Heme metabolism

This mitochondrial enzyme (ALA synthetase) catalyzes the formation of 6-aminolevulinic acid (ALA) from glycine and succinyl-CoA. This is the initial step in heme biosynthesis. 

The assay of Tikerpae et al. (1981) incorporates a novel feature wherein radioactive succinyl-CoA is formed from succinate, which in turn is formed from radioactive S-ketoglutarate. The succinyl-CoA then reacts with glycine to form ALA. For the assay, the ALA is converted to the pyrrole derivative 2-methyl-3-carbethoxy-4-(3-propionic acid) pyrrole. 

The reaction mixture contained glycine, coenzyme A, buffer, a-ketoglutarate, and bone marrow lysate. After incubation for 1 hour, the reaction was terminated by addition of 10% TCA. The samples were chilled and clarified by centrifugation, and the pyrrole formed. After processing, the pyrrole was isolated by HPLC and its radioactivity was quantitated. 

The enzyme was obtained from bone marrow cells. The cells were harvested and pelleted by centrifugation at 2500g for 5 minutes. The pellets were washed, resuspended, counted, and disrupted by sonication to release mitochondria. This lysate was used directly as the source of the enzyme. 

In the assay described by Tomokuni et al. (1991), the product, 6-aminolevulinic acid, is formed from glycine and endogenously generated suc-cinyl-CoA. 

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All mammalian cells are virtually capable of producing CO with heme as the main substrate (Fig. 1) [5]. Enzymatic heme metabolism in vivo is mainly catalyzed by heme oxygenase (HO). In the presence of HO, the porphyrin ring of heme is broken and oxidized at the a-methene bridge, producing equimolar amounts of CO, ferrous iron, and biliverdin. Three isoforms of HO have been identified. Inducible HO-1 (32 kDa) is mostly recognized for its upregulation in response... 

Carbon Monoxide. Figure 1 Heme oxygenase catalyzed heme metabolism (from Pharmacol Rev 57 585-630,... 

Alterations in blood heme metabolism have been proposed as a possible indicator of the biological effects of hydrogen sulfide (Jappinen and Tenhunen 1990), but this does not relate to the mechanism of toxicity in humans. The activities of the enzymes of heme synthesis, i.e., delta-aminolevulinic acid synthase (ALA-S) and heme synthase (Haem-S), were examined in 21 cases of acute hydrogen sulfide toxicity in Finnish pulp mill and oil refinery workers. Subjects were exposed to hydrogen sulfide for periods ranging from approximately 1 minute to up to 3.5 hours. Hydrogen sulfide concentrations were considered to be in the range of 20-200 ppm. Several subjects lost consciousness for up to 3 minutes. 

Activities of ALA-S and Haem-S were decreased after exposure to hydrogen sulfide. However, the changes in heme metabolism are not specific for hydrogen sulfide, and other sulfur-containing compounds such as methyl mercaptan can produce similar effects. 

A few studies have reported associations between prenatal lead exposure and changes in heme metabolism. In a study of 294 mother-infant pairs, Haas et al. (1972) reported mean PbB levels of 16.98 pg/dL for mothers and 14.98 pg/dL for newborns. Infant PbB levels and ALA-U were positively correlated. The authors, however, did not report the levels of ALA-secretion in infants and mothers with no lead exposure. In pregnant urban women (Kuhnert et al. 1977), cord erythrocyte lead levels ranged... 

Heme metabolized in histiocytes Production of biliverdin releases carbon monoxide (CO)... 

Moody DE, Smuckler EA. 1986. Disturbances in hepatic heme metabolism in rats administered alkyl halides. Toxicol Lett 32 209-214. 

Although not specific for kerosene, aminolevulinic acid (ALA) could potentially be used as an adjunct or supplemental biomarker for kerosene exposure. Kerosene may affect heme metabolism by decreasing the activities of enzymes in the heme biosynthetic pathway (hepatic -ALA dehydratase and -ALA synthetase) (Rao and Pandya 1980). Therefore, it may be possible that this effect would generate increased ALA in the urine of exposed individuals. Additional studies of acute, intermediate, and chronic exposure are needed to identify biomarkers of effects for specific target organs following exposure to fuel oils. 

Woods JS, Carver GT, Fowler BA Altered regulations of hepatic heme metabolism by indium chloride. Toxicol Appl Pharmacol 49 455 61, 1979... 

Administration of 1 and 3 mg Sn/kg body weight to rats resulted in inhibition of various enzymes, including hepatic succinate dehydrogenase and the acid phosphatase of the femoral epiphysis. Tin also appears to interact with the absorption and metabolism of biological essential metals such as copper, zinc, and iron and to influence heme metabolism. ... 

This patient s anemia is likely due to inhibition of which of the following enzymes of heme metabolism ... 

This four-volume set has good chapters on disorders of amino acid, porphyrin, and heme metabolism. See also the chapters on inborn errors of purine and pyrimidine metabolism. 

Key concept map for heme metabolism. Note Porphyria cutanea tarda affects both the liver and erythropoietic cells. = Block in the pathway. 

The effect of enflurane on heme metabolism has been tested in mice (381) the authors suggested that enflurane be added to the list of drugs that can precipitate acute attacks of porphyria. 

Rosenberg DW, Drummond GS, Kappas A. 1982. The influence of organometals on heme metabolism In vivo and in vitro studies with organotins. Mol Pharmacol 21 150-158. 

Various vitamin B12 derivatives are shown in Figure 6.2, where the R group is usually taken as CN-. This form of vitamin B12 is cyanocobalamin. In the active coenzyme, the CN" is replaced by a 5 -deoxyriboadenosyl residue or by -CH3. Vitamin B12 seems to be the only mammalian substance that contains cobalt. It also has a unique corrin ring structure, which is very similar to that of heme. Metabolic reactions requiring vitamin B12 are discussed in Chapters 19 and 20. 

Fig. 1 Molecular and biochemical basis of Friedreich s ataxia (FRDA). (a) A GAA-repeat expansion in the first intron of the FRDA gene results in decreased levels of frataxin as a result of inhibition of transcriptional elongation, (b) Alterations in mitochondrial biochemistry that are associated with reduced frataxin levels. Proposed functions for frataxin include iron binding, protection and synthesis of Fe-S clusters, providing a binding partner for ferrochetalase in heme (haem) metabolism, and providing a metabolic switch between heme metabolism and Fe-S cluster biosynthesis. In FRDA, reduction of firataxin results in lowered levels of aconitase and respiratory complexes 1,11, and 111. Cytosolic proteins that contain Fe-S clusters may also be affected. Inability to form Fe-S clusters leads to an accumulation of iron, which leads to increased free radical formation (Fenton chemistry) in these organelles. Increased free radical formation may feed back to further decrease levels of Fe-S clusters, which are known to be sensitive to oxidative stress.

Eiseman JL, Ribas JL, Knight E, Alvares AP. Acute nephropathy induced by gold sodium thiomalate Alterations in renal heme metabolism and morphology. Toxicol AppI Pharmacol 1987 91 193-203. 

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