Porphobilinogen deaminase explained

Porphobilinogen deaminase (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:

4 porphobilinogen + H2O

\rightleftharpoons

hydroxymethylbilane + 4 NH3

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] At least 115 disease-causing mutations in this gene have been discovered.[12]

Further reading

External links

Notes and References

  1. Lannfelt L, Wetterberg L, Lilius L, Thunell S, Jörnvall H, Pavlu B, Wielburski A, Gellerfors P . 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 . November 1989 . 2609111 . 10.3109/00365518909091544.
  2. Louie GV, Brownlie PD, Lambert R, Cooper JB, Blundell TL, Wood SP, Warren MJ, Woodcock SC, Jordan PM . 4264432 . Structure of porphobilinogen deaminase reveals a flexible multidomain polymerase with a single catalytic site . Nature . 359 . 6390 . 33–9 . September 1992 . 1522882 . 10.1038/359033a0 . 1992Natur.359...33L .
  3. 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 Å: the molecular basis of acute intermittent porphyria . Biochem. J. . 420 . 1 . 17–25 . May 2009 . 19207107 . 10.1042/BJ20082077 .
  4. Jordan PM, Warren MJ . Evidence for a dipyrromethane cofactor at the catalytic site of E. coli porphobilinogen deaminase . FEBS Lett. . 225 . 1–2 . 87–92 . December 1987 . 3079571 . 10.1016/0014-5793(87)81136-5. 13483654 . free .
  5. Lander M, Pitt AR, Alefounder PR, Bardy D, Abell C, Battersby AR . Studies on the mechanism of hydroxymethylbilane synthase concerning the role of arginine residues in substrate binding . Biochem. J. . 275 . 2. 447–52 . April 1991 . 2025226 . 1150073 . 10.1042/bj2750447.
  6. Pichon C, Clemens KR, Jacobson AR, Ian Scott A . On the mechanism of porphobilinogen deaminase. Design, synthesis, and enzymatic reactions of novel porphobilinogen analogs. . Tetrahedron . June 1992 . 48 . 23 . 4687–4712 . 10.1016/S0040-4020(01)81567-2 .
  7. Battersby AR . Tetrapyrroles: the pigments of life . Nat Prod Rep . 17 . 6 . 507–26 . December 2000 . 11152419 . 10.1039/b002635m.
  8. Leeper FJ . The biosynthesis of porphyrins, chlorophylls, and vitamin B12 . Nat Prod Rep . 6 . 2 . 171–203 . April 1989 . 2664584 . 10.1039/NP9890600171 .
  9. Web site: Entrez Gene: HMBS hydroxymethylbilane synthase.
  10. Grandchamp B, Picat C, de Rooij F, Beaumont C, Wilson P, Deybach JC, Nordmann Y . 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 . August 1989 . 2789372 . 318356 . 10.1093/nar/17.16.6637 .
  11. Astrin KH, Desnick RJ . Molecular basis of acute intermittent porphyria: mutations and polymorphisms in the human hydroxymethylbilane synthase gene . Hum. Mutat. . 4 . 4 . 243–52 . 1994 . 7866402 . 10.1002/humu.1380040403 . 24402776 .
  12. Šimčíková D, Heneberg P . Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases . Scientific Reports . 9 . 1 . 18577 . December 2019 . 31819097 . 6901466 . 10.1038/s41598-019-54976-4. 2019NatSR...918577S .