7AAK

Human porphobilinogen deaminase R173W mutant crystallized in the ES2 intermediate state

Summary for 7AAK

• Entry DOI: 10.2210/pdb7aak/pdb
• Related: 7AAJ
• Descriptor: Porphobilinogen deaminase, 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, GLYCEROL, ... (4 entities in total)
• Functional Keywords: pbg-d, hydroxymethylbilane synthase, hmbs, porphobilinogen deaminase, heme biosynthesis, porphyria, acute intermittent porphyria, es2, reaction intermediate, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 81158.31

Authors

Kallio, J.P.,Bustad, H.J.,Martinez, A. (deposition date: 2020-09-04, release date: 2021-02-17, Last modification date: 2024-11-06)

Primary citation

Bustad, H.J.,Kallio, J.P.,Laitaoja, M.,Toska, K.,Kursula, I.,Martinez, A.,Janis, J.
Characterization of porphobilinogen deaminase mutants reveals that arginine-173 is crucial for polypyrrole elongation mechanism.
Iscience, 24:102152-102152, 2021

PubMed Abstract: 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 (E) covalently attached to the dipyrromethane cofactor, and three intermediate complexes, ES, ES, and ES, where S represents PBG. In contrast, only ES was detected in AIP-associated mutant R173W, indicating that the formation of ES is inhibited. The R173W crystal structure in the ES-state revealed major rearrangements of the loops around the active site, compared to wild-type PBGD in the E-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.

PubMed: 33665570
DOI: 10.1016/j.isci.2021.102152

Experimental method

X-RAY DIFFRACTION (1.7 Å)