Uroporphyrinogen III decarboxylase (uroporphyrinogen decarboxylase, or UROD) is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
() that in humans is encoded by the ''UROD''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Function
Uroporphyrinogen III decarboxylase is a homodimeric enzyme () that catalyzes the fifth step in
heme
Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.
In biochemical terms, heme is a coordination complex "consisti ...
biosynthesis, which corresponds to the elimination of
carboxyl
In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...
groups from the four
acetate
An acetate is a salt (chemistry), salt formed by the combination of acetic acid with a base (e.g. Alkali metal, alkaline, Alkaline earth metal, earthy, Transition metal, metallic, nonmetallic or radical Radical (chemistry), base). "Acetate" als ...
side chains of
uroporphyrinogen III
Uroporphyrinogen III is a tetrapyrrole, the first macrocyclic intermediate in the biosynthesis of heme, chlorophyll, vitamin B12, and siroheme. It is a colorless compound, like other porphyrinogens.
Structure
The molecular structure of uroporphyri ...
to yield
coproporphyrinogen III
Coproporphyrinogen III is a metabolic intermediate in the biosynthesis of many compounds that are critical for living organisms, such as hemoglobin and chlorophyll. It is a colorless solid.
The compound is a porphyrinogen, a class of compounds ch ...
:
:
uroporphyrinogen III
Uroporphyrinogen III is a tetrapyrrole, the first macrocyclic intermediate in the biosynthesis of heme, chlorophyll, vitamin B12, and siroheme. It is a colorless compound, like other porphyrinogens.
Structure
The molecular structure of uroporphyri ...
coproporphyrinogen III
Coproporphyrinogen III is a metabolic intermediate in the biosynthesis of many compounds that are critical for living organisms, such as hemoglobin and chlorophyll. It is a colorless solid.
The compound is a porphyrinogen, a class of compounds ch ...
+ 4 CO
2
Clinical significance
Mutations and deficiency in this enzyme are known to cause familial
porphyria cutanea tarda
Porphyria cutanea tarda is the most common subtype of porphyria. The disease is named because it is a porphyria that often presents with skin manifestations later in life. The disorder results from low levels of the enzyme responsible for the fift ...
and
hepatoerythropoietic porphyria
Hepatoerythropoietic porphyria is a very rare form of hepatic porphyria caused by a disorder in both genes which code Uroporphyrinogen III decarboxylase (UROD).
It has a similar presentation to porphyria cutanea tarda (PCT), but with earlier onse ...
.
At least 65 disease-causing mutations in this gene have been discovered.
Mechanism
At low substrate concentrations, the reaction is believed to follow an ordered route, with the sequential removal of CO
2 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.
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
Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
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, i.e. catalytic proficiency, is the largest for any enzyme known, 6 x 10
24 M
−1.
References
Further reading
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External links
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