porphobilinogen deaminase

ポルフォビリノゲンデアミナーゼ PBGD

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/01/13 22:10:00」(JST)

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Hydroxymethylbilane synthase
Rendering based on PDB 3ECR.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 3ECR, 3EQ1
Identifiers
Symbols	HMBS ; PBG-D; PBGD; PORC; UPS
External IDs	OMIM: 609806 MGI: 96112 HomoloGene: 158 GeneCards: HMBS Gene
EC number	2.5.1.61
Gene ontology Molecular function • hydroxymethylbilane synthase activity • uroporphyrinogen-III synthase activity • carboxylic acid binding • amine binding • coenzyme binding Cellular component • condensed chromosome • nucleus • cytosol • axon Biological process • response to hypoxia • porphyrin-containing compound metabolic process • protoporphyrinogen IX biosynthetic process • heme biosynthetic process • response to carbohydrate • response to zinc ion • peptidyl-pyrromethane cofactor linkage • organ regeneration • response to cobalt ion • response to estradiol • response to vitamin • response to drug • response to amino acid • small molecule metabolic process • astrocyte differentiation • response to methylmercury • cellular response to antibiotic • cellular response to arsenic-containing substance • cellular response to lead ion • cellular response to cytokine stimulus • cellular response to amine stimulus • cellular response to dexamethasone stimulus Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3145	15288
Ensembl	ENSG00000256269	ENSMUSG00000032126
UniProt	P08397	P22907
RefSeq (mRNA)	NM_000190	NM_001110251
RefSeq (protein)	NP_000181	NP_001103721
Location (UCSC)	Chr 11: 119.08 – 119.09 Mb	Chr 9: 44.34 – 44.34 Mb
PubMed search	[1]	[2]

Porphobilinogen deaminase (EC 2.5.1.61, Older sources categorize it under EC 4.3.1.8), also known as hydroxymethylbilane synthase or uroporphyrinogen I synthase is an enzyme that in humans is encoded by the HMBS gene. Porphobilinogen deaminase is involved in the third step of the heme biosynthetic pathway. It catalyzes the head to tail condensation of four porphobilinogen molecules into the linear hydroxymethylbilane while releasing four ammonia molecules.

Structure and function

Functionally, porphobilinogen deaminase catalyzes the loss of ammonia from the porphobilinogen monomer (deamination) and its subsequent polymerization to a linear tetrapyrrole, which is released as hydroxymethylbilane:

The structure of 40-42 kDa porphobilinogen deaminase, which is highly conserved amongst organisms, consists of three domains. Domains 1 and 2 are structurally very similar: each consisting of five beta-sheets and three alpha helices in humans. Domain 3 is positioned between the other two and has a flattened beta-sheet geometry. A dipyrrole, a cofactor of this enzyme consisting of two condensed porphobilinogen molecules, is covalently attached to domain 3 and extends into the active site, the cleft between domains 1 and 2. Several positively charged arginine residues, positioned to face the active site from domains 1 and 2, have been shown to stabilize the carboxylate functionalities on the incoming porphobilinogen as well as the growing pyrrole chain. These structural features presumably favor the formation of the final hydroxymethylbilane product. Porphobilinogen deaminase usually exists in dimer units in the cytoplasm of the cell.

Reaction mechanism

The first step is believed to involve an E1 elimination of ammonia from porphobilinogen, generating a carbocation intermediate (1). This intermediate is then attacked by the dipyrrole cofactor of porphobilinogen deaminase, which after losing a proton yields a trimer covalently bound to the enzyme (2). This intermediate is then open to further reaction with porphobilinogen (1 and 2 repeated three more times). Once a hexamer is formed, hydrolysis allows hydroxymethylbilane to be released, as well as cofactor regeneration (3).

Pathology

The most well-known health issue involving porphobilinogen deaminase is acute intermittent porphyria, an autosomal dominant genetic disorder where insufficient hydroxymethylbilane is produced, leading to a build-up of porphobilinogen in the cytoplasm. This is caused by a gene mutation that, in 90% of cases, causes decreased amounts of enzyme. However, mutations where less-active enzymes and/or different isoforms have been described.

