|
|
| Line 1: |
Line 1: |
| | | | |
| | ==Crystal Structure of human mARC1== | | ==Crystal Structure of human mARC1== |
| - | <StructureSection load='6fw2' size='340' side='right' caption='[[6fw2]], [[Resolution|resolution]] 1.78Å' scene=''> | + | <StructureSection load='6fw2' size='340' side='right'caption='[[6fw2]], [[Resolution|resolution]] 1.78Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6fw2]] 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=6FW2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FW2 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6fw2]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_virus_T4 Escherichia virus T4] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FW2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6FW2 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B3P:2-[3-(2-HYDROXY-1,1-DIHYDROXYMETHYL-ETHYLAMINO)-PROPYLAMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>B3P</scene>, <scene name='pdbligand=EFK:oxidanyl(oxidanylidene)molybdenum'>EFK</scene>, <scene name='pdbligand=MOO:MOLYBDATE+ION'>MOO</scene>, <scene name='pdbligand=MTE:PHOSPHONIC+ACIDMONO-(2-AMINO-5,6-DIMERCAPTO-4-OXO-3,7,8A,9,10,10A-HEXAHYDRO-4H-8-OXA-1,3,9,10-TETRAAZA-ANTHRACEN-7-YLMETHYL)ESTER'>MTE</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]] 1.78Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MARC1, MOSC1 ([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=B3P:2-[3-(2-HYDROXY-1,1-DIHYDROXYMETHYL-ETHYLAMINO)-PROPYLAMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>B3P</scene>, <scene name='pdbligand=EFK:oxidanyl(oxidanylidene)molybdenum'>EFK</scene>, <scene name='pdbligand=MOO:MOLYBDATE+ION'>MOO</scene>, <scene name='pdbligand=MTE:PHOSPHONIC+ACIDMONO-(2-AMINO-5,6-DIMERCAPTO-4-OXO-3,7,8A,9,10,10A-HEXAHYDRO-4H-8-OXA-1,3,9,10-TETRAAZA-ANTHRACEN-7-YLMETHYL)ESTER'>MTE</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=6fw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fw2 OCA], [http://pdbe.org/6fw2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fw2 RCSB], [http://www.ebi.ac.uk/pdbsum/6fw2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fw2 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=6fw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fw2 OCA], [https://pdbe.org/6fw2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6fw2 RCSB], [https://www.ebi.ac.uk/pdbsum/6fw2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6fw2 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MARC1_HUMAN MARC1_HUMAN]] As a component of an N-hydroxylated prodrug-converting complex required to reduce N-hydroxylated prodrugs, such as benzamidoxime. Also able to reduce N(omega)-hydroxy-L-arginine (NOHA) and N(omega)-hydroxy-N(delta)-methyl-L-arginine (NHAM) into L-arginine and N(delta)-methyl-L-arginine, respectively.<ref>PMID:19053771</ref> | + | [https://www.uniprot.org/uniprot/ENLYS_BPT4 ENLYS_BPT4] Endolysin with lysozyme activity that degrades host peptidoglycans and participates with the holin and spanin proteins in the sequential events which lead to the programmed host cell lysis releasing the mature viral particles. Once the holin has permeabilized the host cell membrane, the endolysin can reach the periplasm and break down the peptidoglycan layer.<ref>PMID:22389108</ref> [https://www.uniprot.org/uniprot/MARC1_HUMAN MARC1_HUMAN] As a component of an N-hydroxylated prodrug-converting complex required to reduce N-hydroxylated prodrugs, such as benzamidoxime. Also able to reduce N(omega)-hydroxy-L-arginine (NOHA) and N(omega)-hydroxy-N(delta)-methyl-L-arginine (NHAM) into L-arginine and N(delta)-methyl-L-arginine, respectively.<ref>PMID:19053771</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 23: |
Line 23: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Escherichia virus T4]] |
| - | [[Category: Kubitza, C]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Scheidig, A]] | + | [[Category: Large Structures]] |
