The overproduction of porphyrins and their precursors in the differ entporphyrias is mainly hepatic or erythropoietic in origin. In the acute porphyrias and in porphyria cutanea tarda (PCT), the liver is the main source of overproduction; in congenital erythropoietic porphyria (CEP), the marrow is the main source; and in erythropoietic protoporphyria (EPP), porphyrins are overproduced by the liver and marrow.

Control of hepatic heme biosynthesis is regulated by the rate of the initial enzymatic step, ALAS1, a housekeeping form of ALAS that is expressed in all cell types, including erythroid cells, whereas ALAS2 encodes a red cell-specific form. ALAS1 is under negative feedback control by heme, which occurs by more than one mechanism. Heme represses transcription of the ALAS1 gene and increases the rate of degradation of the messenger ribonucleic acid (mRNA) (Fig. 1A). At the posttranslational level, heme blocks the translocation of pre-ALAS1 into the mitochondrion. In the mitochondrion, the molecular mass of ALAS1 is smaller than that of the cytosolic pre-ALAS1 because of the removal of the mitochondrial targeting sequence. Finally, heme regulates levels of mature ALAS1 by activation of a mitochondrial proteolysis system.

Fig1. (A) Control of heme synthesis in hepatic and other tissues. The rate of heme synthesis depends on the first and rate-limiting enzymatic step catalyzed by 5-aminolevulinate synthase, nonspecific, mitochondrial (ALAS1). Heme represses transcription of the ALAS1 gene, increases the rate of degradation of its messenger ribonucleic acid (mRNA), and blocks the translocation of the ALAS1 isoenzyme into the mitochondrion. (B) Control of heme synthesis in erythroblasts. Cytosolic iron enhances the translation of mRNA of the pre-ALAS2 by inhibiting the interaction of a repressor protein with an iron-responsive element in the mRNA. The product of the last step, heme controls transcription of genes that may contribute to iron metabolism and ensure adequate supply of iron to the mitochondrion. Heme also may inhibit translocation of ALAS2 into the mitochondrion. The overall result is that the rate of heme synthesis is tightly linked to the availability of iron for the ferrochelatase reaction. Mitoferrin (mfrn) transports Fe2+ into the mitochondrial matrix. ALA, 5-Aminolevulinate.

The erythroid bone marrow is the major heme-forming tissue in the body, producing 85% of the daily heme requirement. Heme syn thesis in erythroid cells varies from that in hepatocytes; it is linked to tissue differentiation, and the half-life of the same end product of the two is quite different. Heme complexed with globin is preserved in circulating red blood cells for approximately 120 days, whereas heme produced in liver for cytochromes and enzymes, such as catalase, is subject to much more rapid turnover, measurable in hours. Regulation in the liver is exquisitely sensitive to fluctuations in intra cellular heme levels and responds rapidly to the requirements for synthesis, as described in Fig. 1A. However, heme synthesis in the bone marrow shows a more leisurely response. This fundamental difference is explained by the finding of two different tissue-specific iso enzymes and two different cDNAs for human liver or “housekeeping” ALAS1 and erythroid specific ALAS2, which is expressed exclusively in erythroid cells. The gene for ALAS2 has been mapped to the X chromosome and that for the hepatic enzyme to chromosome 3. The ALAS2 gene has 12 exons; exons 4 to 11 encode the catalytic domain of the enzyme and include a lysine residue that forms a Schiff base with the pyridoxal phosphate cofactor. Exon 1 contributes to the 5′ untranslated region (UTR) whose structure allows iron to regulate ALAS2 mRNA translation, whereas exons 1 and 2 contribute the sequence that targets the enzyme to the mitochondria and is cleaved after import. Succinyl CoA synthetase associates specifically with ALAS2 within the mitochondrion, which helps promote the first step of heme synthesis.

