| Structural highlights
Disease
[HEM3_HUMAN] Defects in HMBS are the cause of acute intermittent porphyria (AIP) [MIM: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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [:][28] [29] [30] [31] [32] [33]
Function
[HEM3_HUMAN] Tetrapolymerization of the monopyrrole PBG into the hydroxymethylbilane pre-uroporphyrinogen in several discrete steps.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Mutations in the human PBGD (porphobilinogen deaminase) gene cause the inherited defect AIP (acute intermittent porphyria). In the present study we report the structure of the human uPBGD (ubiquitous PBGD) mutant, R167Q, that has been determined by X-ray crystallography and refined to 2.8 A (1 A=0.1 nm) resolution (Rfactor=0.26, Rfree=0.29). The protein crystallized in space group P2(1)2(1)2 with two molecules in the asymmetric unit (a=81.0 A, b=104.4 A and c=109.7 A). Phases were obtained by molecular replacement using the Escherichia coli PBGD structure as a search model. The human enzyme is composed of three domains each of approx. 110 amino acids and possesses a dipyrromethane cofactor at the active site, which is located between domains 1 and 2. An ordered sulfate ion is hydrogen-bonded to Arg26 and Ser28 at the proposed substrate-binding site in domain 1. An insert of 29 amino acid residues, present only in mammalian PBGD enzymes, has been modelled into domain 3 where it extends helix alpha2(3) and forms a beta-hairpin structure that contributes to a continuous hydrogen-bonding network spanning domains 1 and 3. The structural and functional implications of the R167Q mutation and other mutations that result in AIP are discussed.
Structure of human porphobilinogen deaminase at 2.8 A: the molecular basis of acute intermittent porphyria.,Gill R, Kolstoe SE, Mohammed F, Al D-Bass A, Mosely JE, Sarwar M, Cooper JB, Wood SP, Shoolingin-Jordan PM Biochem J. 2009 Apr 28;420(1):17-25. PMID:19207107[34]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Delfau MH, Picat C, de Rooij FW, Hamer K, Bogard M, Wilson JH, Deybach JC, Nordmann Y, Grandchamp B. Two different point G to A mutations in exon 10 of the porphobilinogen deaminase gene are responsible for acute intermittent porphyria. J Clin Invest. 1990 Nov;86(5):1511-6. PMID:2243128 doi:http://dx.doi.org/10.1172/JCI114869
- ↑ Delfau MH, Picat C, De Rooij F, Voortman G, Deybach JC, Nordmann Y, Grandchamp B. Molecular heterogeneity of acute intermittent porphyria: identification of four additional mutations resulting in the CRIM-negative subtype of the disease. Am J Hum Genet. 1991 Aug;49(2):421-8. PMID:1714233
- ↑ Gu XF, de Rooij F, Voortman G, Te Velde K, Nordmann Y, Grandchamp B. High frequency of mutations in exon 10 of the porphobilinogen deaminase gene in patients with a CRIM-positive subtype of acute intermittent porphyria. Am J Hum Genet. 1992 Sep;51(3):660-5. PMID:1496994
- ↑ Mgone CS, Lanyon WG, Moore MR, Connor JM. Detection of seven point mutations in the porphobilinogen deaminase gene in patients with acute intermittent porphyria, by direct sequencing of in vitro amplified cDNA. Hum Genet. 1992 Sep-Oct;90(1-2):12-6. PMID:1427766
- ↑ Kauppinen R, Peltonen L, Pihlaja H, Mustajoki P. CRIM-positive mutations of acute intermittent porphyria in Finland. Hum Mutat. 1992;1(5):392-6. PMID:1301948 doi:http://dx.doi.org/10.1002/humu.1380010508
- ↑ Mgone CS, Lanyon WG, Moore MR, Louie GV, Connor JM. Detection of a high mutation frequency in exon 12 of the porphobilinogen deaminase gene in patients with acute intermittent porphyria. Hum Genet. 1993 Dec;92(6):619-22. PMID:8262523
- ↑ Llewellyn DH, Whatley S, Elder GH. Acute intermittent porphyria caused by an arginine to histidine substitution (R26H) in the cofactor-binding cleft of porphobilinogen deaminase. Hum Mol Genet. 1993 Aug;2(8):1315-6. PMID:8401516
