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Overview for MACiE Entry M0204

Version history

General Information

EC Number: 4.2.1.75 (A member of the Lyases, Carbon-oxygen lyases, Hydro-lyases)

Enzyme Name: uroporphyrinogen-III synthase

Biological Species: Homo sapiens (Human)

Catalytic Chain UniprotKB Accession Codes:

  • P10746 - Uroporphyrinogen-III synthase

Representative PDB Code: 1jr2 - STRUCTURE OF UROPORPHYRINOGEN III SYNTHASE (Resolution = 1.84 Å).

Catalytic CATH Codes:

  • This enzyme has no catalytic CATH domains assigned

"Other" CATH Codes:

Display structure information

Overall Reaction:

Image of hydroxymethylbilane

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Image of Uroporphyrinogen III

Image of Water

hydroxymethylbilane
C01024
CHEBI:57845
Uroporphyrinogen III
C01051
CHEBI:57308
Water
C00001
CHEBI:15377

Overall Comment: Mechanistic studies have shown that the formation of uroporphyrinogen III involves an electrophilic addition of the substrates hydroxymethyl group to C-16 that subsequently results in the cleavage of the C-15 to C-16 bond. This mechanism is referred to as the spiro-mechanism since the key intermediate is a spiropyrrolenine produced by the initial cyclisation. This mechanism is supported by the strong inhibition caused by a spiro-lactam intermediate homologue [2]. Modelling studies with small molecules show that the [1,5]-sigmatropic rearrangement of the substrate is unlikely, whereas fragmentation-recombination should be facile. Thus suggesting that of the various mechanisms suggested for this enzyme, the one shown in here is the most likely [1]. The lack of catalytic amino acid residues can be explained due to the fact that mutation of all the surface-exposed and conserved residues (mostly serine and threonine residue), and several of the other residues in the putative active site cleft, did not reveal any single residue that was absolutely required for catalysis [4,3]. This suggests that the residues may function as hydrogen bond donors and acceptors for the variety of carboxylate side chains or pyrrole nitrogens of the substrate. It is also suggested that the enzyme does not make extensive uses of charge-charge interactions with the carboxylate side chains due to the fact that only one of the conserved residues is positively charged. Instead a potentially larger number of weaker interactions may develop between ligand and polar or hydrophobic side chains. The robustness of enzyme activity to mutational analysis may indicate that no one mutation will disrupt substrate binding when a large number of other contacts are left intact [3]. Finally, it has been noted in modelling studies that the active site is larger than the product which suggests that a large conformational change may be required during catalysis [4]. In all the following steps A represents an acetate moiety. P represents a propionate moiety.


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Stepwise Description of the Reaction

Step 1The aromatic pi system of hydroxymethylbilane pyrrole ring D initiates an electrophilic substitution that cyclises the linear substrate and generates water.
Step 2The C pyrrole ring initiates an elimination that cleaves the C15-C16 bond between pyrrole ring D and the CH2 linker, decyclising the intermediate.
Step 3Pyrrole ring D initiates an electrophilic addition to the C=C group formed, re-cyclising the intermediate.
Step 4Hydroxide deprotonates pyrrole ring D, generating the final uroporphyrinogen III product.

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Catalytic Residues Involved

There are no catalytic residues associated with this reaction mechanism


References

  1. A. R. Battersby et al. (1990), Chem. Rev., 90, 1261-1274. Biosynthesis of the Pigments of Life: Mechanistic Studies on the Conversion of Porphobilinogen to Uroporphyrinogen III.
  2. N. Frankenberg et al. (2003), Appl. Mircobiol. Biotechnol., 63, 115-127. Bacterial heme biosynthesis and its biotechnological application.
    Medline: 13680202
  3. M. A. A. Matthews et al. (2001), The EMBO Journal, 20, 5832-5839. Crystal structure of human uroporphyrinogen III synthase.
    Medline: 11689424
  4. H. L. Schubert et al. (2002), Biochem. Soc. Trans., 30, 595-600. Structural diversity in metal ion chelation and the structure of uroporphyrinogen III synthase.
    Medline: 12196144

Homologue information for M0204 (1jr2)

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

GOA logo
uroporphyrinogen-III synthase activity (molecular function)
mitochondrion (cellular component)
cytosol (cellular component)
porphyrin-containing compound metabolic process (biological process)
uroporphyrinogen III biosynthetic process (biological process)
heme biosynthetic process (biological process)
lyase activity (molecular function)
tetrapyrrole biosynthetic process (biological process)
response to antibiotic (biological process)
cofactor binding (molecular function)
cellular response to arsenic-containing substance (biological process)
cellular response to amine stimulus (biological process)
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