Porphyrin synthesis, enzymes

Figure 3. Activity of porphyrin synthesis enzymes. , excretion , non-excretion condition. Activity is expressed as nmol/mg protein/ min at 40°C.

ALA and PBG are the precursors of porphyrin synthesis (Fig. 7.3.1). ALA is synthesized from glycine and succinyl-coenzyme A by ALAS. Two molecules of ALA are converted to PBG by the enzyme ALAD. 

Reduced synthesis. The synthesis of enzymes may be decreased, resulting in a decrease in the in vivo activity. With cytochrome P-450 there are a number of ways in which this occurs. Thus, administration of the metal cobalt to animals will decrease levels of cytochromes P-450 by inhibiting both the synthesis and increasing the degradation of the enzyme. Thus, cobalt inhibits S-aminolaevulinic acid synthetase, the enzyme involved in heme synthesis. Cobalt will also increase the activity of heme oxygenase, which breaks down the heme portion to biliverdin. The compound 3-amino, 1, 2, 3-triazole decreases cytochromes P-450 levels by inhibiting porphyrin synthesis. 

Heavy metals stimulate or inhibit a wide variety of enzyme systems (16, 71, 72), sometimes for protracted periods (71, 73). These effects may be so sensitive as to precede overt toxicity as in the case of lead-induced inhibition of 8 ALA dehydrase activity with consequential interference of heme and porphyrin synthesis (15, 16). Urinary excretion of 8 ALA is also a sensitive indicator of lead absorption (74). Another erythrocytic enzyme, glucose-6-phosphatase, when present in abnormally low amounts, may increase susceptibility to lead intoxication (75), and for this reason, screens to detect such affected persons in lead-related injuries have been suggested (76). Biochemical bases for trace element toxicity have been described for the heavy metals (16), selenium (77), fluoride (78), and cobalt (79). Heavy metal metabolic injury, in addition to producing primary toxicity, can adversely alter drug detoxification mechanisms (80, 81), with possible secondary consequences for that portion of the population on medication. 

Precautions As noted previously, barbiturates induce the P-450 system and therefore may decrease the effect of drugs that are metabolized by these hepatic enzymes. Barbiturates increase porphyrin synthesis, and are contraindicated in patients with acute intermittent porphyria. 

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. 

Pyrazinamide Unknown, but metabolically activated by bacteria—strains lacking the bioactivating enzyme are resistant Polyarthralgia, myalgia, hepatitis, rash, hyperuricemia, phototoxicity, T porphyrin synthesis... 

Control of porphyrin synthesis. The control of porphyrin synthesis is shown in outline form, including inhibition of the first step, as well as a decreasing amount of the enzyme by protohemin IX (where Fe2+ is oxidized to Fe3+). The pathway of the synthesis of abnormal porphyrins is also... 

We devised a screen for isolating mutants defective in iron-dependent regulation of heme biosynthesis that did not require prior knowledge of the mechanism or of the rate-limiting steps [83]. We speculated that if the pathway as a whole were regulated by iron, a mutant defective in that control would accumulate protoporphyrin under iron limitation. Mutants defective in the heme synthesis enzymes ferrochelatase [75] or protoporphyrinogen oxidase would likely have a similar phenotype, but porphyrin accumulation would likely be independent of iron in the structural gene mutants, and those strains would also be expected to be heme auxotrophs. 

O. Visser, J.W.O. van den Berg, H. Koole-Lesuuis, G. Voortman, J.H.P. Wilson (1991). Porphyrin synthesis by human hepatocytes and HepG2 cells - effect of enzyme inducers and delta-aminolevulinic acid. Toxicology, 67, 75-83. 

Enzyme preparations utilizing PEG for porphyrin synthesis have been isolated from a variety of sources plant 89-92), animal 31, 76, 93-96), and bacterial 97). Bogorad and Granick 89) showed that a preparation from Chlorella formed TJRO-III (Fig. 12) from PEG, but after heating to GO , only URO-I (Fig. 12) was formed. Similar observations have been made with preparations from chicken red blood cells (94) and from a bacterium 97) R. sphercides. 

With the recognition that there is abnormal excretion of certain porphyrins in the hereditary porphyrias it was assumed that as in other metabolic errors, the abnormalities resulted from an enzyme block either in an associated pathway diverting more substrate to porphyrin synthesis or in porphyrin utilization leading to an accumulation of metabolic precursors. However, further observations showed that neither of these hypotheses was tenable. 

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