Porphobilinogen deaminase

From Wikipedia, the free encyclopedia
  (Redirected from HMBS (gene))
Jump to: navigation, search
Hydroxymethylbilane synthase

Rendering based on PDB 3ECR.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols HMBS ; PBG-D; PBGD; PORC; UPS
External IDs OMIM609806 MGI96112 HomoloGene158 GeneCards: HMBS Gene
EC number 2.5.1.61
RNA expression pattern
PBB GE HMBS 203040 s at tn.png
PBB GE HMBS 213344 s at tn.png
PBB GE HMBS 212524 x at tn.png
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:
118.96 – 118.96 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[edit]

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:

Overall reaction of PB deaminase

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[edit]

Full PBG Deaminase 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[edit]

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[edit]

  1. ^ 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. PMID 2609111. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ 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. PMID 3079571. 
  5. ^ 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 ( Pt 2): 447–52. PMC 1150073. PMID 2025226. 
  6. ^ 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. 
  7. ^ Battersby AR (December 2000). "Tetrapyrroles: the pigments of life". Nat Prod Rep 17 (6): 507–26. PMID 11152419. 
  8. ^ 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. 
  9. ^ "Entrez Gene: HMBS hydroxymethylbilane synthase". 
  10. ^ 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. 
  11. ^ 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. 

Further reading[edit]

External links[edit]

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