduce the complexed Fe(3+) iron to Fe(2+) in the presence of FMN and NADPH. In the liver, converts biliverdin to bilirubin.<ref>PMID:10620517</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 19: |
Line 19: |
| | </div> | | </div> |
| | <div class="pdbe-citations 5oog" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5oog" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Flavin reductase|Flavin reductase]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Manso, J A]] | + | [[Category: Large Structures]] |
| - | [[Category: Pereira, P J.B]] | + | [[Category: Manso JA]] |
| - | [[Category: Biliverdin reductase]] | + | [[Category: Pereira PJB]] |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
Function
BLVRB_HUMAN Broad specificity oxidoreductase that catalyzes the NADPH-dependent reduction of a variety of flavins, such as riboflavin, FAD or FMN, biliverdins, methemoglobin and PQQ (pyrroloquinoline quinone). Contributes to heme catabolism and metabolizes linear tetrapyrroles. Can also reduce the complexed Fe(3+) iron to Fe(2+) in the presence of FMN and NADPH. In the liver, converts biliverdin to bilirubin.[1]
Publication Abstract from PubMed
Heme cytotoxicity is minimized by a two-step catabolic reaction that generates biliverdin (BV) and bilirubin (BR) tetrapyrroles. The second step is regulated by two non-redundant biliverdin reductases (IXalpha[BLVRA] and IXbeta [BLVRB]), which retain isomeric specificity and NAD(P)H-dependent redox coupling linked to BR's antioxidant function. Defective BLVRB enzymatic activity with antioxidant mishandling has been implicated in metabolic consequences of hematopoietic lineage fate and enhanced platelet counts in humans. We now outline an integrated platform of in silico and crystallographic studies for the identification of an initial class of compounds inhibiting BLVRB with potencies in the nanomolar range. We found that the most potent BLVRB inhibitors contain a tricyclic hydrocarbon core structure similar to the isoalloxazine ring of flavin mononucleotide and that both xanthene- and acridine-based compounds inhibit BLVRB's flavin and dichlorophenolindophenol (DCPIP) reductase functions. Crystallographic studies of ternary complexes with BLVRB/NADP(+)/xanthene-based compounds confirmed inhibitor binding adjacent to the cofactor nicotinamide and interactions with the Ser-111 side chain. This residue previously has been identified as critical for maintaining the enzymatic active site and cellular reductase functions in hematopoietic cells. Both acridine- and xanthene-based compounds caused selective and concentration-dependent loss of redox coupling in BLVRB-overexpressing promyelocytic HL-60 cells. These results provide promising chemical scaffolds for the development of enhanced BLVRB inhibitors and identify chemical probes to better dissect the role of biliverdins, alternative substrates, and BLVRB function in physiologically relevant cellular contexts.
In silico and crystallographic studies identify key structural features of biliverdin IXbeta reductase inhibitors having nanomolar potency.,Nesbitt NM, Zheng X, Li Z, Manso JA, Yen WY, Malone LE, Ripoll-Rozada J, Pereira PJB, Mantle TJ, Wang J, Bahou WF J Biol Chem. 2018 Feb 27. pii: RA118.001803. doi: 10.1074/jbc.RA118.001803. PMID:29487133[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Cunningham O, Gore MG, Mantle TJ. Initial-rate kinetics of the flavin reductase reaction catalysed by human biliverdin-IXbeta reductase (BVR-B). Biochem J. 2000 Jan 15;345 Pt 2:393-9. PMID:10620517
- ↑ Nesbitt NM, Zheng X, Li Z, Manso JA, Yen WY, Malone LE, Ripoll-Rozada J, Pereira PJB, Mantle TJ, Wang J, Bahou WF. In silico and crystallographic studies identify key structural features of biliverdin IXbeta reductase inhibitors having nanomolar potency. J Biol Chem. 2018 Feb 27. pii: RA118.001803. doi: 10.1074/jbc.RA118.001803. PMID:29487133 doi:http://dx.doi.org/10.1074/jbc.RA118.001803
|