| - | [[Category: Marc]] | + | [[Category: Kubitza C]] |
| - | [[Category: Moco]] | + | [[Category: Scheidig A]] |
| - | [[Category: Molybdenum cofactor]]
| + | |
| - | [[Category: Mosc]]
| + | |
| - | [[Category: N-reduction]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
6fw2 is a 1 chain structure with sequence from Escherichia virus T4 and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.78Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
ENLYS_BPT4 Endolysin with lysozyme activity that degrades host peptidoglycans and participates with the holin and spanin proteins in the sequential events which lead to the programmed host cell lysis releasing the mature viral particles. Once the holin has permeabilized the host cell membrane, the endolysin can reach the periplasm and break down the peptidoglycan layer.[1] MARC1_HUMAN As a component of an N-hydroxylated prodrug-converting complex required to reduce N-hydroxylated prodrugs, such as benzamidoxime. Also able to reduce N(omega)-hydroxy-L-arginine (NOHA) and N(omega)-hydroxy-N(delta)-methyl-L-arginine (NHAM) into L-arginine and N(delta)-methyl-L-arginine, respectively.[2]
Publication Abstract from PubMed
Biotransformation enzymes ensure a viable homeostasis by regulating reversible cycles of oxidative and reductive reactions. The metabolism of nitrogen-containing compounds is of high pharmaceutical and toxicological relevance because N-oxygenated metabolites derived from reactions mediated by cytochrome P450 enzymes or flavin-dependent monooxygenases are in some cases highly toxic or mutagenic. The molybdenum-dependent mitochondrial amidoxime-reducing component (mARC) was found to be an extremely efficient counterpart, which is able to reduce the full range of N-oxygenated compounds and thereby mediates detoxification reactions. However, the 3D structure of this enzyme was unknown. Here we present the high-resolution crystal structure of human mARC. We give detailed insight into the coordination of its molybdenum cofactor (Moco), the catalytic mechanism, and its ability to reduce a wide range of N-oxygenated compounds. The identification of two key residues will allow future discrimination between mARC paralogs and ensure correct annotation. Since our structural findings contradict in silico predictions that are currently made by online databases, we propose domain definitions for members of the superfamily of Moco sulfurase C-terminal (MOSC) domain-containing proteins. Furthermore, we present evidence for an evolutionary role of mARC for the emergence of the xanthine oxidase protein superfamily. We anticipate the hereby presented crystal structure to be a starting point for future descriptions of MOSC proteins, which are currently poorly structurally characterized.
Crystal structure of human mARC1 reveals its exceptional position among eukaryotic molybdenum enzymes.,Kubitza C, Bittner F, Ginsel C, Havemeyer A, Clement B, Scheidig AJ Proc Natl Acad Sci U S A. 2018 Nov 5. pii: 1808576115. doi:, 10.1073/pnas.1808576115. PMID:30397129[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Moussa SH, Kuznetsov V, Tran TA, Sacchettini JC, Young R. Protein determinants of phage T4 lysis inhibition. Protein Sci. 2012 Apr;21(4):571-82. doi: 10.1002/pro.2042. Epub 2012 Mar 2. PMID:22389108 doi:http://dx.doi.org/10.1002/pro.2042
- ↑ Gruenewald S, Wahl B, Bittner F, Hungeling H, Kanzow S, Kotthaus J, Schwering U, Mendel RR, Clement B. The fourth molybdenum containing enzyme mARC: cloning and involvement in the activation of N-hydroxylated prodrugs. J Med Chem. 2008 Dec 25;51(24):8173-7. doi: 10.1021/jm8010417. PMID:19053771 doi:http://dx.doi.org/10.1021/jm8010417
- ↑ Kubitza C, Bittner F, Ginsel C, Havemeyer A, Clement B, Scheidig AJ. Crystal structure of human mARC1 reveals its exceptional position among eukaryotic molybdenum enzymes. Proc Natl Acad Sci U S A. 2018 Nov 5. pii: 1808576115. doi:, 10.1073/pnas.1808576115. PMID:30397129 doi:http://dx.doi.org/10.1073/pnas.1808576115
|
