Heme, biosynthesis

Note the Schiff base formation that forms the 5-membered ring. 

Heme contains four of these rings. Four porphobilinogens condense head to tail to form the first tetrapyrrole species, which is then circularized to form the porphyrin skeleton. Further modifications, followed by Fe(II) addition, lead to heme. 

Inborn metabolic diseases that interfere with heme biosynthesis are called porphyrias. Porphyrias have a variety of symptoms. A deficiency in the enzyme responsible for the condensation of porphobilinogen to the 4-membered ring system leads to a condition called acute intermittent porphyria, which is characterized by occasional episodes of abdominal pain and psychiatric symptoms. Defects in the later enzymes of the pathway lead to an excess accumulation of the uroporphobilinogens in the tissues, where they cause a variety of symptoms, including hairy skin, skeletal abnormalities, light sensitivity, and red urine. Individuals with this disease are still anemic—a condition that can be alleviated somewhat by the heme acquired from drinking blood. This combination of traits sounds like the werewolf and vampire legends of Europe, which may have their base in this rare biochemical disease. 

5-Aminolevulinic acid (ALA ) formation is catalyzed by mitochondrial ALA synthase, which condenses glycine and succinyl-CoA to ALA. The enzyme is located on the matrix side of the inner mitochondrial membrane. It is encoded by a nuclear gene and is synthesized in the cytosol on the free polyribosomes as a 

The primary regulatory step of heme synthesis in the liver is apparently that catalyzed by ALA synthase. The regulatory effects are multiple. The normal end product, heme, when in excess of need for production of heme proteins, is oxidized to hematin, which contains a hydroxyl group attached to the Fe + atom. Replacement of the hydroxyl group by a chloride ion produces hemin. Hemin and heme inhibit ALA synthase allosterically. Hemin also inhibits the transport of cytosolic ALA synthase precursor protein into mitochondria. 

ALA synthase has a turnover rate of 70 minutes in adult rat liver and is inducible. Its induction is suppressed by hemin and increased by a variety of xenobiotics (e.g., environmental pollutants) and natural steroids. In erythropoietic tissues, where the largest amount of heme is synthesized, regulation of heme biosynthesis may also involve the process of cell differentiation and proliferation of the erythron, which occurs to meet change in requirements for the synthesis of heme. The differentiation and proliferation are initiated by erythropoietin. 

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Lead-induced anemia results from impairment of heme biosynthesis and acceleration of red blood cell destmction (10,13). Lead-induced inhibition of heme biosynthesis is caused by inhibition of S-aminolevulinic acid dehydratase and ferrochelatase which starts to occur at blood lead levels of 10 to 20 pu gjdL and 25 to 30 //g/dL, respectively (10,13). Anemia, however, is not manifested until higher levels are reached. 

Heat of combustion, 113 Heat of hydrogenation, 186 table of, 187 Heat of reaction, 154 Helicase, DNA replication and, 1106 Hell-Volhard-Zelinskii reaction, 849 amino acid synthesis and. 1025 mechanism of, 849 Heme, biosynthesis of, 966 structure of, 946 Hemiacetal, 717 Hemiketal, 717 Hemithioacetal, 1148 Henderson-Hasselbalch equation,... 

A summary of the steps in the biosynthesis of the porphyrin derivatives from PBG is given in Figure 32-8. The last three enzymes in the pathway and ALA synthase are located in the mitochondrion, whereas the other enzymes are cytosolic. Both erythroid and non-erythroid ( housekeeping ) forms of the first four enzymes are found. Heme biosynthesis occurs in most mammalian cells with the exception of mature erythrocytes, which do not contain mitochondria. However,... 

In general, the porphyrias described are inherited in an autosomal dominant manner, with the exception of congenital erythropoietic porphyria, which is inherited in a recessive mode. The precise abnormalities in the genes directing synthesis of the enzymes involved in heme biosynthesis have been determined in some instances. Thus, the use of appropriate gene probes has made possible the prenatal diagnosis of some of the porphyrias. 

Anderson KE et al Disorders of heme biosynthesis X-linked sideroblastic anemia and the porphyrias. In The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Scriver CR et al (editors). McGraw-Hill, 2001. 

Hematological Effects. Lead has long been known to have profound effects on heme biosynthesis. 

In summary, lead inhibits the activity of certain enzymes involved in heme biosynthesis, namely, 5-aminolevulinic acid dehydratase (ALAD), and ferrochelatase. As a consequence of these changes, heme biosynthesis is decreased and the activity of the rate limiting enzyme of the pathway,... 

