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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.^[1]^[2] Domains 1 and 2 are structurally very similar: each consisting of five beta-sheets and three alpha helices in humans.^[3] 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.^[4] 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.^[5] 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).^[6] 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).^[7]^[8]

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.^[9]^[10]^[11]

References

^ Lannfelt L, Wetterberg L, Lilius L, Thunell S, Jörnvall H, Pavlu B, Wielburski A, Gellerfors P (November 1989). "Porphobilinogen deaminase in human erythrocytes: purification of two forms with apparent molecular weights of 40 kDa and 42 kDa". Scand. J. Clin. Lab. Invest. 49 (7): 677–84. doi:10.3109/00365518909091544. PMID 2609111.
^ Louie GV, Brownlie PD, Lambert R, Cooper JB, Blundell TL, Wood SP, Warren MJ, Woodcock SC, Jordan PM (September 1992). "Structure of porphobilinogen deaminase reveals a flexible multidomain polymerase with a single catalytic site". Nature 359 (6390): 33–9. doi:10.1038/359033a0. PMID 1522882.
^ Gill R, Kolstoe SE, Mohammed F, Al D-Bass A, Mosely JE, Sarwar M, Cooper JB, Wood SP, Shoolingin-Jordan PM (May 2009). "Structure of human porphobilinogen deaminase at 2.8 Å: the molecular basis of acute intermittent porphyria". Biochem. J. 420 (1): 17–25. doi:10.1042/BJ20082077. PMID 19207107.
^ Jordan PM, Warren MJ (December 1987). "Evidence for a dipyrromethane cofactor at the catalytic site of E. coli porphobilinogen deaminase". FEBS Lett. 225 (1-2): 87–92. doi:10.1016/0014-5793(87)81136-5. PMID 3079571.
^ Lander M, Pitt AR, Alefounder PR, Bardy D, Abell C, Battersby AR (April 1991). "Studies on the mechanism of hydroxymethylbilane synthase concerning the role of arginine residues in substrate binding". Biochem. J. 275 (2): 447–52. PMC 1150073. PMID 2025226.
^ Pichon C, Clemens KR, Jacobson AR, Ian Scott A (June 1992). "On the mechanism of porphobilinogen deaminase. Design, synthesis, and enzymatic reactions of novel porphobilinogen analogs.". Tetrahedron 48 (23): 4687–4712. doi:10.1016/S0040-4020(01)81567-2.
^ Battersby AR (December 2000). "Tetrapyrroles: the pigments of life". Nat Prod Rep 17 (6): 507–26. doi:10.1039/b002635m. PMID 11152419.
^ Leeper FJ (April 1989). "The biosynthesis of porphyrins, chlorophylls, and vitamin B12". Nat Prod Rep 6 (2): 171–203. doi:10.1039/NP9890600171. PMID 2664584.
^ "Entrez Gene: HMBS hydroxymethylbilane synthase".
^ Grandchamp B, Picat C, de Rooij F, Beaumont C, Wilson P, Deybach JC, Nordmann Y (August 1989). "A point mutation G----A in exon 12 of the porphobilinogen deaminase gene results in exon skipping and is responsible for acute intermittent porphyria". Nucleic Acids Res. 17 (16): 6637–49. doi:10.1093/nar/17.16.6637. PMC 318356. PMID 2789372.
^ Astrin KH, Desnick RJ (1994). "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.

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. 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
3. ポルフィリン症：概要 porphyrias an overview
4. 成人における初回痙攣発作の評価 evaluation of the first seizure in adults
5. ALA脱水酵素欠損性ポルフィリン症 ala dehydratase porphyria

English Journal

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

Relative levels of let‑7a, miR‑17, miR‑27b, miR‑125a, miR‑125b and miR‑206 as potential molecular markers to evaluate grade, receptor status and molecular type in breast cancer.

Lehmann TP1, Korski K2, Gryczka R3, Ibbs M2, Thieleman A4, Grodecka-Gazdecka S3, Jagodziński PP1.
Molecular medicine reports.Mol Med Rep.2015 Sep;12(3):4692-702. doi: 10.3892/mmr.2015.4002. Epub 2015 Jun 26.
MicroRNAs (miRNAs/miRs) are a class of short, single‑stranded nucleic acids, which have been investigated as potential molecular markers for various types of cancer. The gold‑standard and most sensitive method for comparing miRNA levels in cancer tissues is reverse transcription‑quantitative p
PMID 26130254

High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria.

Pallet N1, Mami I2, Schmitt C3, Karim Z4, François A5, Rabant M6, Nochy D7, Gouya L3, Deybach JC3, Xu-Dubois Y8, Thervet E9, Puy H3, Karras A9.
Kidney international.Kidney Int.2015 Aug;88(2):386-95. doi: 10.1038/ki.2015.97. Epub 2015 Apr 1.
Acute intermittent porphyria (AIP) is a genetic disorder of the synthesis of heme caused by a deficiency in hydroxymethylbilane synthase (HMBS), leading to the overproduction of the porphyrin precursors δ-aminolevulinic acid and porphobilinogen. The aim of this study is to describe the clinical and
PMID 25830761

Japanese Journal

False-Positive Accumulation of Metaiodobenzylguanidine in a Case with Acute Intermittent Porphyria

Masuda Tomoko,Ota Rie,Ando Takao,Maeda Naoto,Horie Yutaka,Yoshimura Toshiro,Motomura Masakatsu,Kawakami Atsushi
Internal Medicine 50(9), 1029-1032, 2011
… A diagnosis of acute intermittent porphyria was finally confirmed based on the characteristic pictures, increased urinary excretion of porphobilinogen, and identification of a heterozygous missense mutation of R173W in the hydroxymethylbilane synthase gene. …
NAID 130000650107

Purification and Characterization of Human Uroporphyrinogen III Synthase Expressed in Escherichia coli

Omata Yoshiaki,Sakamoto Hiroshi,Higashimoto Yuichiro [他],HAYASHI Shunsuke,NOGUCHI Masato
The journal of biochemistry 136(2), 211-220, 2004-08-01
NAID 10016201529

Purification and Characterization of Human Uroporphyrinogen III Synthase Expressed in Escherichia coli

Omata Yoshiaki,Sakamoto Hiroshi,Higashimoto Yuichiro,Hayashi Shunsuke,Noguchi Masato
The Journal of Biochemistry 136(2), 211-220, 2004
… The side-chain asymmetry of physiological porphyrins is produced by the coopera-tive action of hydroxymethylbilane synthase and uroporphyrinogen (uro'gen) III syn-thase. … Although the role of uro'gen III synthase is essential for the chemistry of por-phyrin biosynthesis, many aspects, structural as well as mechanical, of uro'gen III synthase have yet to be studied. …
NAID 130003418166

Related Pictures

★リンクテーブル★

リンク元	「ヒドロキシメチルビラン合成酵素」「ヒドロキシメチルビランシンターゼ」
関連記事	「synthase」「hydroxymethylbilane」

「ヒドロキシメチルビラン合成酵素」

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
	v; t; e;