| 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.
Publication Abstract from PubMed
Hydroxymethylbilane synthase (HMBS), involved in haem biosynthesis, catalyses the head-to-tail coupling of four porphobilinogens (PBGs) via a dipyrromethane (DPM) cofactor. DPM is composed of two PBGs, and a hexapyrrole is built before the tetrapyrrolic 1-hydroxymethylbilane product is released. During this elongation, stable enzyme (E) intermediates are formed from the holoenzyme, with additional PBG substrates (S): ES, ES(2) , ES(3) and ES(4) . Native PAGE and mass spectrometry of the acute intermittent porphyria (AIP)-associated HMBS variant p.Arg167Gln demonstrated an increased amount of ES(3) and, although kinetic parameters indicated catalytic dysfunction, the product release was not entirely prevented. Isolation and crystal structure analysis of the ES(3) intermediate (PDB: 8PND) showed that a pentapyrrole was fully retained within the active site, revealing that polypyrrole elongation proceeds within the active site via a third interaction site, intermediate pyrrole site 3 (IPS3). The AIP-associated HMBS variant p.Arg195Cys, located in the opposite side to p.Arg167Gln in the active site, on the other hand, accumulated the ES(4) intermediate in the presence of excess PBG, implying that product hydrolysis was obstructed. Arg167 is thus involved in all elongation steps and is a determinant for the rate of enzyme catalysis, whereas Arg195 is important for releasing the product. Moreover, by substituting residues in the vicinity of IPS3, our results indicate that the fully retained hexapyrrole could be hydrolysed in a novel site in proximity of the IPS3.
One ring closer to a closure: the crystal structure of the ES(3) hydroxymethylbilane synthase intermediate.,Bustad HJ, Christie MS, Laitaoja M, Aarsand AK, Martinez A, Janis J, Kallio JP FEBS J. 2023 Oct 20. doi: 10.1111/febs.16982. PMID:37863644[34]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ 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:https://dx.doi.org/10.1002/humu.1380010508
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- ↑ 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
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- ↑ 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:https://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
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- ↑ 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
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- ↑ 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
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- ↑ 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
- ↑ Bustad HJ, Christie MS, Laitaoja M, Aarsand AK, Martinez A, Jänis J, Kallio JP. One ring closer to a closure: the crystal structure of the ES(3) hydroxymethylbilane synthase intermediate. FEBS J. 2023 Oct 20. PMID:37863644 doi:10.1111/febs.16982
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