5-aminolevulinic acids synthase

X-linked sideroblastic anemia is not a porphyria but is included here because 6-aminolevulinic acid synthase is involved. 

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. 

ALA = 5-aminolevulinic acid ALAD = 6-aminolevulinic acid dehydratase ALAS = 5-aminolevulinic acid synthase EP = erythrocyte protoporphyrins FEP = free erythrocyte protoporphyrins FSH = follicle stimulating hormone IQ = intelligence quotient LH = luteinizing hormone NS = not specified (occup) = occupational Py-5 -N = pyrimidine-5-nucleotidase TSH = thyroid stimulating hormone ZPP = erythrocyte protoporphyrin... 

An extremely important role of iron is the synthesis of haem for formation of erythrocytes and also for proliferating cells for synthesis of the mitochondrial enzymes that contain haem (e.g. cytochromes). The flux-generating enzyme in the synthesis of haem is aminolevulinic acid synthase (ALS) (Figure 15.20). If the cellular iron concentration is low, the concentration of this enzyme is increased in an attempt to maintain the rate of synthesis. As with the other two proteins, the concentration of ALS is controlled at the level of translation in a similar manner to that for transferrin, i.e. by increased stability of the mRNA, which is achieved by the binding of the IRP to the mRNA. 

Figure 15.20 Control of the rate of haem synthesis. The concentration of the enzyme aminolevulinic acid synthase, the first enzyme in the synthesis of haem, and the flux-generab ng enzyme, is increased by IRP. This ensures an adequate rate of synthesis of haem, even though the iron level in the cell may be low. This is achieved by stimulation of translation. Full details of the pathway are presented in Appendix 15.3.

Strand LJ, Swanson AL, Manning J et al. (1972) Radiochemical microassay of delta-aminolevulinic acid synthase in hepatic and erythroid tissue. Anal Biochem 47 457 170... 

Cytochrome synthesis was examined in the fat body of adult male B. discoidalis by measuring the synthesis of cytochrome hemes. Heme is synthesized from the condensation of succinate and glycine by aminolevulinic acid synthase to produce aminolevulinic acid (ALA), a specific heme precursor. A developmental pattern exists for the incorporation of [i CjALA into cytohemes of fat body mitochondria with a peak of synthesis between days 4 and 6 of adult age (60). CC ablation eliminates this peak of synthesis for cytohemes a and b CC extract injections return the synthesis of cytohemes a+b to normal levels in CC-ablated cockroaches but have no effects on the synthesis of the c-type hemes for cytochromes c and Cj, The synthesis of cytohemes a+b in response to CC extracts requires a latent period of 24-48 hr to obtain a maximum response and is dose-dependent over a range of 0.01 to 0.08 CC pair (61). The active factor in CC extracts is sensitive to chymotrypsin but not to trypsin. This "cytochromogenic hormone (CGH) is secreted on days 2-3 of adult age in males (62). Since maximal synthesis of cytohemes a+b occurs on day 4, CGH secretion on days 2-3 agrees with the earlier observation that CGH requires about 48 hr to produce its response (61). 

Several other iron metabolism proteins contain IREs, including ferroportin, an iron exporter, the erythrocyte form of aminolevulinic acid synthase, an enzyme important in heme biosynthesis, an alternatively spliced transcript of the iron transporter DMTl, and mammalian mitochondrial aconitase. The importance of these IREs in regulation of these transcripts is the subject of ongoing research. 

The first and rate-limiting step in heme biosynthesis is the condensation of glycine and succinyl-CoA to give 5-aminolevulinic acid by aminolevulinic acid synthase (ALAS) (Fig. 3). Two... 

Aminolevulinic acid synthase (ALAS) Mitochondrial matrix enzyme that catalyzes the rate-limiting synthesis of ALA via condensation of succinyl-CoA and glycine. 

A number of metagenomic libraries hosted in E. coli have now been screened for clones that produce either antibacterial activities or color. In addition to hits that are unique to each library, these studies have encountered four common hits. These include the antibacterially active long-chain A-acyl amino acid-producing clones described earlier in this section, red antibacterially active clones that express aminolevulinic acid synthases (hemA), brown clones that produce melanin-like polymers, and blue clones that produce mixtures of indigo (25) and indinibin... 

