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Structural insight into acute intermittent porphyria
Author(s) -
Song Gaojie,
Li Yang,
Cheng Chongyun,
Zhao Yu,
Gao Ang,
Zhang Rongguang,
Joachimiak Andrzej,
Shaw Neil,
Liu ZhiJie
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-115469
Subject(s) - porphobilinogen deaminase , acute intermittent porphyria , porphobilinogen , active site , heme , chemistry , porphyria , enzyme , biochemistry , protein structure , stereochemistry , medicine
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 Å 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.— 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)