References

Further reading

• Deybach JC, Puy H (1995). "Porphobilinogen deaminase gene structure and molecular defects.". J. Bioenerg. Biomembr. 27 (2): 197–205. doi:10.1007/BF02110034. PMID 7592566. 
• Astrin KH, Desnick RJ (1995). "Molecular basis of acute intermittent porphyria: mutations and polymorphisms in the human hydroxymethylbilane synthase gene.". Hum. Mutat. 4 (4): 243–52. doi:10.1002/humu.1380040403. PMID 7866402. 
• Helliwell JR, Nieh YP, Habash J, et al. (2003). "Time-resolved and static-ensemble structural chemistry of hydroxymethylbilane synthase.". Faraday Discuss. 122: 131–44; discussion 171–90. doi:10.1039/b201331b. PMID 12555854. 
• Hessels J, Voortman G, van der Wagen A, et al. (2004). "Homozygous acute intermittent porphyria in a 7-year-old boy with massive excretions of porphyrins and porphyrin precursors.". J. Inherit. Metab. Dis. 27 (1): 19–27. doi:10.1023/B:BOLI.0000016613.75677.05. PMID 14970743. 
• Kauppinen R (2004). "Molecular diagnostics of acute intermittent porphyria.". Expert Rev. Mol. Diagn. 4 (2): 243–9. doi:10.1586/14737159.4.2.243. PMID 14995910. 
• Hrdinka M, Puy H, Martasek P (2007). "May 2006 update in porphobilinogen deaminase gene polymorphisms and mutations causing acute intermittent porphyria: comparison with the situation in Slavic population.". Physiological research / Academia Scientiarum Bohemoslovaca. 55 Suppl 2: S119–36. PMID 17298216. 
• Kauppinen R, Peltonen L, Pihlaja H, Mustajoki P (1993). "CRIM-positive mutations of acute intermittent porphyria in Finland.". Hum. Mutat. 1 (5): 392–6. doi:10.1002/humu.1380010508. PMID 1301948. 
• Mgone CS, Lanyon WG, Moore MR, Connor JM (1992). "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. 90 (1–2): 12–6. doi:10.1007/BF00210738. PMID 1427766. 
• Gu XF, de Rooij F, Voortman G, et al. (1992). "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. 51 (3): 660–5. PMC 1682727. PMID 1496994. 
• Delfau MH, Picat C, De Rooij F, et al. (1991). "Molecular heterogeneity of acute intermittent porphyria: identification of four additional mutations resulting in the CRIM-negative subtype of the disease". Am. J. Hum. Genet. 49 (2): 421–8. PMC 1683312. PMID 1714233. 
• Namba H, Narahara K, Tsuji K, et al. (1991). "Assignment of human porphobilinogen deaminase to 11q24.1----q24.2 by in situ hybridization and gene dosage studies". Cytogenet. Cell Genet. 57 (2–3): 105–8. doi:10.1159/000133123. PMID 1914516. 
• Lee JS, Anvret M (1992). "Identification of the most common mutation within the porphobilinogen deaminase gene in Swedish patients with acute intermittent porphyria". Proc. Natl. Acad. Sci. U.S.A. 88 (23): 10912–5. doi:10.1073/pnas.88.23.10912. PMC 53042. PMID 1961762. 
• Tunnacliffe A, McGuire RS (1991). "A physical linkage group in human chromosome band 11q23 covering a region implicated in leukocyte neoplasia". Genomics 8 (3): 447–53. doi:10.1016/0888-7543(90)90030-X. PMID 1981047. 
• Scobie GA, Llewellyn DH, Urquhart AJ, et al. (1990). "Acute intermittent porphyria caused by a C----T mutation that produces a stop codon in the porphobilinogen deaminase gene". Hum. Genet. 85 (6): 631–4. doi:10.1007/BF00193588. PMID 2227955. 
• Delfau MH, Picat C, de Rooij FW, et al. (1990). "Two different point G to A mutations in exon 10 of the porphobilinogen deaminase gene are responsible for acute intermittent porphyria". J. Clin. Invest. 86 (5): 1511–6. doi:10.1172/JCI114869. PMC 296897. PMID 2243128. 
• Raich N, Romeo PH, Dubart A, et al. (1986). "Molecular cloning and complete primary sequence of human erythrocyte porphobilinogen deaminase". Nucleic Acids Res. 14 (15): 5955–68. doi:10.1093/nar/14.15.5955. PMC 311614. PMID 2875434. 
• Vidaud M, Gattoni R, Stevenin J, et al. (1989). "A 5' splice-region G----C mutation in exon 1 of the human beta-globin gene inhibits pre-mRNA splicing: a mechanism for beta+-thalassemia". Proc. Natl. Acad. Sci. U.S.A. 86 (3): 1041–5. doi:10.1073/pnas.86.3.1041. PMC 286617. PMID 2915972. 

External links

• GeneReviews/NCBI/NIH/UW entry on Hydroxymethylbilane Synthase Deficiency

Heme synthesis—note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow)

UpToDate Contents

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• 1. 急性間欠性ポルフィリン症の病因、臨床症状および診断 pathogenesis clinical manifestations and diagnosis of acute intermittent porphyria
• 2. ポルフィリン症：概要 porphyrias an overview
• 3. 成人に生じる初回痙攣発作の評価とマネージメント evaluation and management of the first seizure in adults
• 4. 急性間欠性ポルフィリン症のマネージメントおよび予後 management and prognosis of acute intermittent porphyria
• 5. ALA脱水酵素欠損性ポルフィリン症 ala dehydratase porphyria

English Journal

• [Acute intermittent porphyria: Long-term follow up of 35 patients].

