Porphobilinogen synthase inhibition

Aminolevulinate now leaves the mitochondria. In the cytoplasm, two molecules condense to form porphobilinogen, a compound that already contains the pyrrole ring. Porphobilinogen synthase is inhibited by lead ions. This is why acute lead poisoning is associated with increased concentrations of ALA in the blood and urine. 

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. 

ALAD (also known as porphobilinogen synthase) is a cytoplasmic enzyme that catalyzes the formation of the mono-pyrrole porphobilinogen (PEG) from two molecules of ALA with elimination of two molecules of water. The enzyme requires zinc ions as a cofactor and reduced sulfhydryl groups at the active site and is therefore susceptible to inhibition by lead. 

We have already seen the diversity of function in the lyases, hydrolases, and oxidoreductases. Several other types of zinc coordination are found in a number of other enzymes, illustrated in Figure 12.12. These include enzymes with the coordination motif [(His)2(Cys) Zn " -OH2], found in the lysozyme of bacteriophage T7, or [(Cys)3 Zn " "-OH2] which occurs in 5-aminolaevulinate dehydratase (or porphobilinogen synthase). This latter enzyme catalyses the condensation of two molecules of 5-aminolaevulinate to form the pyrrole precursor of the porphyrins (haem, chlorophyll, and cobalamines), and its inhibition by Pb is the cause of lead poisoning (saturnism), frequently observed among inner city children (Chapter 1). 

Goering PL and Rehm S (1990) Inhibition of liver, kidney, and erythrocyte aminolevulinic acid dehydratase (porphobilinogen synthase) by gallium in the rat. Environ Res 53 135-151. 

Increased excretion of (5-ALA in urine can be an indication for lead poisoning since, as a result of inhibition of the specific 6-ALA dehydratase (porphobilinogen synthase, EC 4.2.1.24), no condensation to porphobilinogen can occur. (5-ALA can, however, also be degraded to 4,5-dloxopentanoic acid. A. is used in the... 

The exogenously administered Bchl precursor, 5-aminolevulinic acid (ALA), inhibited the Bchl biosynthesis in Erythrobacter sp. OCh 114 (7). This was due to the conversion of ALA to the metabolite, 4-hydroxy-5-aminovaleric acid, which caused the inhibition of porphobilinogen synthase in the porphyrin synthetic pathway (7). In R. sulfidophllus, there was no inhibition, but rather a 1 to 6% increase by the addition of 1 to 10 mM ALA which suggested that the formation of 4-hydroxy-5-aminovaleric acid did not occur. The effect of ALA was quite different among the three species of bacteria used. 

The most studied of the genetic polymorphisms for blood components in potentially lead-exposed populations and relevant to Pb toxicokinetics is that for the erythrocyte heme pathway enzyme 6-ALAD (EC 4.2.1.24). This enzyme, also known as porphobilinogen synthase (PBG-S), participates in the heme biosynthesis pathway, catalyzing the cyclodehydration of two units of 6-ALA to PBG. Inhibition by lead leads to the accumulation of 6-ALA in plasma and urine. Excess substrate is neurotoxic in animals and may play a role in manifestations of lead poisoning (Audeskirk, 1985) and, presumably, in the genetic disorder acute intermittent porphyria (Bonkowsky, 1982). It is... 

Enzymatic method. Inhibition of porphobilinogen synthase by boiled plasma given in the equivalent succinylacetone concentration. 

Hydroxymethylbilane Synthase (EC 2.5.1.61), HMBS HMBS (also known as porphobilinogen [PEG] deaminase) is a cytoplasmic enzyme that catalyzes the formation of one molecule of the linear tetrapyrrole 1-hydroxymethylbilane (HMB also known as preuroporphyrinogen) from four molecules of PEG with the release of four molecules of ammonia. The former enzyme committee designation for HMBS was EC 4.3.1.8, but in 2003 the enzyme was redesignated as EC 2.5.1.61. The enzyme has two molecules of its own substrate PEG, attached covalently to the apoenzyme as a prosthetic group. The enzyme is susceptible to allosteric inhibition by intermediates further down the heme biosynthetic pathway, notably coproporphyrinogen-III and protoporphyrinogen-IX. 

Protoporphyrinogen III oxidase (EC 1.3.3.4). Ferro-chelatase activity may also be decreased. Impaired feedback inhibition of 5-aminolevulinate synthase results in excessive porphyrin production. Increased urinary porphobilinogen, 5-aminolevulinate, protoporphyrin and coproporphyrin during acute attacks. Fecal protoporphyrin and coproporphyrin constantly elevated. Fecal porphyrin-peptide conjugates increased. Mild photodermatoses clinical picture otherwise similar to that of acute intermittent porphyria. Treatment as for latter. Rare, except in white South Africans, where frequency is 0.4%. Autosomal dominant. 

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