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PubMed1986

Generation of active oxygen species during coupled autoxidation of oxyhemoglobin and delta-aminolevulinic acid.

The conversion of oxyhemoglobin to methemoglobin has been shown via spectrophotometric, circular dichroism and polarographic studies to be accelerated by delta-aminolevulinic acid, a major heme-precursor accumulated in a number of heme-linked pathologies. Concomitantly, delta-aminolevulinic acid undergoes aerobic oxidation. The intermediacy of oxygen radicals in these processes was evidenced by the inhibitory effect of catalase, superoxide dismutase and mannitol. These results are relevant to the exacerbated production of active oxygen species in intermittent acute porphyria and saturnism carriers.

Aminolevulinic Acid↗
PubMed1984

The effect of delta-aminolaevulinic acid on the high affinity uptake of aspartic acid by rat brain synaptosomes.

delta-Aminolaevulinic (delta-ALA) acid is an analogue of GABA, glutamate and aspartate. High affinity GABA uptake by synaptosomes is inhibited by delta-ALA in a competitive fashion at high concentrations (greater than 0.5 mM). Glutamate uptake is inhibited in a non-competitive fashion at all delta-ALA concentrations (0.05-2.0 mM). High affinity aspartate uptake is inhibited in a non-competitive fashion at high concentration (greater than 1.0 mM) but exhibits a curve which resembles that for the inhibition of GABA uptake. The different interactions between delta-ALA, glutamate and aspartate may be evidence for a separate transport system for aspartate.

Aminolevulinic Acid↗
PubMed1992

5-Chlorolevulinate modification of porphobilinogen synthase identifies a potential role for the catalytic zinc.

Porphobilinogen synthase (PBGS) is a Zn(II) metalloenzyme which catalyzes the asymmetric condensation of two molecules of 5-aminolevulinate (ALA). The nitrogen of the first substrate ends up in the pyrrole ring of product (P-side ALA); by contrast, the nitrogen of the second substrate molecule remains an amino group (A-side ALA). A reactive mimic of the substrate molecules, 5-chlorolevulinate (5-CLA), has been prepared and used as an active site directed irreversible inhibitor of PBGS. Native octameric PBGS binds eight substrate molecules and eight Zn(II) ions, with two types of sites for each ligand. As originally demonstrated by Seehra and Jordan [(1981) Eur. J. Biochem. 113, 435-446], 5-CLA inactivates the enzyme at the site where one of the two substrate molecules binds, and modification at four sites per octamer (one per active site) affords near-total inactivation. Here we report that 5-CLA-modified PBGS (5-CLA-PBGS) can bind up to four substrate molecules and four Zn(II) ions. Contrary to the conclusion of Seehra and Jordan, we find that the preferential site of 5-CLA inactivation is the A-side ALA binding site. On the basis of the dissociation constants, the metal ion binding sites lost upon 5-CLA modification are assigned to the four catalytic Zn(II) sites. 5-CLA-PBGS is shown to be modified at cysteine-223 on half of the subunits. We conclude that cysteine-223 is near the amino group of A-side ALA and propose that this cysteine is a ligand to the catalytic Zn(II). The vacant substrate binding site on 5-CLA-PBGS is that of P-side ALA. We have used 13C and 15N NMR to view [4-13C]ALA and [15N]ALA bound to 5-CLA-PBGS. The NMR results are nearly identical to those obtained previously for the enzyme-bound P-side Schiff base intermediate [Jaffe et al. (1990) Biochemistry 29, 8345-8350]. It appears that, in the absence of the catalytic Zn(II), 5-CLA-PBGS does not catalyze the condensation of the amino group of the P-side Schiff base intermediate with the C4 carbonyl derived from 5-CLA. On this basis we propose that Zn(II) plays an essential role in formation of the first bond between the two substrate molecules.

Amino Acid Sequence↗
PubMed1971

Repression of the overproduction of porphyrin precursors in acute intermittent porphyria by intravenous infusions of hematin.

In a patient with a severe attack of acute intermittent porphyria, hematin given intravenously caused marked diminution of serum delta-aminolevulinic acid and porphobilinogen. The decline of aminolevulinate was more rapid than that of porphobilinoge. After 2 days of hematin administration, about 5 days were required for delta-aminolevulinic acid, and 11 days for porphobilinogen to return to the concentrations that were detected before treatment. Urinary excretion of both compounds also decreased after hematin administration. Considerable amounts of porphobilinogen were also found in the cerebrospinal fluid of the patient.

Adult↗
PubMed1988

Blood lead and maximal urinary excretion of delta-aminolevulinic acid.

Reliability and ease of use are certainly the two major qualities of a screening test or medical surveillance in the workplace. The advantages of using a reliable urinary test thus are evident: the sampling is easy, rapid, noninvasive and, therefore, well accepted. Screening tests or medical surveillance can measure the toxic chemical itself, its metabolites or its consequences on metabolism. In this study the relation between blood lead levels--the most commonly used test for screening and surveillance of saturnism--and urinary excretion of delta-aminolevulinic acid (ALA-U) was measured. The original part of this study is that it takes into account the chronobiology of ALA-U excretion. The samples are collected in the afternoon when ALA urinary excretion is at its highest level. Using a 5 mg/g of creatinine level as a threshold to detect blood lead levels equal to or higher than 60 micrograms/dL the test has an 88% sensitivity, a 91% specificity and a 37% positive predictive value. No worker whose blood lead level is equal to or higher than 65 micrograms/dL has been missed. It is suggested that using 5 mg of ALA-U/g of creatinine as a threshold to prescreen workers who should have their blood lead level measured could be useful in workplaces where lead exposure is moderate or low.