• Herrero C1, Badenas C2, Aguilera P1, To-Figueras J3.
• Medicina clínica.Med Clin (Barc).2015 Oct 21;145(8):332-7. doi: 10.1016/j.medcli.2014.06.012. Epub 2014 Sep 4.
• BACKGROUND AND OBJECTIVES: Acute intermittent porphyria (AIP) is a rare disease that results from a deficiency of porphobilinogen deaminase, the third enzyme of the heme biosynthetic pathway. AIP carriers are at risk of presenting acute neurovisceral attacks associated with overproduction of heme-pr
• PMID 25194977

• Influence of Age on Cerebral Housekeeping Gene Expression for Normalization of Quantitative Polymerase Chain Reaction after Acute Brain Injury in Mice.

• Timaru-Kast R1, Herbig EL1, Luh C1, Engelhard K1, Thal SC1.
• Journal of neurotrauma.J Neurotrauma.2015 Sep 18. [Epub ahead of print]
• To prevent methodological errors of quantitative PCR (qPCR) normalization with reference genes is obligatory. Although known to influence gene expression, impact of age on housekeeping gene expression has not been determined after acute brain lesions such as traumatic brain injury (TBI). Therefore,
• PMID 26102571

• Mitochondrial energetic defects in muscle and brain of a Hmbs-/- mouse model of acute intermittent porphyria.

• Homedan C1, Schmitt C2, Laafi J3, Gueguen N4, Desquiret-Dumas V4, Lenglet H5, Karim Z5, Gouya L2, Deybach JC2, Simard G1, Puy H2, Malthièry Y1, Reynier P6.
• Human molecular genetics.Hum Mol Genet.2015 Sep 1;24(17):5015-23. doi: 10.1093/hmg/ddv222. Epub 2015 Jun 12.
• Acute intermittent porphyria (AIP), an autosomal dominant metabolic disease (MIM #176000), is due to a deficiency of hydroxymethylbilane synthase (HMBS), which catalyzes the third step of the heme biosynthetic pathway. The clinical expression of the disease is mainly neurological, involving the auto
• PMID 26071363

Japanese Journal

• 色素関係 ポルホビリノーゲン・デアミナーゼ(PBGD) (広範囲 血液・尿化学検査,免疫学的検査(第7版・1)その数値をどう読むか) -- (生化学的検査(1))

• 日本臨床 67(-), 797-800, 2009-12
• NAID 40016874618

• 急性間欠性ポルフィリン症の一家系

• 臨床血液 = The Japanese Journal of Clinical Hematology 45(7), 562-567, 2004-07-30
• NAID 10013335662

• A novel mutation in a family with non-erythroid variant form of acute intermittent porphyria

• Journal of human genetics 45(6), 367-369, 2000-11-01
• NAID 10011571103

Related Links

• Porphobilinogen deaminase deficiency - RightDiagnosis.com

Porphobilinogen deaminase deficiency symptoms, causes, diagnosis, and treatment information for Porphobilinogen deaminase deficiency (Acute intermittent porphyria) with alternative diagnoses, full-text book chapters, misdiagnosis ... ...

• PBGD_ - Clinical: Porphobilinogen Deaminase (PBGD ...

Abstinence from alcohol for at least 24 hours prior to specimen collection is essential as ethanol induces porphobilinogen deaminase (PBGD) activity, which may lead to a false-normal result. A normal result does not rule out acute ...

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★リンクテーブル★

リンク元	「ポルフォビリノゲンデアミナーゼ」「ヒドロキシメチルビラン」「PBGD」「PBGD deficiency」
関連記事	「deaminase」「porphobilinogen」

「ポルフォビリノゲンデアミナーゼ」

　　[★]

英

porphobilinogen deaminase

同

ポルホビリノーゲンデアミナーゼ

関

ポルフォビリノゲン

[show details]

ポルホビリノゲンデアミナーゼ : 10 件
ポルホビリノーゲンデアミナーゼ : 55 件
ポルフォビリノゲンデアミナーゼ : 約 7,160 件
ポルフォビリノーゲンデアミナーゼ : 約 7,160 件

「ヒドロキシメチルビラン」

　　[★]

英

hydroxymethylbilane, HMB

関

ビルフィリン症、ヘム

• [3]［propphobilinogen, PBG］--([cE2]［porphobilinogen deaminase］)--→[4]［hydroxymethylbilane, HMB］--([cE3]［uroporphyrinogen III synthase］)--→[5]［uroporphyrinogen III］

「PBGD」

　　[★]

同

porphobilinogen deaminase

「PBGD deficiency」

　　[★]

同

porphobilinogen deaminase

「deaminase」

　　[★]

デアミナーゼ、脱アミノ酵素

「porphobilinogen」

　　[★] ポルホビリノーゲン PBG