- ↑ Gu XF, de Rooij F, de Baar E, Bruyland M, Lissens W, Nordmann Y, Grandchamp B. Two novel mutations of the porphobilinogen deaminase gene in acute intermittent porphyria. Hum Mol Genet. 1993 Oct;2(10):1735-6. PMID:8268934
- ↑ Gu XF, de Rooij F, Voortman G, Te Velde K, Deybach JC, Nordmann Y, Grandchamp B. Detection of eleven mutations causing acute intermittent porphyria using denaturing gradient gel electrophoresis. Hum Genet. 1994 Jan;93(1):47-52. PMID:8270254
- ↑ Lundin G, Wedell A, Thunell S, Anvret M. Two new mutations in the porphobilinogen deaminase gene and a screening method using PCR amplification of specific alleles. Hum Genet. 1994 Jan;93(1):59-62. PMID:8270256
- ↑ Mgone CS, Lanyon WG, Moore MR, Louie GV, Connor JM. Identification of five novel mutations in the porphobilinogen deaminase gene. Hum Mol Genet. 1994 May;3(5):809-11. PMID:8081367
- ↑ Chen CH, Astrin KH, Lee G, Anderson KE, Desnick RJ. Acute intermittent porphyria: identification and expression of exonic mutations in the hydroxymethylbilane synthase gene. An initiation codon missense mutation in the housekeeping transcript causes "variant acute intermittent porphyria" with normal expression of the erythroid-specific enzyme. J Clin Invest. 1994 Nov;94(5):1927-37. PMID:7962538 doi:http://dx.doi.org/10.1172/JCI117543
- ↑ Kauppinen R, Mustajoki S, Pihlaja H, Peltonen L, Mustajoki P. Acute intermittent porphyria in Finland: 19 mutations in the porphobilinogen deaminase gene. Hum Mol Genet. 1995 Feb;4(2):215-22. PMID:7757070
- ↑ Lundin G, Hashemi J, Floderus Y, Thunell S, Sagen E, Laegreid A, Wassif W, Peters T, Anvret M. Four mutations in the porphobilinogen deaminase gene in patients with acute intermittent porphyria. J Med Genet. 1995 Dec;32(12):979-81. PMID:8825929
- ↑ Puy H, Deybach JC, Lamoril J, Robreau AM, Da Silva V, Gouya L, Grandchamp B, Nordmann Y. Molecular epidemiology and diagnosis of PBG deaminase gene defects in acute intermittent porphyria. Am J Hum Genet. 1997 Jun;60(6):1373-83. PMID:9199558 doi:S0002-9297(07)64229-3
- ↑ Lundin G, Lee JS, Thunell S, Anvret M. Genetic investigation of the porphobilinogen deaminase gene in Swedish acute intermittent porphyria families. Hum Genet. 1997 Jul;100(1):63-6. PMID:9225970
- ↑ Mustajoki S, Pihlaja H, Ahola H, Petersen NE, Mustajoki P, Kauppinen R. Three splicing defects, an insertion, and two missense mutations responsible for acute intermittent porphyria. Hum Genet. 1998 May;102(5):541-8. PMID:9654202
- ↑ Ong PM, Lanyon WG, Hift RJ, Halkett J, Cramp CE, Moore MR, Connor JM. Identification of two novel mutations in the hydroxymethylbilane synthase gene in three patients from two unrelated families with acute intermittent porphyria. Hum Hered. 1998 Jan-Feb;48(1):24-9. PMID:9463797
- ↑ De Siervi A, Rossetti MV, Parera VE, Astrin KH, Aizencang GI, Glass IA, Batlle AM, Desnick RJ. Identification and characterization of hydroxymethylbilane synthase mutations causing acute intermittent porphyria: evidence for an ancestral founder of the common G111R mutation. Am J Med Genet. 1999 Oct 8;86(4):366-75. PMID:10494093
- ↑ Whatley SD, Woolf JR, Elder GH. Comparison of complementary and genomic DNA sequencing for the detection of mutations in the HMBS gene in British patients with acute intermittent porphyria: identification of 25 novel mutations. Hum Genet. 1999 Jun;104(6):505-10. PMID:10453740
- ↑ De Siervi A, Mendez M, Parera VE, Varela L, Batlle AM, Rossetti MV. Acute intermittent porphyria: characterization of two novel mutations in the porphobilinogen deaminase gene, one amino acid deletion (453-455delAGC) and one splicing aceptor site mutation (IVS8-1G>T). Hum Mutat. 1999 Oct;14(4):355. PMID:10502788 doi:<355::AID-HUMU19>3.0.CO;2-T 10.1002/(SICI)1098-1004(199910)14:4<355::AID-HUMU19>3.0.CO;2-T
