The biosynthesis of heme involves both cytosolic and mitochondrial reactions and intermediates. Heme biosynthesis occurs in most mammalian cells except mature erythrocytes, which lack mitochondria. Approximately 85% of heme syn thesis occurs in erythroid precursor cells in the bone mar row, and the majority of the remainder in hepatocytes. Heme biosynthesis is initiated by the condensation of succinyl-CoA and glycine in a pyridoxal phosphate-dependent reaction catalyzed by mitochondrial δ-aminolevulinate synthase (ALA synthase, EC 2.3.1.37).

(1) Succinyl-CoA + glycine → δ-aminolevulinate + CoA-SH + CO₂

Humans express two isozymes of ALA synthase. ALAS1 is ubiquitously expressed throughout the body, whereas ALAS2 is expressed in erythrocyte precursor cells. Formation of δ-aminolevulinate is rate-limiting for porphyrin biosynthesis in mammalian liver (Figure 1).

Fig1. Synthesis of δ-aminolevulinate (ALA).This mitochondrial reaction is catalyzed by ALA synthase.

Following the exit of δ-aminolevulinate into the cytosol, the reaction catalyzed by cytosolic ALA dehydratase (EC 4.2.1.24; porphobilinogen synthase) condenses two molecules of ALA, forming porphobilinogen:

(2) 2 δ-Aminolevulinate → porphobilinogen + 2 H₂O

(Figure 2). A zinc metalloprotein, ALA dehydratase is sensitive to inhibition by lead, as can occur in lead poisoning.

Fig2. Formation of porphobilinogen.Cytosolicpor phobilinogen synthase converts two molecules o δ-aminolevulinate to porphybilinogen.

The third reaction, catalyzed by cytosolic hydroxymethyl bilane synthase (uroporphyrinogen I synthase, EC 2.5.1.61) involves head-to-tail condensation of four molecules of porphobilinogen to form the linear tetrapyrrole hydroxymethyl bilane (Figure 3, top):

Fig3. Synthesis of hydroxymethylbilane and its subsequent cyclization to porphobilinogen III. Cytosolic hydroxy methylbilane synthase (ALA dehydratase) forms a linear tetrapyrrole, which cytosolic uroporphyrinogen synthase cyclizes to form uroporphyrinogen III. Notice the asymmetry of the substituents on ring 4, so that the highlighted acetate and propionate substituents are reversed in uroporphyrinogens I and III. (A, acetate [—CH₂ COO–]; P, propionate [—CH₂CH₂ COO–].)

(3) 4 Porphobilinogen + H₂O →hydroxymethylbilane + 4 NH3

Subsequent cyclization of hydroxymethylbilane, catalyzed by cytosolic uroporphyrinogen III synthase, EC 4.2.1.75:

(4) Hydroxymethylbilane → uroporphyrinogen III + H2 O

forms uroporphyrinogen III (Figure 3, bottom right). Hydroxymethylbilane can undergo spontaneous cyclization forming uroporphyrinogen I (Figure 3, bottom left), but under normal conditions, the uroporphyrinogen formed is almost exclusively the type III isomer. The type I isomers of porphyrinogens are, however, formed in excess in certain porphyrias. Since the pyrrole rings of these uroporphyrinogens are connected by methylene (—CH2 —) rather than by methyne bridges (—HC—), the double bonds do not form a conjugated system. Porphyrinogens thus are colorless. They are, however, readily auto-oxidized to colored porphyrins.

All four acetate moieties of uroporphyrinogen III next undergo decarboxylation to methyl (M) substituents, forming coproporphyrinogen III in a cytosolic reaction catalyzed by uroporphyrinogen decarboxylase, EC 4.1.1.37 (Figure 4):

(5) Uroporphyrinogen III → coproporphyrinogen III + 4 CO₂

This decarboxylase can also convert uroporphyrinogen I, if present, to coproporphyrinogen I.

Fig4. Decarboxylation of uroporphyrinogen III to coproporphyrinogen III. Shown is a representation of the tetrapyrrole to emphasize the conversion of four attached acetyl groups to methyl groups. (A, acetyl; M, methyl; P, propionyl.)

