ALA dehydratase

Figure 32-5. Biosynthesis of porphobiiinogen. ALA synthase occurs in the mitochondria, whereas ALA dehydratase is present in the cytosol.

ALA dehydratase deficiency (hepatic) (MIM 125270) Acute intermittent porphyria (hepatic) (MIM 176000) Congenital erythropoietic (erythropoietic) (MIM 263700)... 

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. 

Most of the subsequent steps of tetrapyrrole synthesis are identical in plants, animals, and bacteria. The pathway includes synthesis of the monopyrrole porphobilinogen from two molecules of ALA by the action of ALA dehydratase with the elimination of two molecules of water, followed by the assembling of a linear tetrapyrrole hydroxymethylbilane from fonr molecnles of porphobilinogen, ring closure and two modification reactions of side chains. This produces the first tetrapyrrole macrocycle, uroporphyrinogen HI. Therefore, eight molecules of ALA are necessary to form one tetrapyrrole. 

Beside the use of a single enzyme, a cocktail of different biocatalysts can also be used in performing a domino process, provided that the enzymes do not interfere one with another. This approach was used by Scott and coworkers in the synthesis of precorrin-5 (8-61) (Scheme 8.16) [24]. Starting from 6-amino levulinic acid (ALA) 8-60, a mixture of eight different enzymes including the ALA-dehydratase to form porphobilinogen (PBG), as well as PBG deaminase and co-synthetase to furnish the tetracyclic uroporphyrinogen III (8-62) as intermediates, was employed to provide precorrin-5 (8-61) in 30% yield. 

A novel interesting approach is the use of multienzyme cocktails described by Scott et al. for the synthesis of precorrin-5159 starting from 8-amino levu-linic acid 158 (scheme 32).1871 For the process, a multienzyme cocktail of eight different enzymes including the ALA-dehydratase to form porphobilinogen as well as PBG deaminase and cosynthetase to give the tetracyclic uroporphyrinogen HI (10) was employed. 

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 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. 

In plants, algae and many bacteria there is an alternative route for ALA synthesis that involves the conversion of the intact five-carbon skeleton of glutamate in a series of three steps to yield ALA. In all organisms, two molecules of ALA then condense to form porphobilinogen in a reaction catalyzed by ALA dehydratase (also called porphobilinogen synthase) (Fig. 2a). Inhibition of this enzyme by lead is one of the major manifestations of acute lead poisoning. 

The inhibition of chlorophyll biosynthesis by metals was described for higher plants (Bazinsky et al., 1980 Prassad and Prassad, 1987) as well as for algae (De Filippis and Pallaghy, 1976 De Filippis et al., 1981 a). Sensitivity to metals was found for two enzymes of this pathway 8-aminolaevulinic acid (ALA)-dehydratase (EC 4.2.1.24) and protochlorophyllide reductase. Stobart et al. (1985) reported that the synthesis of 8-ALA is also an important site of inhibition in barley (Hordeum vulgare). 

The acute porphyrias include ALA dehydratase deficiency porphyria (ADP), AIP, VP, and HCP. These disorders are autosomal dominant except for ADP, which is autosomal recessive. 

Two molecules of ALA are condensed by cytosolic zinc containing ALA dehydratase to... 

The reaction mechanism consists of Schiff base formation by the keto group of one molecule of ALA with the e-amino group of a lysyl residue of the enzyme, followed by nucleophilic attack by the enzyme-ALA anion on the carbonyl group of a second ALA molecule with elimination of water. Then, a proton is transferred from the amino group of the second ALA molecule to the e-amino group of the lysyl residue with formation of PBG. Lead is a potent inhibitor of ALA dehydratase, presumably by displacement of zinc by lead because the lead-inhibited enzyme can be reactivated by the addition of zinc. ALA dehydratase is inhibited competitively by suc-cinyl acetone (HOOC-CH2-CH2-CO-CH2-CO-CH3), which occurs in urine and blood in hereditary tyrosinemia (Chapter 17). Genetic deficiency of ALA dehydratase is known to occur. 

ALA-dehydratase, and isocitrate dehydrogenase and decreases Na+, K -ATPase activity, Mg +-ATPase activity, and choline uptake into synaptosomes. In vitro, aluminum displaces magnesium from Mg +-ATP complexes, and it could thus antagonize virtually any phosphatetransferring reaction that uses Mg +-nucleotide triphosphate complexes. 

ALA dehydratase (ALAD) Cytosolic enzyme that catalyzes the asymmetric condensation of two molecules of ALA to form PBG. 

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