Add group to favorites
Back to post list
Send new message to groupPost Subject:
Oxidation reaction causes porphyria cutanea tarda
<<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
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