The final three reactions of heme biosynthesis all occur in mitochondria. Coproporphyrinogen III enters the mitochondria and is converted, successively, to protoporphyrinogen III, and then to protoporphyrin III. These reactions are catalyzed by coproporphyrinogen oxidase (EC 1.3.3.3), which decarboxylates and oxidizes the two propionic acid side chains to form protoporphyrinogen III:

(6) Coproporphyrinogen III + O₂ + 2 H⁺ → protoporphyrinogen III + 2 CO₂ + 2 H₂O

This oxidase is specific for type III coproporphyrinogen, so type I protoporphyrins generally do not occur in humans. Protoporphyrinogen III is next oxidized to protoporphyrin III in a reaction catalyzed by protoporphyrinogen oxidase, EC 1.3.3.4:

(7) Protoporphyrinogen III + 3 O₂ → protoporphyrin III + 3 H₂O₂

The eighth and final step in heme synthesis involves the incorporation of ferrous iron into protoporphyrin III in a reaction catalyzed by ferrochelatase (heme synthase, EC 4.99.1.1), (Figure 5):

(8) Protoporphyrin III + Fe2+ → heme + 2 H+

Figure 6 summarizes the stages of the biosynthesis of the porphyrin derivatives from porphobilinogen. For the above reactions, numbers correspond to those in Figure 6 and in Table 1.

Fig5. Biosynthesis from porphobilinogen of the indicated porphyrin derivatives.

Fig6. Intermediates, enzymes, and regulation of heme synthesis. The numbers of the enzymes that catalyze the indicated reactions are those used in the accompanying text and in column 1 of Table 1. Enzymes 1, 6, 7, and 8 are mitochondrial, but enzymes 2 to 5 are cytosolic. Regulation of hepatic heme synthesis occurs at ALA synthase (ALAS1) by a repression–derepression mechanism mediated by heme and a hypothetical aporepressor (not shown). Mutations in the gene encoding enzyme 1 cause X-linked sideroblastic anemia. Mutations in the genes encoding enzymes 2 to 8 give rise to the porphyrias.

Table1. Summary of Major Findings in the Porphyrias^a

ALA Synthase Is the Key Regulatory Enzyme in Hepatic Biosynthesis of Heme

Unlike ALAS2, which is expressed exclusively in erythrocyte precursor cells, ALAS1 is expressed throughout body tissues.

The reaction catalyzed by ALA synthase 1 (Figure 1) is rate-limiting for biosynthesis of heme in liver. Typically for an enzyme that catalyzes a rate-limiting reaction, ALAS1 has a short half-life. Heme, acting through the Erg-1 aporepressor and one of its NAB corepressors, acts as a negative regulator of the synthesis of ALAS1 (Figure 6). Synthesis of ALAS1 thus increases greatly in the absence of heme, but diminishes in its presence. Heme also affects translation of ALAS1 and its translocation from its cytosolic site of synthesis into the mitochondrion. Many drugs whose metabolism requires the hemoprotein cytochrome P450 increase cytochrome P450 biosynthesis. The resulting depletion of the intracellular heme pool induces synthesis of ALAS1, and the rate of heme syn thesis rises to meet metabolic demand. By contrast, since ALAS2 is not feedback regulated by heme, its biosynthesis is not induced by these drugs.

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متى يجب تنظيف الأسنان في الصباح.. قبل أم بعد الإفطار؟

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الآخبار التكنلوجية

أكبر مشروع طاقة رياح في نصف الكرة الجنوبي يحقق إنجازين جديدين

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المزيد

مواضيع ذات صلة

The Deoxyribonucleosides of Uracil & Cytosine are Salvaged

Biosynthesis of Pyrimidine Nucleotides

Hepatic Purine Biosynthesis is Stringently Regulated

Inosine Monophosphate (IMP) is Synthesized From Amphibolic Intermediates

DNA & RNA are Polynucleotides

Synthetic Nucleotide Analogs are Used in Chemotherapy

Chemistry of Purines, Pyrimidines, Nucleosides, & Nucleotides

Disorders of Bilirubin Metabolism

Catabolism of HEME Produces Bilirubin

Disorders of Heme Biosynthesis

Porphyrins are Colored & Fluoresce

NON–α-AMINO ACIDS