Uroporphyrinogen III decarboxylase

Uroporphyrinogen decarboxylase
250px PDB rendering based on 1jph.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1JPH, 1JPI, 1JPK, 1R3Q, 1R3R, 1R3S, 1R3T, 1R3V, 1R3W, 1R3Y, 1URO, 2Q6Z, 2Q71, 3GVQ, 3GVR, 3GVV, 3GVW, 3GW0, 3GW3
Identifiers
Symbols	UROD ; PCT; UPD
External IDs	OMIM: 613521 MGI: 98916 HomoloGene: 320 ChEMBL: 1681619 GeneCards: UROD Gene
EC number	4.1.1.37
Gene ontology Molecular function • uroporphyrinogen decarboxylase activity • protein binding • ferrous iron binding Cellular component • nucleoplasm • cytoplasm • cytosol Biological process • liver development • porphyrin-containing compound metabolic process • protoporphyrinogen IX biosynthetic process • heme biosynthetic process • response to iron ion • response to amine • response to estradiol • small molecule metabolic process • response to ethanol • uroporphyrinogen III metabolic process • response to mercury ion • response to methylmercury • response to fungicide • cellular response to arsenic-containing substance Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE UROD 208970 s at tn.png
File:PBB GE UROD 208971 at tn.png
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7389	22275
Ensembl	ENSG00000126088	ENSMUSG00000028684
UniProt	P06132	P70697
RefSeq (mRNA)	NM_000374	NM_009478
RefSeq (protein)	NP_000365	NP_033504
Location (UCSC)	Chr 1: 45.01 – 45.02 Mb	Chr 4: 116.99 – 116.99 Mb
PubMed search	[1]	[2]

Uroporphyrinogen decarboxylase, also known as UROD, is an enzyme that in humans is encoded by the UROD gene.

Function

This gene encodes the fifth enzyme of the heme biosynthetic pathway. This enzyme is responsible for catalyzing the conversion of uroporphyrinogen to coproporphyrinogen through the removal of four carboxymethyl side chains.

Uroporphyrinogen III decarboxylase (UroD) is a homodimeric enzyme (EC 4.1.1.37, PDB: 1URO​) that catalyzes the fifth step in heme biosynthesis: the elimination of carboxyl groups from the four acetate side chains of uroporphyrinogen III to yield coproporphyrinogen III.

Clinical significance

Mutations and deficiency in this enzyme are known to cause familial porphyria cutanea tarda and hepatoerythropoietic porphyria.

Mechanism

At low substrate concentrations, the reaction is believed to follow an ordered route, with the sequential removal of CO₂ from the D, A, B, and C rings, whereas at higher substrate/enzyme levels a random route seems to be operative. The enzyme functions as a dimer in solution, and both the enzymes from human and tobacco have been crystallized and solved at good resolutions.

The reaction catalyzed by UroD

UroD is regarded as an unusual decarboxylase, since it performs decarboxylations without the intervention of any cofactors, unlike the vast majority of decarboxylases. Its mechanism has recently been proposed to proceed through substrate protonation by an arginine residue. A 2008 report demonstrated that the uncatalyzed rate for UroD's reaction is 10⁻¹⁹ s⁻¹, so at pH 10 the rate acceleration of UroD relative to the uncatalyzed rate, catalytic proficiency, is the largest for any enzyme known, 6 x 10²⁴ M⁻¹.

File:UroD mechanism.svg

Proposed reaction mechanism of uroporphyrinogen III decarboxyklase

Further reading

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