Structural insight into acute intermittent porphyria

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)

[1]  Ruth Nussinov,et al.  HingeProt: Automated prediction of hinges in protein structures , 2008, Proteins.

[2]  Fei Long,et al.  BALBES: a molecular-replacement pipeline , 2007, Acta crystallographica. Section D, Biological crystallography.

[3]  Kiriko Kaneko,et al.  Heme as a magnificent molecule with multiple missions: heme determines its own fate and governs cellular homeostasis. , 2007, The Tohoku journal of experimental medicine.

[4]  R. Stevens,et al.  Structure-based epitope and PEGylation sites mapping of phenylalanine ammonia-lyase for enzyme substitution treatment of phenylketonuria. , 2007, Molecular genetics and metabolism.

[5]  H. Puy,et al.  May 2006 update in porphobilinogen deaminase gene polymorphisms and mutations causing acute intermittent porphyria: comparison with the situation in Slavic population. , 2006, Physiological research.

[6]  R. Stevens,et al.  Response of patients with phenylketonuria in the US to tetrahydrobiopterin. , 2005, Molecular genetics and metabolism.

[7]  M. Hørder,et al.  Characterization of two isoalleles and three mutations in both isoforms of purified recombinant human porphobilinogen deaminase , 2005, Scandinavian journal of clinical and laboratory investigation.

[8]  Kevin Cowtan,et al.  research papers Acta Crystallographica Section D Biological , 2005 .

[9]  P. Shoolingin-Jordan,et al.  Human porphobilinogen deaminase mutations in the investigation of the mechanism of dipyrromethane cofactor assembly and tetrapyrrole formation. , 2003, Biochemical Society transactions.

[10]  S. Sassa.  The porphyrias , 2002, Photodermatology, photoimmunology & photomedicine.

[11]  Randy J Read,et al.  Electronic Reprint Biological Crystallography Phenix: Building New Software for Automated Crystallographic Structure Determination Biological Crystallography Phenix: Building New Software for Automated Crystallographic Structure Determination , 2022 .

[12]  F. Collart,et al.  A new vector for high-throughput, ligation-independent cloning encoding a tobacco etch virus protease cleavage site. , 2002, Protein expression and purification.

[13]  Christophe Combet,et al.  Geno3D: automatic comparative molecular modelling of protein , 2002, Bioinform..

[14]  K. Anderson.  Disorders of heme biosynthesis : X-linked sideroblastic anemia and the porphyrias , 2001 .

[15]  H. Dailey,et al.  Multiple regulatory steps in erythroid heme biosynthesis. , 2000, Archives of biochemistry and biophysics.

[16]  R. Stevens,et al.  Structure of Tetrameric Human Phenylalanine Hydroxylase and Its Implications for Phenylketonuria* , 1998, The Journal of Biological Chemistry.

[17]  R. Stevens,et al.  Crystal structure of the catalytic domain of human phenylalanine hydroxylase reveals the structural basis for phenylketonuria , 1997, Nature Structural Biology.

[18]  J. Deybach,et al.  Molecular epidemiology and diagnosis of PBG deaminase gene defects in acute intermittent porphyria. , 1997, American journal of human genetics.

[19]  Z. Otwinowski,et al.  Processing of X-ray diffraction data collected in oscillation mode. , 1997, Methods in enzymology.

[20]  M. Warren,et al.  Discovery that the assembly of the dipyrromethane cofactor of porphobilinogen deaminase holoenzyme proceeds initially by the reaction of preuroporphyrinogen with the apoenzyme. , 1996, The Biochemical journal.

[21]  H. Dailey,et al.  Regulation of heme biosynthesis in Escherichia coli. , 1995, Archives of biochemistry and biophysics.

[22]  P. Jordan,et al.  Purification and properties of porphobilinogen deaminase from Arabidopsis thaliana. , 1994, The Biochemical journal.

[23]  P. Jordan,et al.  Evidence for participation of aspartate-84 as a catalytic group at the active site of porphobilinogen deaminase obtained by site-directed mutagenesis of the hemC gene from Escherichia coli. , 1994, Biochemistry.

[24]  T. Blundell,et al.  Structure of porphobilinogen deaminase reveals a flexible multidomain polymerase with a single catalytic site , 1992, Nature.

[25]  R. Kauppinen,et al.  Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases. , 1992, Medicine.

[26]  Studies on Porphobilinogen-Deaminase from Saccharomyces cerevisiae , 1991, Zeitschrift fur Naturforschung. C, Journal of biosciences.

[27]  P. M. Jordan,et al.  Biosynthesis of Tetrapyrroles , 1991 .

[28]  Edward N. Baker,et al.  Apolactoferrin structure demonstrates ligand-induced conformational change in transferrins , 1990, Nature.

[29]  M. Warren,et al.  Investigation into the nature of substrate binding to the dipyrromethane cofactor of Escherichia coli porphobilinogen deaminase. , 1988, Biochemistry.

[30]  M. Mazzetti,et al.  Characterization of porphobilinogen deaminase from rat liver. , 1988, Biochimica et biophysica acta.

[31]  M. Warren,et al.  Purification, crystallization and properties of porphobilinogen deaminase from a recombinant strain of Escherichia coli K12. , 1988, The Biochemical journal.

[32]  S. Tsai,et al.  Purification and properties of uroporphyrinogen III synthase from human erythrocytes. , 1987, The Journal of biological chemistry.

[33]  C. Beaumont,et al.  Tissue-specific expression of porphobilinogen deaminase. Two isoenzymes from a single gene. , 1987, European journal of biochemistry.

[34]  P. Anderson,et al.  Purification and properties of uroporphyrinogen I synthase from human erythrocytes. Identification of stable enzyme-substrate intermediates. , 1980, The Journal of biological chemistry.

[35]  S. Granick,et al.  Hemes, chlorophylls, and related compounds: biosynthesis and metabolic regulation. , 1978, Advances in enzymology and related areas of molecular biology.

[36]  L. Wetterberg.  [Acute intermittent porphyria]. , 1974, Lakartidningen.

[37]  P. Jordan,et al.  Purification and properties of uroporphyrinogen I synthetase from Rhodopseudomonas spheroides. , 1973, The Journal of biological chemistry.

[38]  H. Marver,et al.  Decreased red cell uroporphyrinogen I synthetase activity in intermittent acute porphyria. , 1972, The Journal of clinical investigation.