Formation of Heme

Formation of Heme Involves Incorporation of Iron Into Protoporphyrin... 

As discussed earlier, lead clearly inhibits the formation of heme at several points, adversely affects blood chemistry, and accumulates in hematopoietic organs of aquatic organisms. In addition, it ... 

The metalloporphyrin complexes and their derivatives have been studied from the standpoint of model compounds of hemoglobin. The polymer-metalloporphyrin complexes are also formed by the reaction in Scheme 8, and a few qualitative investigations have been made with poly(L-lysine)9,10, poly(L-histidine)11, and poly(vinylimidazole)12 as the polymer ligand. Blauer9 has studied the complex formation of heme with poly(L-lysine) and has discussed the effects of the molecular weight and secondary structure of poly(L-lysine) on complex formation. 

Formation of heme Uroporphyrinogen III is converted to heme by a series of decarboxylations and oxidations summarized in Figure 21.4. The introduction of Fe2+into protoporphyrin IX occurs spontaneously, but the rate is enhanced by the enzyme ferrochelatase—an enzyme that is inhibited by lead (see p. 279). 

Pathway of porphyrin synthesis formation of heme. (Continued from Figure 21.3.)... 

Green plants, algae, fungi, cyanobacteria and bacteria that assimilate nitrate also produce assimilatory nitrite reductases, which catalyze the six-electron reduction of nitrite to ammonia (equation 89). The formation of heme-nitrosyl intermediates has been detected in several cases,1515 while hydroxylamine is commonly thought to be an intermediate. Added hydroxylamine is rapidly reduced to ammonia. However, no intermediates are released, and ammonia is the only product... 

Additional reactions of glycine include its ability to become conjugated with bile acids to form conjugated bile salts (see Chapter 19), formation of heme (Chapter 7), formation of purine nucleotides (Chapter 10), formation of creatine (see later), and the formation of hippuric acid from benzoic acid. In the last case, an amide linkage is formed between the carboxyl group of benzoic acid and the amino group of glycine. 

Figure 24.35. Heme Biosynthetic Pathway. The pathway for the formation of heme starts with eight molecules of 6-aminolevulinate.

Formation of heme. In the reaction catalyzed by protoporphyrinogen oxidase, six hydrogens are removed and the primary electron acceptor is not known, but oxygen is required for enzyme activity. In the terminal step of heme synthesis, only Fe + is incorporated into protoporphyrin. 

Lead has an inhibitory effect on steps in the chain of reactions that lead to the formation of heme, affecting for example the enzymes ALA dehydratase (ALAD) and ferrochelatase (heme synthetase). Lead also inhibits the activity of the enzyme pyrimidine-5-nucleo-tidase (P5N) in red cells. 

Figure 6. The biosynthetic pathway for the production of heme. The enzymes and metabolites are located in the mitochondria (M) and the cytosol (C). Heme negatively regulates ALA synthase at several points, three of which are shown in the figure. Exogenous ALA induces excess formation of heme precursors, including PpIX that can be utilized for photosensitization. (N) nucleus where transcriptional control occurs.

The final step in the formation of heme is the insertion of iron into protoporphyrin. This function is performed in the mitochondrion. It suggests that heme, the end product of the biosynthetic chain, would be ideally situated to act as an allosteric end-product inhibitor of the first enzyme, ALA-synthetase. No satisfactory evidence has yet been obtained, however, that the activity of mitochondrial ALA-synthetase is inhibited directly by heme, except when heme is added in concentrations which appear to us too high to be considered physiological. For example, even soluble ALA-synthetase isolated from mitochondria required Q M heme to inhibit the activity 77% [Bottomley and Smithiee, 32]. Whether the free heme in mitochondria could attain these high concentrations could be determined on mitochondria isolated from ALA-treated cells. Another problem that requires study is the... 

D. Induction in Whole-Animal Experiments and the Formation of Heme... 

The formation of heme, the platelet, and serum folate levels 15-18 180... 

Virtually no part of the body is immune from the effects of lead. Lead in the body dismpts energy metabolism at the cellular level, interferes with neural cell function in the brain, disrupts the formation of heme and in the nervous system, inhibits communication and decreases nerve conduction velocity. Even at relatively low exposures, lead s neurotoxic effects can cause decreased intelligence, short-term memory loss, reading under-achievement, impairment of visual-motor function, loss of auditory memory, poor percepmal integration, poor classroom behavior, and impaired reaction time. 

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