3ECR

Structure of human porphobilinogen deaminase

Summary for 3ECR

• Entry DOI: 10.2210/pdb3ecr/pdb
• Descriptor: Porphobilinogen deaminase, 3-[5-{[3-(2-carboxyethyl)-4-(carboxymethyl)-5-methyl-1H-pyrrol-2-yl]methyl}-4-(carboxymethyl)-1H-pyrrol-3-yl]propanoic acid (3 entities in total)
• Functional Keywords: human porphobilinogen deaminase, heme biosynthesis, porphobilinogen hinge, alternative splicing, cytoplasm, disease mutation, porphyrin biosynthesis, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm (Probable): P08397
• Total number of polymer chains: 2
• Total formula weight: 80151.37

Authors

Song, G.,Li, Y.,Cheng, C.,Zhao, Y.,Gao, A.,Zhang, R.,Joachimiak, A.,Shaw, N.,Liu, Z.J. (deposition date: 2008-09-01, release date: 2008-09-30, Last modification date: 2024-03-20)

Primary citation

Song, G.,Li, Y.,Cheng, C.,Zhao, Y.,Gao, A.,Zhang, R.,Joachimiak, A.,Shaw, N.,Liu, Z.J.
Structural insight into acute intermittent porphyria.
Faseb J., 23:396-404, 2009

PubMed Abstract: Acute intermittent porphyria (AIP), an inherited disease of heme biosynthesis, is one of the most common types of porphyria. Reduced activity of the enzyme porphobilinogen deaminase (PBGD), which catalyzes the sequential condensation of 4 molecules of porphobilinogen to yield preuroporphyrinogen, has been linked to the symptoms of AIP. We have determined the 3-dimensional structure of human PBGD at 2.2 A resolution. Analysis of the structure revealed a dipyrromethane cofactor molecule covalently linked to C261, sitting in a positively charged cleft region. In addition to the critical catalytic D99, a number of other residues are seen hydrogen bonded to the cofactor and play a role in catalysis. Sequential entry of 4 pyrrole molecules into the active site is accomplished by movement of the domains around the hinges. H120P mutation resulted in an inactive enzyme, supporting the role of H120 as a hinge residue. Interestingly, some of the mutations of the human PBGD documented in patients suffering from AIP are located far away from the active site. The structure provides insights into the mechanism of action of PBGD at the molecular level and could aid the development of potential drugs for the up-regulation of PBGD activity in AIP.

PubMed: 18936296
DOI: 10.1096/fj.08-115469

Experimental method

X-RAY DIFFRACTION (2.182 Å)