Porphyrin metabolism

Porphyrins are nitrogen-containing, cyclic compounds that bind metal ions in coordination complexes, ie, metalloporphyrins. 

The main metalloporphyrin in the body is heme, which has a ferrous Fe iron atom coordinated by protoporphyrin DC 

Heme synthesis takes place in all cells, but most of the body s heme is made in the liver and bone marrow. 

When the amount of heme available exceeds the amount of the core proteins, 

ALA synthase in the liver is inhibited to reduce flux through the pathway. 

The synthesis and turnover of porphyrins, heme precursors, are important because of the central roles of the heme proteins, hemoglobin, and the cytochromes. Quantitatively, hemoglobin synthesis is a major part of the nitrogen economy in humans. 

The first step of porphyrin synthesis is the condensation of succinyl-CoA and glycine to form 8-aminolevulinate. The reaction takes place in mitochondria, where succinyl-CoA is available. The reaction is irreversible and requires pyridoxal phosphate and Mg2+. It is catalyzed by the enzyme 8-aminolevulinate synthase. 

Subsequent reactions occur in the cytoplasm and they are irreversible. Two molecules of 8-aminolevulinate are condensed by the enzyme porphobilinogen synthase to form the trisubstituted pyrrole porphobilinogen. Two enzymes, uroporphyrinogen synthase and uroporphyrinogen cosynthase, condense four molecules of porphobilinogen to the porphyrin uroporphyrinogen III. 

Note that uroporphyrinogen III is not a symmetrical molecule. During its synthesis, one of the pyrrole rings (ring D) is reversed, with the result that the acetate and propionate side chains are not symmetrically arranged around the porphyrin ring. The key porphyrin intermediate in cytochrome and hemoglobin synthesis is protoporphyrin IX (Fig. 15-21). 

What determines the function of the heme group in different proteins  

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Aplastic anemia and leukemia are not the only health effects ascribed to benzene exposure. A number of recent studies have associated benzene exposure with chromosomal changes (aberrations) (118). Other studies have shown abnormalities in porphyrin metabolism and decrease in leucocyte alkaline phosphatase activity in apparendy healthy workers exposed to 10—20 ppm benzene (119,120). Increases in leukoagglutinins, as well as increases in blood fibrinolytic activity, have also been reported and are believed to be responsible for the persistent hemorrhages in chronic benzene poisoning (121,122). 

High levels of lead can affect heme metabohsm by combining with SH groups in enzymes such as fer-rochelatase and ALA dehydratase. This affects porphyrin metabolism. Elevated levels of protoporphyrin are found in red blood cells, and elevated levels of ALA and of coproporphyrin are found in urine. 

Because hexachlorobenzene can interfere with porphyrin metabolism and produce chemical porphyria, the evaluation of the urinary porphyrin pattern has been proposed as an early biomarker of effect (San Martin et al., 1977 Schmid, I960, 1966 Wray et al., 1962). However, apart from an outbreak of chemical porphyria which occurred in Turkey in the 1950s following ingestion of hexachlorobenzene-contaminated food, cases of chemical porphyria among... 

Tomokuni, K. and M. Ichiba. 1990. Interaction between nickel and lead in relation to porphyrin metabolism in mice. Indust. Health (Kawasaki, Japan) 28 145-149. 

Wada O et ah Behavior of hepatic microsomal cytochromes after treatment of mice with drugs known to disturb porphyrin metabolism in liver. Biochem Pharmacol 17 595-603, 1968... 

The porphyrias are a heterogeneous group of diseases of porphyrin metabolism characterized by a variety of dermatologic, neurologic, and psychological manifestations. 

Hill RH. 1985. Effects of polylialogeanted aromatic compounds on porphyrin metabolism. Environ Health Perspect 60 139-143. 

Wainstok de Calmanovici, R. San Martin de Viale, L.C. (1980) Effect of chlorophenols on porphyrin metabolism in rats and chick embryo. Int. J. Biochem., 12, 1039-1044... 

Pantothenic acid participates as part of coenzvme A in carbohydrate metabolism (2-carbon transfer-acetate, or pyruvate), lipid metabolism (biosynthesis and catabolism of fatty acids, sterols, +phospholipids), protein metabolism (acetylations of amines and amino acids), porphyrin metabolism, acetylcholine production, isoprene production. 

Griseofulvin interferes with porphyrin metabolism. In man, transient increases in erythrocyte protoporphyrin concentrations have been demonstrated, and the production and excretion of porphyrins is increased. Acute intermittent porphyria is an absolute contraindication to griseofulvin. In patients with other forms of porphyria it should also be avoided, in view of the many alternatives (458-463). 

A Goldberg, C Remington. Diseases of porphyrin metabolism. Springfield, Illinois Thomas, 1962. 

Kahn H, Muzyka V. 1973. The chronic effect of benzene on porphyrin metabolism. Work Environ Health 10 140-143. 

High homocysteine levels and vascular disease Section 24.2.9 Inherited disorders of porphyrin metabolism Section 24.4.4 Anticancer drugs that block the synthesis of thymidylate Section 25.3.3... 

Porphyrins Accumulate in Some Inherited Disorders of Porphyrin Metabolism... 

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