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

The porphyrias are inherited or acquired disorders of certain enzymes in the heme biosynthetic pathway (also called porphyrin pathway). They are broadly classified as hepatic porphyrias or erythropoietic porphyrias, based on the site of the overproduction and mainly accumulation of the porphyrins (or their chemical precursors). more...

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Overview

In humans, porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, and cytochrome.

Deficiency in the enzymes of the porphyrin pathway leads to insufficient production of heme. This is, however, not the main problem; most enzymes—even when less functional—have enough residual activity to assist in heme biosynthesis. The largest problem in these deficiencies is the accumulation of porphyrins, the heme precursors, which are toxic to tissue in high concentrations. The chemical properties of these intermediates determine in which tissue they accumulate, whether they are photosensitive, and how the compound is excreted (in the urine or feces).

Subtypes

There are eight enzymes in the heme biosynthetic pathway: the first and the last three are in the mitochondria, while the other four are in the cytosol.

  1. δ-aminolevulinate (ALA) synthase
  2. δ-aminolevulinate (ALA) dehydratase
  3. hydroxymethylbilane (HMB) synthase
  4. uroporphyrinogen (URO) synthase
  5. uroporphyrinogen (URO) decarboxylase
  6. coproporphyrinogen (COPRO) oxidase
  7. protoporphyrinogen (PROTO) oxidase
  8. ferrochelastase

Hepatic porphyrias

The hepatic porphyrias include:

  • ALA dehydratase deficiency
  • acute intermittent porphyria (AIP): a deficiency in HMB synthase
  • hereditary coproporphyria (HCP): a deficiency in COPRO oxidase
  • variegate porphyria (VP): a deficiency in PROTO oxidase
  • porphyria cutanea tarda (PCT): a deficiency in URO decarboxylase

Erythropoietic porphyria

The erythropoietic porphyrias include:

  • X-linked sideroblastic anemia (XLSA): a deficiency in ALA synthase
  • congenital erythropoietic porphyria (CEP): a deficiency in URO synthase
  • erythropoietic protoporphyria (EPP): a deficiency in ferrochelatase

Porphyria variegata

Variegate porphyria (also porphyria variegata or mixed porphyria) results from a partial deficiency in PROTO oxidase, manifesting itself with skin lesions similar to those of porphyria cutanea tarda combined with acute neurologic attacks. It may first occur in the second decade of life; there is a cohort of sufferers living in South Africa descended from a single person from the Netherlands, Berrit Janisz, who emigrated in the 17th century.

Signs and symptoms

The hepatic porphyrias primarily affect the nervous system, resulting in abdominal pain, vomiting, acute neuropathy, seizures, and mental disturbances, including hallucinations, depression, anxiety, and paranoia. Cardiac arrhythmias and tachycardia (fast heart rate) may develop as the autonomic nervous system is affected. Pain can be severe and can, in some cases, be both acute and chronic in nature. Constipation is frequently present, as the nervous system of the gut is affected.

Read more at Wikipedia.org


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Protein fingered in rare psychosis
From Science News, 9/10/05

Doctors have long known that fasting exacerbates porphyria, an inherited disease marked by psychotic episodes. They've also known that glucose infusions, which induce insulin secretion, can mitigate the attacks.

Researchers report in the Aug. 26 Cell that a protein called PGC-l-alpha is the linchpin connecting fasting, glucose, and insulin with porphyria episodes.

Porphyria probably caused the madness of King George III (SN: 8/6/05, p. 94). In people with this condition, mutated enzymes lead to the manufacture of defective heme, an essential iron compound found in many proteins. Instead of having healthy heme, porphyria patients accumulate toxic versions, bringing on sporadic attacks of psychosis.

To sort out the effect of fasting, biochemist Bruce M. Spiegelman of Harvard Medical School and the Dana-Farber Cancer Center in Boston and his colleagues chemically induced porphyria in mice. Some of the animals were also genetically engineered to lack PGC-1-alpha, which, when present, boosts the production of heme, normal or not.

The scientists found that mice with porphyria but lacking PGC-1-alpha didn't have attacks when fasting, suggesting that the animals had stopped accumulating defective heme, Spiegelman says. The finding suggests that inhibiting PGC-1-alpha might ward off porphyria attacks in people.--N.S.

COPYRIGHT 2005 Science Service, Inc.
COPYRIGHT 2005 Gale Group

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