Enzyme levels of ubiquitous and erythroid isoenzymes of ALAS are controlled by different mechanisms. Ubiquitous ALAS1 levels in the liver are regulated by negative feedback by heme that inhibits gene transcription and import of pre-ALAS1 (see Fig. 1A). More recently ALAS1 has been shown to be upregulated by peroxisome proliferator-activated receptor-gamma, coactivator 1, alpha (PPAR-γ coactivator 1-α), which regulates mitochondrial biogenesis and oxidative metabolism. Transcription of PPAR-γ coactivator 1-α is controlled by glucose availability. PPAR-γ coactivator 1-α production increases when glucose levels are low, leading to increased levels of ALAS1 and heme. These conditions are conducive to an acute attack of porphyria. However, the relative contribution of heme and PPAR-γ coactivator 1-α in regulating ALAS1 expression remains to be resolved. In contrast, heme does not affect transcription of the ALAS2 gene, which is under the control of erythroid-specific promoters such as GATA1, a globin transcription factor. Whether heme inhibits import of pre-ALAS2 into the mitochondrial matrix remains to be unequivocally established, although this is supported by in vitro experiments. Heme also regulates the transcription of ferroportin, and H- and L-ferritin during erythroid differentiation, which may ensure adequate iron supply to mitochondria for heme synthesis (see Fig. 1B). In addition to transport of iron from plasma to the cytosol by the transferrin receptor, a second transport step is required for mitochondrial uptake of iron. The passage of iron across the outer mitochondrial membrane is ill-defined but is due largely to the presence of voltage-dependent anion channels. Iron import across the inner mitochondrial membrane is fulfilled by mitoferrin, a member of the solute carrier 25 family of proteins located in the inner mitochondrial membrane, which, to import iron into the mitochondrion, must interact both with FECH and with the adenosine tri phosphate (ATP)-binding cassette transporter ABCB10. Levels of intracellular iron regulate the translation of ALAS2 mRNA. Cellular iron homeostasis is maintained through a posttranscriptional regulatory mechanism, which is mediated by iron regulatory proteins that bind to iron-responsive elements (IRE) in mRNA of target genes to either increase or decrease translation. The RNA binding activity of iron-responsive proteins (IRP) is regulated by mitochondrial iron-sulfur cluster synthesis and cytosolic iron levels. When iron is available for heme synthesis, translation of ALAS2 is allowed to proceed as a result of decreased IRP binding to the 5′ UTR iron responsive elements of ALAS2 mRNA. In contrast, under iron depleted conditions, increased IRP binding to ALAS2 mRNA blocks translation and ensures that ALAS2 and protoporphyrin levels are not produced in excess of available iron. Furthermore, to prevent the cell from becoming iron deficient, increased translation of mRNA from genes that increase cellular iron, such as the transferrin 1 gene, results from stabilization of mRNA by binding of IRPs to mRNA. This effect ensures that protoporphyrin synthesis is coupled to iron availability.

A second rate-limiting step in the overall heme synthetic pathway lies at the level of porphobilinogen deaminase (PBGD), which has a low endogenous activity and is inhibited by protoporphyrinogen and coproporphyrinogen. There are also two forms of PBGD. The PBGD gene (hydroxymethylbilane synthase; HMBS) encodes two enzymes, which arise from alternative splicing of PBGD mRNA. One isoform is expressed in all cells, whereas a second is restricted to red cells. Erythroid PBGD is stimulated by erythropoiesis in vitro and may play a regulatory role in heme biosynthesis during differentiation.

HMBS, the human PBGD gene, has attracted extensive investigation because of the practical importance of detecting carriers of the gene for acute intermittent porphyria (AIP). Studies of the genetic locus of PBGD on chromosome 11 show great molecular heterogeneity, with over 380 mutations associated with AIP in the Human Gene Mutation Database (HGMD Professional 2019, www.hgmd.org). Most human mutations have been described in exons 10 and 12, which is consistent with alteration of the binding sites for the dipyrrommethane cofactor for the enzyme. The three-dimensional structure of PBGD has been defined by X-ray crystallography, which has allowed study of the structural and functional implications of mutations.

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