P.R. Ortiz de Montellano (1988). 2,2-Dialkyl-1,2-dihydroquinolines Cytochrome P-450 catalyzed N-alkylporphyrin formation, ferrochelatase inhibition, and induction of 5-aminolevulinic acid synthase activity. Chem. Res. Toxicol. 1, 208—215. 

Heme, the most abundant iron cofactor, can play diversified roles in the cell. These roles include not only the already-mentioned regulatory and signal transduction processes, but also electron transfer, oxygen binding and transport, and direct involvement in the oxygen metabolism. The first step of the heme biosynthetic pathway in mammalian cells is catalyzed by 5-aminolevulinic acid synthase (ALAS), which is considered a rate-limiting step in the production of heme. The rate of synthesis of erythroid ALAS is directly dependent on the cellular iron concentration. Ferreira reviews recent structural and site-directed mutagenesis studies on ALAS (Chapter 2), which, for example, have revealed that the homodimeric enzyme s active site is located at the subunit interface and contains catalytically essential residues from both subunits. 

Several other classes of proteins have also been implicated as possible targets for lead, including other proteins in the heme biosynthetic pathway, leadbinding proteins in the kidney and brain, and heat shock proteins (342, 500-502). Lead is known to affect several steps in the heme biosynthetic pathway other than that catalyzed by ALAD Other profound effects include stimulation of 5-aminolevulinic acid synthase (ALAS) and decreased levels of iron incorporation into protoporphyrin by ferrochelatase (see Section VI.E.2 and Fig. 34) (10, 503-505). However, not all of these effects are due to direct interactions between lead and enzymes in the heme biosynthetic pathway. For instance, the widespread assertion that lead inhibits ferrochelatase is not supported by studies on the isolated enzyme (506, 507). Furthermore, increased levels of both erythrocyte protoporphyrin IX (EP) and zinc protoporphyrin (ZPP) are observed at high BLLs, suggesting that ferrochelatase is stiU competent to insert zinc into EP and that the increased levels of EP and ZPP associated with lead poisoning are most likely caused by lead interfering with iron uptake or transport (see Sections VI.C.4 and VI.E) (10, 506, 507). 

The site of heme synthesis for leghemoglobin in nodules has been proposed as being in the bacteroids on the basis of studies examining the incorporation of 8-amino[4- C]levulinic acid into haem in different fractions from legume nodules (Cutting and Schulman, 1969 Godfrey and Dilworth, 1971). Support for this hypothesis has been obtained from studies showing that the level of 8-aminolevulinic acid synthase, a key enzyme in porphyrin biosynthesis, increases in bacteroids from soybean over the same time course as... 

A more complex case was described % Nandi (1978). -Aminolevulinic acid synthase from Rhodopseudomonas spheroides is a pyridoxal phosphate-dependent enzyme that catalyzes the formation of -aminolevulinic acid from glycine and succinyl coenzyme A in this case, the release of products is random and more than one product can exchange back into substrate. 

Haematology - Sideroblastic anaemia is a known side effect of both INH and PZA as they inhibit the enzyme 5-aminolevulinic acid synthase-2, catalysing the first step of haeme biosynthesis [63, 64 ]. 

ABCB7, ATP-binding cassette sub-family B, member 7 ALA-S2/eALAS, erythroid-speeifie 5-aminolevulinic acid synthase ISC, iron-sulfur cluster. 

Defects in mitochondrial iron transport and utilization can result in mitochondrial iron overload. There is extensive iron accumulation in erythroblast mitochondria of both patients with X-linked sideroblastic anemia due to defective erythroid-speeifie 5-aminolevulinic acid synthase (eALAS) and those with ring sideroblasts associated with myelodysplastic syndrome. Mitochondrial iron overload has also been documented in patients with Friedreich s ataxia with defective frataxin" and in those with sideroblastic anemia with ataxia from defects in the Fe-S transporter ABC7. In addition, studies with yeast, the best studied eukaryotic model of Fe-S cluster synthesis, showed that defects in any of the enzymes of the Fe-S cluster assembly pathway caused mitochondrial iron accumulation and lack of normal mitochondrial function. ... 

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