- ↑ Gross U, Puy H, Doss M, Robreau AM, Nordmann Y, Doss MO, Deybach JC. New mutations of the hydroxymethylbilane synthase gene in German patients with acute intermittent porphyria. Mol Cell Probes. 1999 Dec;13(6):443-7. PMID:10657149 doi:10.1006/mcpr.1999.0276
- ↑ Solis C, Lopez-Echaniz I, Sefarty-Graneda D, Astrin KH, Desnick RJ. Identification and expression of mutations in the hydroxymethylbilane synthase gene causing acute intermittent porphyria (AIP). Mol Med. 1999 Oct;5(10):664-71. PMID:10602775
- ↑ Ramdall RB, Cunha L, Astrin KH, Katz DR, Anderson KE, Glucksman M, Bottomley SS, Desnick RJ. Acute intermittent porphyria: novel missense mutations in the human hydroxymethylbilane synthase gene. Genet Med. 2000 Sep-Oct;2(5):290-5. PMID:11399210 doi:10.109700125817-200009000-00004
- ↑ Robreau-Fraolini AM, Puy H, Aquaron C, Bogard C, Traore M, Nordmann Y, Aquaron R, Deybach JC. Porphobilinogen deaminase gene in African and Afro-Caribbean ethnic groups: mutations causing acute intermittent porphyria and specific intragenic polymorphisms. Hum Genet. 2000 Aug;107(2):150-9. PMID:11030413
- ↑ Schneider-Yin X, Bogard C, Rufenacht UB, Puy H, Nordmann Y, Minder EI, Deybach J. Identification of a prevalent nonsense mutation (W283X) and two novel mutations in the porphobilinogen deaminase gene of Swiss patients with acute intermittent porphyria. Hum Hered. 2000 Jul-Aug;50(4):247-50. PMID:10782018 doi:22924
- ↑ De Siervi A, Weiss Cadiz DE, Parera VE, del C Batlle AM, Rossetti MV. Identification and characterization of two novel mutations that produce acute intermittent porphyria: A 3-base deletion (841-843delGGA) and a missense mutation (T35M). Hum Mutat. 2000 Oct;16(4):373. PMID:11013452 doi:<373::AID-HUMU14>3.0.CO;2-A 10.1002/1098-1004(200010)16:4<373::AID-HUMU14>3.0.CO;2-A
- ↑ Kauppinen R, von und zu Fraunberg M. Molecular and biochemical studies of acute intermittent porphyria in 196 patients and their families. Clin Chem. 2002 Nov;48(11):1891-900. PMID:12406973
- ↑ Floderus Y, Shoolingin-Jordan PM, Harper P. Acute intermittent porphyria in Sweden. Molecular, functional and clinical consequences of some new mutations found in the porphobilinogen deaminase gene. Clin Genet. 2002 Oct;62(4):288-97. PMID:12372055
- ↑ Gregor A, Schneider-Yin X, Szlendak U, Wettstein A, Lipniacka A, Rufenacht UB, Minder EI. Molecular study of the hydroxymethylbilane synthase gene (HMBS) among Polish patients with acute intermittent porphyria. Hum Mutat. 2002 Mar;19(3):310. PMID:11857754 doi:10.1002/humu.9020
- ↑ Gouya L, Puy H, Robreau AM, Lyoumi S, Lamoril J, Da Silva V, Grandchamp B, Deybach JC. Modulation of penetrance by the wild-type allele in dominantly inherited erythropoietic protoporphyria and acute hepatic porphyrias. Hum Genet. 2004 Feb;114(3):256-62. Epub 2003 Dec 11. PMID:14669009 doi:10.1007/s00439-003-1059-5
- ↑ Hessels J, Voortman G, van der Wagen A, van der Elzen C, Scheffer H, Zuijderhoudt FM. Homozygous acute intermittent porphyria in a 7-year-old boy with massive excretions of porphyrins and porphyrin precursors. J Inherit Metab Dis. 2004;27(1):19-27. PMID:14970743 doi:10.1023/B:BOLI.0000016613.75677.05
- ↑ Schneider-Yin X, Hergersberg M, Schuurmans MM, Gregor A, Minder EI. Mutation hotspots in the human porphobilinogen deaminase gene: recurrent mutations G111R and R173Q occurring at CpG motifs. J Inherit Metab Dis. 2004;27(5):625-31. PMID:15669678
- ↑ Gill R, Kolstoe SE, Mohammed F, Al D-Bass A, Mosely JE, Sarwar M, Cooper JB, Wood SP, Shoolingin-Jordan PM. Structure of human porphobilinogen deaminase at 2.8 A: the molecular basis of acute intermittent porphyria. Biochem J. 2009 Apr 28;420(1):17-25. PMID:19207107 doi:10.1042/BJ20082077
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