7aak

<table><tr><td colspan='2'>[[7aak]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AAK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AAK FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7J8:3-[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]-1~{H}-pyrrol-3-yl]propanoic+acid'>7J8</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>

<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Hydroxymethylbilane_synthase Hydroxymethylbilane synthase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.61 2.5.1.61] </span></td></tr>

== 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 ==

Porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthesis, catalyzes the sequential coupling of four porphobilinogen (PBG) molecules into a heme precursor. Mutations in PBGD are associated with acute intermittent porphyria (AIP), a rare metabolic disorder. We used Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) to demonstrate that wild-type PBGD and AIP-associated mutant R167W both existed as holoenzymes (Eholo) covalently attached to the dipyrromethane cofactor, and three intermediate complexes, ES, ES2, and ES3, where S represents PBG. In contrast, only ES2 was detected in AIP-associated mutant R173W, indicating that the formation of ES3 is inhibited. The R173W crystal structure in the ES2-state revealed major rearrangements of the loops around the active site, compared to wild-type PBGD in the Eholo-state. These results contribute to elucidating the structural pathogenesis of two common AIP-associated mutations and reveal the important structural role of Arg173 in the polypyrrole elongation mechanism.

 

== References ==

[[Category: Human]]

[[Category: Hydroxymethylbilane synthase]]

[[Category: Bustad, H J]]

[[Category: Kallio, J P]]

[[Category: Martinez, A]]

[[Category: Transferase]]