Ironjustic
Fri, Mar-16-07, 06:15
<<snip>> The oxidation reaction is iron-dependent <<snip>>
Proc Natl Acad Sci U S A. 2007 Mar 9; [Epub ahead of print]A
porphomethene inhibitor of uroporphyrinogen decarboxylase
causes porphyria cutanea tarda.Phillips JD, Bergonia HA,
Reilly CA, Franklin MR, Kushner JP. Departments of Medicine
and Pharmacology and Toxicology, University of Utah School of
Medicine, Salt Lake City, UT 84132.
Porphyria cutanea tarda (PCT), the most common form of
porphyria in humans, is due to reduced activity of
uroporphyrinogen decarboxylase (URO-D) in the liver. Previous
studies have demonstrated that protein levels of URO-D do not
change when catalytic activity is reduced, suggesting that an
inhibitor of URO-D is generated in hepatocytes. Here, we
describe the identification and characterization of an
inhibitor of URO-D in liver cytosolic extracts from two murine
models of PCT: wild-type mice treated with iron,
delta-aminolevulinic acid, and polychlorinated biphenyls; and
mice with one null allele of Uro-d and two null alleles of the
hemochromatosis gene (Uro-d(+/-), Hfe(-/-)) that develop PCT
with no treatments. In both models, we identified an inhibitor
of recombinant human URO-D (rhURO-D). The inhibitor was
characterized by solid-phase extraction, chromatography,
UV-visible spectroscopy, and mass spectroscopy and proved to
be uroporphomethene, a compound in which one bridge carbon in
the uroporphyrinogen macrocycle is oxidized. We synthesized
uroporphomethene by photooxidation of enzymatically generated
uroporphyrinogen I or III. Both uroporphomethenes inhibited
rhURO-D, but the III isomer porphomethene was a more potent
inhibitor. Finally, we detected an inhibitor of rhURO-D in
cytosolic extracts of liver biopsy samples of patients with
PCT. These studies define the mechanism underlying clinical
expression of the PCT phenotype, namely oxidation of
uroporphyrinogen to uroporphomethene, a competitive inhibitor
of URO-D. The oxidation reaction is iron-dependent.
PMID: 17360334 [PubMed - as supplied by publisher]
Who loves ya. Tom
Jesus Was A Vegetarian! http://jesuswasavegetarian.7h.com
Man Is A Herbivore! http://tinyurl.com/a3cc3
DEAD PEOPLE WALKING http://tinyurl.com/zk9fk
Proc Natl Acad Sci U S A. 2007 Mar 9; [Epub ahead of print]A
porphomethene inhibitor of uroporphyrinogen decarboxylase
causes porphyria cutanea tarda.Phillips JD, Bergonia HA,
Reilly CA, Franklin MR, Kushner JP. Departments of Medicine
and Pharmacology and Toxicology, University of Utah School of
Medicine, Salt Lake City, UT 84132.
Porphyria cutanea tarda (PCT), the most common form of
porphyria in humans, is due to reduced activity of
uroporphyrinogen decarboxylase (URO-D) in the liver. Previous
studies have demonstrated that protein levels of URO-D do not
change when catalytic activity is reduced, suggesting that an
inhibitor of URO-D is generated in hepatocytes. Here, we
describe the identification and characterization of an
inhibitor of URO-D in liver cytosolic extracts from two murine
models of PCT: wild-type mice treated with iron,
delta-aminolevulinic acid, and polychlorinated biphenyls; and
mice with one null allele of Uro-d and two null alleles of the
hemochromatosis gene (Uro-d(+/-), Hfe(-/-)) that develop PCT
with no treatments. In both models, we identified an inhibitor
of recombinant human URO-D (rhURO-D). The inhibitor was
characterized by solid-phase extraction, chromatography,
UV-visible spectroscopy, and mass spectroscopy and proved to
be uroporphomethene, a compound in which one bridge carbon in
the uroporphyrinogen macrocycle is oxidized. We synthesized
uroporphomethene by photooxidation of enzymatically generated
uroporphyrinogen I or III. Both uroporphomethenes inhibited
rhURO-D, but the III isomer porphomethene was a more potent
inhibitor. Finally, we detected an inhibitor of rhURO-D in
cytosolic extracts of liver biopsy samples of patients with
PCT. These studies define the mechanism underlying clinical
expression of the PCT phenotype, namely oxidation of
uroporphyrinogen to uroporphomethene, a competitive inhibitor
of URO-D. The oxidation reaction is iron-dependent.
PMID: 17360334 [PubMed - as supplied by publisher]
Who loves ya. Tom
Jesus Was A Vegetarian! http://jesuswasavegetarian.7h.com
Man Is A Herbivore! http://tinyurl.com/a3cc3
DEAD PEOPLE WALKING http://tinyurl.com/zk9fk