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Overview for MACiE Entry M0260

Version history

General Information

EC Number: 2.5.1.61 (A member of the Transferases, Transferring alkyl or aryl groups, other than methyl groups, Transferring alkyl or aryl groups, other than methyl groups (only sub-subclass identified to date))

Enzyme Name: hydroxymethylbilane synthase

Biological Species: Escherichia coli (bacteria)

Catalytic Chain UniprotKB Accession Codes:

  • P06983 - Porphobilinogen deaminase

Representative PDB Code: 1gtk - TIME-RESOLVED AND STATIC-ENSEMBLE STRUCTURAL CHEMISTRY OFHYDROXYMETHYLBILANE SYNTHASE (Resolution = 1.66 Å).

Catalytic CATH Codes:

Display structure information

Overall Reaction:

Image of porphobilinogen

Image of water

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Image of hydroxymethylbilane

Image of ammonia

4 porphobilinogen
C00931
CHEBI:17381
water
C00001
CHEBI:15377
hydroxymethylbilane
C01024
CHEBI:57845
4 ammonia
C00014
CHEBI:16134

Overall Comment: The enzyme works by stepwise addition of pyrrolylmethyl groups until a hexapyrrole is present at the active centre. The terminal tetrapyrrole is then hydrolysed to yield the product, leaving a cysteine-bound dipyrrole on which assembly continues. In the presence of a second enzyme, EC 4.2.1.75 uroporphyrinogen-III synthase, which is often called cosynthase, the product is cyclised to form uroporphyrinogen-III. If EC 4.2.1.75 is absent, the hydroxymethylbilane cyclises spontaneously to form uroporphyrinogen I. It is currently still unclear how the cysteine-bound dipyrrole is formed. There are two current alternative mechanisms that have been suggested. Either by a stepwise addition of porphobilinogen to the cysteine [1,2], or by addition of the preuroporphyinogen and thus the first catalytic turnover of the enzyme proceeds via the addition of only a further two porphobilinogen molecules [3].


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Stepwise Description of the Reaction

Step 1Asp84 deprotonates the porphobilinogen substrate, which causes rearrangement of the double bonds to eliminate ammonia and form the reactive azafulvene intermediate.
Step 2Asp84 deprotonates the dipyrromethane cofactor, which causes rearrangement of the double bonds an addition to the azafulvene intermediate in a nucleophilic manner.
Step 3Asp84 deprotonates C4 of the intermediate, causing double bond rearrangement to produce the cofactor elongated by one pyrrole unit.
Step 4Asp84 deprotonates the porphobilinogen substrate, which causes rearrangement of the double bonds to eliminate ammonia and form the reactive azafulvene intermediate.
Step 5Asp84 deprotonates the dipyrromethane cofactor, which causes rearrangement of the double bonds an addition to the azafulvene intermediate in a nucleophilic manner.
Step 6Asp84 deprotonates C4 of the intermediate, causing double bond rearrangement to produce the cofactor elongated by one pyrrole unit.
Step 7Asp84 deprotonates the porphobilinogen substrate, which causes rearrangement of the double bonds to eliminate ammonia and form the reactive azafulvene intermediate.
Step 8Asp84 deprotonates the dipyrromethane cofactor, which causes rearrangement of the double bonds an addition to the azafulvene intermediate in a nucleophilic manner.
Step 9Asp84 deprotonates C4 of the intermediate, causing double bond rearrangement to produce the cofactor elongated by one pyrrole unit.
Step 10Asp84 deprotonates the porphobilinogen substrate, which causes rearrangement of the double bonds to eliminate ammonia and form the reactive azafulvene intermediate.
Step 11Asp84 deprotonates the dipyrromethane cofactor, which causes rearrangement of the double bonds an addition to the azafulvene intermediate in a nucleophilic manner.
Step 12Asp84 deprotonates C4 of the intermediate, causing double bond rearrangement to produce the cofactor elongated by one pyrrole unit.
Step 13Asp84 deprotonates N of the second pyrrole in the chain, causing double bond rearrangement to protonate the chain at the C4 position, this proton comes from a bound water molecule.
Step 14The hydroxide initiates a nucleophilic attack on the intermediate in an substitution reaction. The cofactor is re-protonated from Asp84

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Catalytic Residues Involved

Type Number Chain Location of Function
Asp 84 A Side Chain
Lys 83 A Side Chain
Arg 131 A Side Chain
Arg 132 A Side Chain
Cys 242 A Side Chain

Organic Cofactors for M0260

Type Identity Chain
Dipyrromethane DPM 315 A Overview

References

  1. G. V. Louie et al. (1992), Nature, 359, 33-39. Structure of porphobilinogen deaminase reveals a flexible multidomain polymerase with a single catalytic site.
    Medline: 1522882
  2. S. C. Woodcock et al. (1994), Biochemistry, 33, 2688-2695. Evidence for participation of aspartate-84 as a catalytic group at the active site of porphobilinogen deaminase obtained by site-directed mutagenesis of the hemC gene from Escherichia coli.
    Medline: 8117733
  3. P. M. Shoolingin-Jordan et al. (1996), Biochem. J., 316, 373-376. Discovery that the assembly of the dipyrromethane cofactor of porphobilinogen deaminase holoenzyme proceeds initially by the reaction of preuroporphyrinogen with the apoenzyme.
    Medline: 8687374

Homologue information for M0260 (1gtk)

CSA Homologues

MACiE Homologues (within the PDB)

MACiE Homologues (within UniprotKB/SwissProt)


Links to this entry in other databases

Link to EC-PDB-SUM Link to PDB-SUM Link to RCSB PDB Link to PDBe Link to CSA
Link to MetaCyc Link to KEGG Link to BRENDA Link to ExplorENZ
Link to EzCatDB

GOA logo
hydroxymethylbilane synthase activity (molecular function)
peptidyl-pyrromethane cofactor linkage (biological process)
tetrapyrrole biosynthetic process (biological process)
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