Abstract
Heme, like chlorophyll, is a primordial molecule and is one of the fundamental pigments of life. Disorders of normal heme synthesis may cause human diseases, including certain anemias (X-linked sideroblastic anemias) and porphyrias. Porphyrias are classified as hepatic and erythropoietic porphyrias based on the organ system in which heme precursors (5-aminolevulinic acid (ALA), porphobilinogen and porphyrins) are chiefly overproduced. The hepatic porphyrias are further subdivided into acute porphyrias and chronic hepatic porphyrias. The acute porphyrias include acute intermittent, hereditary copro-, variegate and ALA dehydratase deficiency porphyria. Chronic hepatic porphyrias include porphyria cutanea tarda and hepatoerythropoietic porphyria. The erythropoietic porphyrias include congenital erythropoietic porphyria (Gűnther’s disease) and erythropoietic protoporphyria. In this review, we summarize the key features of normal heme synthesis and its differing regulation in liver versus bone marrow. In both organs, principal regulation is exerted at the level of the first and rate-controlling enzyme, but by different molecules (heme in the liver and iron in the bone marrow). We also describe salient clinical, laboratory and genetic features of the eight types of porphyria.
Highlights
We first present an overview of normal heme synthesis and breakdown, with emphasis on the key roles played by the first and rate-controlling steps of heme synthesis and breakdown, catalyzed, respectively, by 5-aminolevulinic acid (ALA) synthase and heme oxygenase (HMOX)
It is all too common to see patients, especially those with mild and non-specific symptoms and non-diagnostic mild to moderate increases in urinary porphyrins who have been erroneously labeled as having porphyria and who, too often, have been treated with intravenous heme administered by way of central venous catheters or ports
We have recently shown that heme increases the degradation of the mature, mitochondrial form of ALAS1 protein through proteolysis mediated by LONP1, an ATP-dependent protease that controls the selective turnover of mitochondrial matrix proteins [22]
Summary
We first present an overview of normal heme synthesis and breakdown, with emphasis on the key roles played by the first and rate-controlling steps of heme synthesis and breakdown, catalyzed, respectively, by 5-aminolevulinic acid (ALA) synthase and heme oxygenase (HMOX). It is important that a clear diagnosis be made or that a diagnosis of porphyria is excluded early on when patients present with symptoms or signs suggestive of it. It is all too common to see patients, especially those with mild and non-specific symptoms and non-diagnostic mild to moderate increases in urinary porphyrins (usually mainly coproporphyrins) who have been erroneously labeled as having porphyria and who, too often, have been treated with intravenous heme administered by way of central venous catheters or ports. We hope that this review will reduce the number of false diagnoses in the future
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