8pnd

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Line 1: Line 1:
-
'''Unreleased structure'''
 
-
The entry 8pnd is ON HOLD until Paper Publication
+
==The ES3 intermediate of hydroxymethylbilane synthase R167Q variant==
 +
<StructureSection load='8pnd' size='340' side='right'caption='[[8pnd]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 +
== Structural highlights ==
 +
<table><tr><td colspan='2'>[[8pnd]] is a 2 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=8PND OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8PND FirstGlance]. <br>
 +
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
 +
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZWW:3-[4-(2-hydroxy-2-oxoethyl)-5-[[4-(2-hydroxy-2-oxoethyl)-5-[[4-(2-hydroxy-2-oxoethyl)-5-[[4-(2-hydroxy-2-oxoethyl)-5-[[4-(2-hydroxy-2-oxoethyl)-3-(3-hydroxy-3-oxopropyl)-5-methyl-1~{H}-pyrrol-2-yl]methyl]-3-(3-hydroxy-3-oxopropyl)-1~{H}-pyrrol-2-yl]methyl]-3-(3-hydroxy-3-oxopropyl)-1~{H}-pyrrol-2-yl]methyl]-3-(3-hydroxy-3-oxopropyl)-1~{H}-pyrrol-2-yl]methyl]-1~{H}-pyrrol-3-yl]propanoic+acid'>ZWW</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=8pnd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8pnd OCA], [https://pdbe.org/8pnd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8pnd RCSB], [https://www.ebi.ac.uk/pdbsum/8pnd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8pnd ProSAT]</span></td></tr>
 +
</table>
 +
== Disease ==
 +
[https://www.uniprot.org/uniprot/HEM3_HUMAN HEM3_HUMAN] Defects in HMBS are the cause of acute intermittent porphyria (AIP) [MIM:[https://omim.org/entry/176000 176000]. AIP is a form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. AIP is an autosomal dominant form of hepatic porphyria characterized by acute attacks of neurological dysfunctions with abdominal pain, hypertension, tachycardia, and peripheral neuropathy. Most attacks are precipitated by drugs, alcohol, caloric deprivation, infections, or endocrine factors.<ref>PMID:2243128</ref> <ref>PMID:1714233</ref> <ref>PMID:1496994</ref> <ref>PMID:1427766</ref> <ref>PMID:1301948</ref> <ref>PMID:8262523</ref> <ref>PMID:8401516</ref> <ref>PMID:8268934</ref> <ref>PMID:8270254</ref> <ref>PMID:8270256</ref> <ref>PMID:8081367</ref> <ref>PMID:7962538</ref> <ref>PMID:7757070</ref> <ref>PMID:8825929</ref> <ref>PMID:9199558</ref> <ref>PMID:9225970</ref> <ref>PMID:9654202</ref> <ref>PMID:9463797</ref> <ref>PMID:10494093</ref> <ref>PMID:10453740</ref> <ref>PMID:10502788</ref> <ref>PMID:10657149</ref> <ref>PMID:10602775</ref> <ref>PMID:11399210</ref> <ref>PMID:11030413</ref> <ref>PMID:10782018</ref> <ref>PMID:11013452</ref> [:]<ref>PMID:12406973</ref> <ref>PMID:12372055</ref> <ref>PMID:11857754</ref> <ref>PMID:14669009</ref> <ref>PMID:14970743</ref> <ref>PMID:15669678</ref>
 +
== Function ==
 +
[https://www.uniprot.org/uniprot/HEM3_HUMAN HEM3_HUMAN] Tetrapolymerization of the monopyrrole PBG into the hydroxymethylbilane pre-uroporphyrinogen in several discrete steps.
 +
<div style="background-color:#fffaf0;">
 +
== Publication Abstract from PubMed ==
 +
Hydroxymethylbilane synthase (HMBS), involved in haem biosynthesis, catalyses the head-to-tail coupling of four porphobilinogens (PBGs) via a dipyrromethane (DPM) cofactor. DPM is composed of two PBGs, and a hexapyrrole is built before the tetrapyrrolic 1-hydroxymethylbilane product is released. During this elongation, stable enzyme (E) intermediates are formed from the holoenzyme, with additional PBG substrates (S): ES, ES(2) , ES(3) and ES(4) . Native PAGE and mass spectrometry of the acute intermittent porphyria (AIP)-associated HMBS variant p.Arg167Gln demonstrated an increased amount of ES(3) and, although kinetic parameters indicated catalytic dysfunction, the product release was not entirely prevented. Isolation and crystal structure analysis of the ES(3) intermediate (PDB: 8PND) showed that a pentapyrrole was fully retained within the active site, revealing that polypyrrole elongation proceeds within the active site via a third interaction site, intermediate pyrrole site 3 (IPS3). The AIP-associated HMBS variant p.Arg195Cys, located in the opposite side to p.Arg167Gln in the active site, on the other hand, accumulated the ES(4) intermediate in the presence of excess PBG, implying that product hydrolysis was obstructed. Arg167 is thus involved in all elongation steps and is a determinant for the rate of enzyme catalysis, whereas Arg195 is important for releasing the product. Moreover, by substituting residues in the vicinity of IPS3, our results indicate that the fully retained hexapyrrole could be hydrolysed in a novel site in proximity of the IPS3.
-
Authors:
+
One ring closer to a closure: the crystal structure of the ES(3) hydroxymethylbilane synthase intermediate.,Bustad HJ, Christie MS, Laitaoja M, Aarsand AK, Martinez A, Janis J, Kallio JP FEBS J. 2023 Oct 20. doi: 10.1111/febs.16982. PMID:37863644<ref>PMID:37863644</ref>
-
Description:
+
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-
[[Category: Unreleased Structures]]
+
</div>
 +
<div class="pdbe-citations 8pnd" style="background-color:#fffaf0;"></div>
 +
== References ==
 +
<references/>
 +
__TOC__
 +
</StructureSection>
 +
[[Category: Homo sapiens]]
 +
[[Category: Large Structures]]
 +
[[Category: Aarsand AK]]
 +
[[Category: Bustad HJ]]
 +
[[Category: Janis J]]
 +
[[Category: Kallio JP]]
 +
[[Category: Laitaoja M]]
 +
[[Category: Martinez A]]
 +
[[Category: Saeter MC]]

Revision as of 13:11, 1 November 2023

The ES3 intermediate of hydroxymethylbilane synthase R167Q variant

PDB ID 8pnd

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8pnd"
Personal tools