Adult↗
PubMed1977

Studies in porphyria. VI. Biosynthesis of porphyrins in mammalian skin and in the skin of porphyric patients.

Porphyrin biosynthesis in mammalian skin and in skin obtained from patients with selected types of porphyria has been studied. Cutaneous porphyrinogenesis required the precursor delta-aminolevulinic acid (ALA) which, when added to murine, rat, and human skin in vitro, was rapidly converted to porphyrins. Total porphyrin content was quantitated by fluorescence assay, and spectral studies indicated that more than 80% of the porphyrin produced was protoporphyrin. The majority of skin porphyrinogenesis occurrred in epidermis or in epidermal derivatives such as hair roots. Known inducers of hepatic delta-aminolevulinic acid synthetase (ALAS), the rate-limiting enzyme for heme biosynthesis, were not inducers when added to skin in vitro. Skin from patients with acute intermittent porphyria demonstrated a 43% decrease in cutaneous porphyrin production as compared to unaffected normals. This is consistent with the known deficiency of uroporphyrinogen synthetase that has been previously demonstrated in the liver and red blood cells of these patients. Porphyrinogenesis in skin of patients with porphyria cutanea tarda was not different from controls. These studies demonstrate that skin has the enzymatic capacity to synthesize porphyrins from added ALA and that cutaneous porphyrinogenesis from ALA is deficient in patients with acute intermittent porphyria.

Allylisopropylacetamide↗
PubMed1966

Coordinate synthesis of heme and apoenzyme in the formation of tryptophan pyrrolase.

Reciprocal control mechanisms between hemoprotein and 8-aminolevulinic acid synthetase take part in coordinate synthesis of the heme and apoenzyme moieties of tryptophan pyrrolase. Stimulation of heme biosynthesis increases tryptophan pyrrolase, whereas enhancement of heme binding by apotryptophan pyrrolase secondarily increases the formation of delta-aminolevulinic acid synthetase, the rate-limiting enzyme in heme formation. Tryptophan-mediated induction of delta-aminolevulinic acid synthetase suggests that heme participates in repression of that enzyme

Amino Acids↗
PubMed1983

Biosynthesis of 5-aminolevulinic acid and heme from 4,5-dioxovalerate in the rat.

We previously demonstrated an alternate pathway for the biosynthesis of 5-aminolevulinic acid (ALA) in bovine liver mitochondria and of tetrapyrroles in suspensions of rat hepatocytes (1980. J. Biol. Chem. 255: 3742; 1981. Proc. Natl. Acad. Sci. USA. 78: 5335). This pathway involves a transamination reaction that incorporates the intact 5-carbon skeleton of 4,5-dioxovaleric acid (DOVA) into ALA. We investigated this alternate pathway in vivo by the intraperitoneal injection of DOVA into rats. Incorporation of DOVA and [5-14C]DOVA into urinary ALA and hepatic and erythroid heme was quantified and compared with the incorporation of [4-14C]ALA and [2-14C]glycine into heme. Within 3 h of injection of 175 mumol of DOVA, urinary ALA excretion increased 2.4-fold over controls. After injection of [5-14C]DOVA, 0.11% of the radioactivity was recovered as urinary ALA, which quantitatively accounted for the 2.4-fold increase in ALA excretion. After the injection 175 mumol of [5-14C]DOVA, 0.14% of the radioactivity was recovered after 3 h as hepatic heme. The injection of 1.75 mmol of [2-14C]glycine or 175 mumol of [4-14C]ALA resulted in recovery of 0.2 and 3.4%, respectively, of the radioactivity as hepatic heme after 3 h. These doses of radiolabeled DOVA, glycine, and ALA were injected into rats with phenylhydrazine-induced anemia. Recovery of radioactivity after 3 h as splenic (erythroid) heme was 0.35% for DOVA, 0.072% for glycine, and 0.25% for ALA. These studies establish that the intact 5-carbon skeleton of DOVA can be incorporated into ALA and heme in vivo.

Aminolevulinic Acid↗
PubMed1975

[Vergleichende Untersuchungen mit (14c)5-Aminolävulinat und (14c)Uroporphyrinogen (author's transl)].

Cell-free extracts from Clostridium tetanomorphum, a microorganism which synthesizes corrins but no heme, are capable of converting both 5-aminolevulinate and uroporphyrinogen III into cobyrinic acid. Comparative examinations with (14C)5-aminolevulinate and (14C)uroporphyrinogen yielded corresponding results. Cell-free extracts from Clostridium tetanomorphum contain uroporphyrinogen III. To obtain good radiochemical yields it is therefore necessary to use substrates of high specific radioactivity. A method for the preparation of 14C-labelled uroporphyrin I-IV with high specific radioactivity is described.

Aminolevulinic Acid↗