5w4b

From Proteopedia

(Difference between revisions)

Revision as of 08:48, 30 September 2020

The crystal structure of human S-adenosylhomocysteine hydrolase (AHCY) bound to benzothiazole inhibitor

Structural highlights

5w4b is a 6 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	5w49
Activity:	Adenosylhomocysteinase, with EC number 3.3.1.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[SAHH_HUMAN] Defects in AHCY are the cause of hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency (HMAHCHD) [MIM:613752]. A metabolic disorder characterized by hypermethioninemia associated with failure to thrive, mental and motor retardation, facial dysmorphism with abnormal hair and teeth, and myocardiopathy.^[1] ^[2] ^[3] ^[4]

Function

[SAHH_HUMAN] Adenosylhomocysteine is a competitive inhibitor of S-adenosyl-L-methionine-dependent methyl transferase reactions; therefore adenosylhomocysteinase may play a key role in the control of methylations via regulation of the intracellular concentration of adenosylhomocysteine.^[5]

Publication Abstract from PubMed

S-adenosylhomocysteine hydrolase (AHCY) catalyzes the reversible hydrolysis of S-adenosylhomocysteine (SAH) to adenosine and l-homocysteine. This enzyme is frequently overexpressed in many tumor types and is considered to be a validated anti-tumor target. In order to enable the development of small molecule AHCY inhibitors as targeted cancer therapeutics we developed an assay based on a RapidFire high-throughput mass spectrometry detection system, which allows the direct measurement of AHCY enzymatic activity. This technique avoids many of the problems associate with the previously reported method of using a thiol-reactive fluorescence probes to measure AHCY activity. Screening of a approximately 500,000 compound library using this technique identified multiple SAH competitive hits. Co-crystal structures of the hit compounds complexed with AHCY were obtained showing that the compounds indeed bind in the SAH site of the enzyme. In addition, some hit compounds increased the SAH levels in HCT116 cells and showed growth inhibition. These compounds could be promising starting points for the optimization of cancer treatments.

Identification of AHCY inhibitors using novel high-throughput mass spectrometry.,Uchiyama N, Dougan DR, Lawson JD, Kimura H, Matsumoto SI, Tanaka Y, Kawamoto T Biochem Biophys Res Commun. 2017 Sep 9;491(1):1-7. doi:, 10.1016/j.bbrc.2017.05.107. Epub 2017 May 19. PMID:28533090^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Baric I, Fumic K, Glenn B, Cuk M, Schulze A, Finkelstein JD, James SJ, Mejaski-Bosnjak V, Pazanin L, Pogribny IP, Rados M, Sarnavka V, Scukanec-Spoljar M, Allen RH, Stabler S, Uzelac L, Vugrek O, Wagner C, Zeisel S, Mudd SH. S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4234-9. Epub 2004 Mar 15. PMID:15024124 doi:10.1073/pnas.0400658101
↑ Buist NR, Glenn B, Vugrek O, Wagner C, Stabler S, Allen RH, Pogribny I, Schulze A, Zeisel SH, Baric I, Mudd SH. S-adenosylhomocysteine hydrolase deficiency in a 26-year-old man. J Inherit Metab Dis. 2006 Aug;29(4):538-45. Epub 2006 May 30. PMID:16736098 doi:10.1007/s10545-006-0240-0
↑ Vugrek O, Beluzic R, Nakic N, Mudd SH. S-adenosylhomocysteine hydrolase (AHCY) deficiency: two novel mutations with lethal outcome. Hum Mutat. 2009 Apr;30(4):E555-65. doi: 10.1002/humu.20985. PMID:19177456 doi:10.1002/humu.20985
↑ Grubbs R, Vugrek O, Deisch J, Wagner C, Stabler S, Allen R, Baric I, Rados M, Mudd SH. S-adenosylhomocysteine hydrolase deficiency: two siblings with fetal hydrops and fatal outcomes. J Inherit Metab Dis. 2010 Dec;33(6):705-13. doi: 10.1007/s10545-010-9171-x. Epub , 2010 Sep 18. PMID:20852937 doi:10.1007/s10545-010-9171-x
↑ Yang X, Hu Y, Yin DH, Turner MA, Wang M, Borchardt RT, Howell PL, Kuczera K, Schowen RL. Catalytic strategy of S-adenosyl-L-homocysteine hydrolase: transition-state stabilization and the avoidance of abortive reactions. Biochemistry. 2003 Feb 25;42(7):1900-9. PMID:12590576 doi:http://dx.doi.org/10.1021/bi0262350
↑ Uchiyama N, Dougan DR, Lawson JD, Kimura H, Matsumoto SI, Tanaka Y, Kawamoto T. Identification of AHCY inhibitors using novel high-throughput mass spectrometry. Biochem Biophys Res Commun. 2017 Sep 9;491(1):1-7. doi:, 10.1016/j.bbrc.2017.05.107. Epub 2017 May 19. PMID:28533090 doi:http://dx.doi.org/10.1016/j.bbrc.2017.05.107

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5w4b"

@@ Line 1: / Line 1: @@
 ==The crystal structure of human S-adenosylhomocysteine hydrolase (AHCY) bound to benzothiazole inhibitor==
-<StructureSection load='5w4b' size='340' side='right' caption='[[5w4b]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
+<StructureSection load='5w4b' size='340' side='right'caption='[[5w4b]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5w4b]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W4B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5W4B FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5w4b]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W4B OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5W4B FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9W4:4-[(2,5-dioxo-2,5-dihydro-1H-imidazol-1-yl)methyl]-N-[2-(morpholin-4-yl)-1,3-benzothiazol-6-yl]benzamide'>9W4</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9W4:4-[(2,5-dioxo-2,5-dihydro-1H-imidazol-1-yl)methyl]-N-[2-(morpholin-4-yl)-1,3-benzothiazol-6-yl]benzamide'>9W4</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5w49|5w49]]</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Adenosylhomocysteinase Adenosylhomocysteinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.3.1.1 3.3.1.1] </span></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=5w4b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w4b OCA], [http://pdbe.org/5w4b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5w4b RCSB], [http://www.ebi.ac.uk/pdbsum/5w4b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5w4b ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5w4b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w4b OCA], [http://pdbe.org/5w4b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5w4b RCSB], [http://www.ebi.ac.uk/pdbsum/5w4b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5w4b ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 22: / Line 22: @@
 </div>
 <div class="pdbe-citations 5w4b" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[S-adenosylhomocysteine hydrolase|S-adenosylhomocysteine hydrolase]]
 == References ==
 <references/>
@@ Line 27: / Line 30: @@
 </StructureSection>
 [[Category: Adenosylhomocysteinase]]
+[[Category: Large Structures]]
 [[Category: Dougan, D R]]
 [[Category: Lane, W]]
 [[Category: Lawson, J D]]
 [[Category: Hydrolase-hydrolase inhibitor complex]]

5w4b

From Proteopedia

Revision as of 08:48, 30 September 2020

The crystal structure of human S-adenosylhomocysteine hydrolase (AHCY) bound to benzothiazole inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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