Hematological Effects. The effects of lead on the hematopoietic system have been well documented. These effects, which are seen in both humans and animals, include increased urinary porphyrins, coproporphyrins, ALA, EP, FEP, ZPP, and anemia. The process of heme biosynthesis is outlined in Figure 2-10. Lead interferes with heme biosynthesis by altering the activity of three enzymes ALAS,... 

ALAD, and ferrochelatase. Lead indirectly stimulates the mitochondrial enzyme ALAS, which catalyzes the condensation of glycine and succinyl-coenzyme A to form ALA. The activity of ALAS is the rate-limiting step in heme biosynthesis increase of ALAS activity occurs through feedback derepression. Lead... 

Chmielnicka J, Zareba G, Nasiadek. 1994. Combined effect of tin and lead on heme biosynthesis in rats. Ecotox Environ Safety 29 165-173. 

Goldberg AM, Meredith PA, Miller S, et al. 1978. Hepatic drug metabolism and heme biosynthesis in lead-poisoned rats. Br J Pharmacol 62 529-536. 

Meredith PA, Moore MR. 1979. The influence of lead on heme biosynthesis and biodegradation in the rat. Biochem Soc Trans 7 637-639. 

Acute intermittent porphyria is a dominantly inherited partial deficiency of porphobilinogen deaminase, and causes axonal polyneuropathy. Acute intermittent porphyria is caused by partial deficiency of porphobilinogen deaminase, an enzyme required for heme biosynthesis. Patients may present with acute abdominal pain, rapidly progressive sensorimotor axonal polyneuropathy or psychosis, and have elevated concentrations of the heme precursor 8-amino-levulinic acid in their urine. Symptoms may be precipitated by treatment with barbiturates or other drugs and are suppressed by treatment with hematin [59]. 

Although generalizations regarding the hematological effects of fuel oils on humans cannot be made, the effect of kerosene on the first two steps of the heme synthetic pathway has been studied in an animal model. Both hepatic -aminolevulinic acid ( -ALA) dehydratase and -ALA synthetase activities were decreased in female rats after intraperitoneal injection of kerosene, while heme oxygenase was unaffected (Rao and Pandya 1980). Since -ALA synthetase is the rate-limiting enzyme of the heme biosynthesis pathway, hepatic heme biosynthesis may be inhibited by kerosene. It is conceivable that this may be related to the extramedullary hematopoiesis reported in other studies (NTP/NIH 1986) however, there are no direct data to support this. 

Although lung response to aerosolized kerosene and the effect of kerosene on heme biosynthesis have been partially investigated, the toxicides of fuel oils as well as their mechanisms are not well defined. As such, no known therapies are available that disrupt the mechanisms of action. 

The incorporation of iron(II) into the protoporphyrin IX ring, the final step in heme biosynthesis, is catalyzed by ferrochelatase. Kinetic parameters were reported both for this process and for the reaction of Fe " with ferrochelatase, whose kinetics were used to characterize the latter. ... 

Heme, an iron-containing tetrapyrrole pigment, is a component of 02-binding proteins (see p. 106) and a coenzyme of various oxi-doreductases (see p. 32). Around 85% of heme biosynthesis occurs in the bone marrow, and a much smaller percentage is formed in the liver. Both mitochondria and cytoplasm are involved in heme synthesis. 

Mitochondria are also described as being the cell s biochemical powerhouse, since—through oxidative phosphorylation (see p. 112)—they produce the majority of cellular ATP. Pyruvate dehydrogenase (PDH), the tricarboxylic acid cycle, p-oxidation of fatty acids, and parts of the urea cycle are located in the matrix. The respiratory chain, ATP synthesis, and enzymes involved in heme biosynthesis (see p. 192) are associated with the inner membrane. 

Figure 9-7. Pathway for heme biosynthesis. Regulation by hemin at the key aminolevulinic acid (ALA) synthase-catalyzed step and by lead at two steps is indicated.

How the division of spoils came about I do not recall—it may have been by drawing lots. At any rate, David Shemin drew amino acid metabolism, which led to his classical work on heme biosynthesis. David Rittenburg was to continue his interest in protein synthesis and turnover, and lipids were to be my territory. 

Tissues that synthesize heme, and the sources of porphyrin s carbon and nitrogen The major sites of heme biosynthesis are the liver (where the rate of synthesis is highly variable) and the erythrocyte-producing cells of the bone marrow (where the rate is generally constant). All the carbon and nitrogen atoms are provided by glycine and succinyl CoA. 

Nadler, K.D. (1981). A mutant strain of Rhizobium leguminosarium with an abnormality in heme biosynthesis. In Current Perspectives in Nitrogen Fixation, ed. A.H. Gibson W.E. Newton, p. 414. Canberra Australian Academy of Science. 

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