This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

2wm1

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 06:28, 25 December 2014

THE CRYSTAL STRUCTURE OF HUMAN ALPHA-AMINO-BETA-CARBOXYMUCONATE-EPSILON-SEMIALDEHYDE DECARBOXYLASE IN COMPLEX WITH 1,3- DIHYDROXYACETONEPHOSPHATE SUGGESTS A REGULATORY LINK BETWEEN NAD SYNTHESIS AND GLYCOLYSIS

Structural highlights

2wm1 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Activity:	Aminocarboxymuconate-semialdehyde decarboxylase, with EC number 4.1.1.45
Resources:	FirstGlance, OCA, RCSB, PDBsum

Function

[ACMSD_HUMAN] Converts alpha-amino-beta-carboxymuconate-epsilon-semialdehyde (ACMS) to alpha-aminomuconate semialdehyde (AMS). ACMS can be converted non-enzymatically to quinolate (QA), a key precursor of NAD, and a potent endogenous excitotoxin of neuronal cells which is implicated in the pathogenesis of various neurodegenerative disorders. In the presence of ACMSD, ACMS is converted to AMS, a benign catabolite. ACMSD ultimately controls the metabolic fate of tryptophan catabolism along the kynurenine pathway.^[1] ^[2]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The enzyme alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD) is a zinc-dependent amidohydrolase that participates in picolinic acid (PA), quinolinic acid (QA) and NAD homeostasis. Indeed, the enzyme stands at a branch point of the tryptophan to NAD pathway, and determines the final fate of the amino acid, i.e. transformation into PA, complete oxidation through the citric acid cycle, or conversion into NAD through QA synthesis. Both PA and QA are key players in a number of physiological and pathological conditions, mainly affecting the central nervous system. As their relative concentrations must be tightly controlled, modulation of ACMSD activity appears to be a promising prospect for the treatment of neurological disorders, including cerebral malaria. Here we report the 2.0 A resolution crystal structure of human ACMSD in complex with the glycolytic intermediate 1,3-dihydroxyacetonephosphate (DHAP), refined to an R-factor of 0.19. DHAP, which we discovered to be a potent enzyme inhibitor, resides in the ligand binding pocket with its phosphate moiety contacting the catalytically essential zinc ion through mediation of a solvent molecule. Arg47, Asp291 and Trp191 appear to be the key residues for DHAP recognition in human ACMSD. Ligand binding induces a significant conformational change affecting a strictly conserved Trp-Met couple, and we propose that these residues are involved in controlling ligand admission into ACMSD. Our data may be used for the design of inhibitors with potential medical interest, and suggest a regulatory link between de novo NAD biosynthesis and glycolysis.

The crystal structure of human alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase in complex with 1,3-dihydroxyacetonephosphate suggests a regulatory link between NAD synthesis and glycolysis.,Garavaglia S, Perozzi S, Galeazzi L, Raffaelli N, Rizzi M FEBS J. 2009 Nov;276(22):6615-23. Epub 2009 Oct 16. PMID:19843166^[3]

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

References

↑ Garavaglia S, Perozzi S, Galeazzi L, Raffaelli N, Rizzi M. The crystal structure of human alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase in complex with 1,3-dihydroxyacetonephosphate suggests a regulatory link between NAD synthesis and glycolysis. FEBS J. 2009 Nov;276(22):6615-23. Epub 2009 Oct 16. PMID:19843166 doi:10.1111/j.1742-4658.2009.07372.x
↑ Fukuoka S, Ishiguro K, Yanagihara K, Tanabe A, Egashira Y, Sanada H, Shibata K. Identification and expression of a cDNA encoding human alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD). A key enzyme for the tryptophan-niacine pathway and "quinolinate hypothesis". J Biol Chem. 2002 Sep 20;277(38):35162-7. Epub 2002 Jul 24. PMID:12140278 doi:http://dx.doi.org/10.1074/jbc.M200819200
↑ Garavaglia S, Perozzi S, Galeazzi L, Raffaelli N, Rizzi M. The crystal structure of human alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase in complex with 1,3-dihydroxyacetonephosphate suggests a regulatory link between NAD synthesis and glycolysis. FEBS J. 2009 Nov;276(22):6615-23. Epub 2009 Oct 16. PMID:19843166 doi:10.1111/j.1742-4658.2009.07372.x

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2wm1"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[2wm1]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WM1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WM1 FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=13P:1,3-DIHYDROXYACETONEPHOSPHATE'>13P</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene><br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=13P:1,3-DIHYDROXYACETONEPHOSPHATE'>13P</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Aminocarboxymuconate-semialdehyde_decarboxylase Aminocarboxymuconate-semialdehyde decarboxylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.1.1.45 4.1.1.45] </span></td></tr>
+<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Aminocarboxymuconate-semialdehyde_decarboxylase Aminocarboxymuconate-semialdehyde decarboxylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.1.1.45 4.1.1.45] </span></td></tr>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2wm1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wm1 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2wm1 RCSB], [http://www.ebi.ac.uk/pdbsum/2wm1 PDBsum]</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=2wm1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wm1 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2wm1 RCSB], [http://www.ebi.ac.uk/pdbsum/2wm1 PDBsum]</span></td></tr>
-<table>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/ACMSD_HUMAN ACMSD_HUMAN]] Converts alpha-amino-beta-carboxymuconate-epsilon-semialdehyde (ACMS) to alpha-aminomuconate semialdehyde (AMS). ACMS can be converted non-enzymatically to quinolate (QA), a key precursor of NAD, and a potent endogenous excitotoxin of neuronal cells which is implicated in the pathogenesis of various neurodegenerative disorders. In the presence of ACMSD, ACMS is converted to AMS, a benign catabolite. ACMSD ultimately controls the metabolic fate of tryptophan catabolism along the kynurenine pathway.<ref>PMID:19843166</ref> <ref>PMID:12140278</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 31: / Line 33: @@
 [[Category: Aminocarboxymuconate-semialdehyde decarboxylase]]
 [[Category: Homo sapiens]]
-[[Category: Galeazzi, L.]]
+[[Category: Galeazzi, L]]
-[[Category: Garavaglia, S.]]
+[[Category: Garavaglia, S]]
-[[Category: Perozzi, S.]]
+[[Category: Perozzi, S]]
-[[Category: Raffaelli, N.]]
+[[Category: Raffaelli, N]]
-[[Category: Rizzi, M.]]
+[[Category: Rizzi, M]]
 [[Category: Cerebral malaria]]
 [[Category: Decarboxylase]]

2wm1

From Proteopedia

Revision as of 06:28, 25 December 2014

THE CRYSTAL STRUCTURE OF HUMAN ALPHA-AMINO-BETA-CARBOXYMUCONATE-EPSILON-SEMIALDEHYDE DECARBOXYLASE IN COMPLEX WITH 1,3- DIHYDROXYACETONEPHOSPHATE SUGGESTS A REGULATORY LINK BETWEEN NAD SYNTHESIS AND GLYCOLYSIS

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox