Porphobilinogen synthase, the first source of Heme's asymmetry

Jaffe, Eileen K.

doi:10.1007/bf02110032

Cited by 146 publications

(147 citation statements)

References 65 publications

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“…The mechanism of oxidation of thiol groups in low-and high-molecular weight molecules by selenium varies with the chemical structure of the compounds and can involve the formation of selenoxides, selenotrisulfides and selenylsulfide (10,11). OS compounds such as selenocystine and a variety of diselenides can react with thiols such as cysteine, dithiothreitol (DTT) and reduced glutathione (GSH) to produce selenocysteine and selenols, respectively, and disulfides.…”

Section: Toxicologymentioning

confidence: 99%

“…OS compounds such as selenocystine and a variety of diselenides can react with thiols such as cysteine, dithiothreitol (DTT) and reduced glutathione (GSH) to produce selenocysteine and selenols, respectively, and disulfides. The interaction between DPDS and thiol groups has been investigated in several biological models, such as the enzyme Interaction with δ δ δ δ δ-aminolevulinate dehydratase ALA-D, or porphobilinogen synthase, is an enzyme sensitive to sulfydryl (SH)-blocking agents that participates in the second step of heme, chlorophyll and corrin biosynthesis (11,12). It catalyzes the condensation of two molecules of 5-aminolevulinic acid to porphobilinogen, thus playing an essential role in animals and photosynthetic organisms (11,12).…”

Section: Toxicologymentioning

confidence: 99%

“…The interaction between DPDS and thiol groups has been investigated in several biological models, such as the enzyme Interaction with δ δ δ δ δ-aminolevulinate dehydratase ALA-D, or porphobilinogen synthase, is an enzyme sensitive to sulfydryl (SH)-blocking agents that participates in the second step of heme, chlorophyll and corrin biosynthesis (11,12). It catalyzes the condensation of two molecules of 5-aminolevulinic acid to porphobilinogen, thus playing an essential role in animals and photosynthetic organisms (11,12). ALA-D inhibition inhibits heme biosynthesis, resulting in accumulation of aminolevulinic acid, which affects aerobic metabolism, and has some pro-oxidant activity (13).…”

Section: Toxicologymentioning

confidence: 99%

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Pharmacology and toxicology of diphenyl diselenide in several biological models

Rosa

Roesler

Braga

et al. 2007

Braz J Med Biol Res

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The pharmacology of synthetic organoselenium compounds indicates that they can be used as antioxidants, enzyme inhibitors, neuroprotectors, anti-tumor and anti-infectious agents, and immunomodulators. In this review, we focus on the effects of diphenyl diselenide (DPDS) in various biological model organisms. DPDS possesses antioxidant activity, confirmed in several in vitro and in vivo systems, and thus has a protective effect against hepatic, renal and gastric injuries, in addition to its neuroprotective activity. The activity of the compound on the central nervous system has been studied since DPDS has lipophilic characteristics, increasing adenylyl cyclase activity and inhibiting glutamate and MK-801 binding to rat synaptic membranes. Systemic administration facilitates the formation of long-term object recognition memory in mice and has a protective effect against brain ischemia and on reserpine-induced orofacial dyskinesia in rats. On the other hand, DPDS may be toxic, mainly because of its interaction with thiol groups. In the yeast Saccharomyces cerevisiae, the molecule acts as a pro-oxidant by depleting free glutathione. Administration to mice during cadmium intoxication has the opposite effect, reducing oxidative stress in various tissues. DPDS is a potent inhibitor of δ-aminolevulinate dehydratase and chronic exposure to high doses of this compound has central effects on mouse brain, as well as liver and renal toxicity. Genotoxicity of this compound has been assessed in bacteria, haploid and diploid yeast and in a tumor cell line.

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Section: Toxicologymentioning

confidence: 99%

Section: Toxicologymentioning

confidence: 99%

Section: Toxicologymentioning

confidence: 99%

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Pharmacology and toxicology of diphenyl diselenide in several biological models

Rosa

Roesler

Braga

et al. 2007

Braz J Med Biol Res

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“…Because most ALADs purified so far are octamers (22,23), an assessment of the oligomeric state of rPfALAD was made based on the gel filtration profile on a Superdex 200 analytical FPLC column. The results presented in Fig.…”

Section: Oligomeric Naturementioning

confidence: 99%

“…A considerable amount of literature exists on the metal cofactor requirement of ALAD from different sources (22)(23)(24)(25)(26)(27). The enzyme species are classified into five different types based on whether they require Zn 2ϩ (mammalian and yeast), Mg 2ϩ (plant, algae, and bacteria), or both (some bacteria).…”

Section: Effect Of Metal Ionsmentioning

confidence: 99%

δ-Aminolevulinic Acid Dehydratase from Plasmodium falciparum

Dhanasekaran

Chandra

Sagar

et al. 2004

Journal of Biological Chemistry

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The heme biosynthetic pathway of the malaria parasite is a drug target and the import of host ␦-aminolevulinate dehydratase (ALAD), the second enzyme of the pathway, from the red cell cytoplasm by the intra erythrocytic malaria parasite has been demonstrated earlier in this laboratory. In this study, ALAD encoded by the Plasmodium falciparum genome (PfALAD) has been cloned, the protein overexpressed in Escherichia coli, and then characterized. The mature recombinant enzyme (rPfALAD) is enzymatically active and behaves as an octamer with a subunit M r of 46,000. The enzyme has an alkaline pH optimum of 8.0 to 9.0. rPfALAD does not require any metal ion for activity, although it is stimulated by 20 -30% upon addition of Mg 2؉ . The enzyme is inhibited by Zn 2؉ and succinylacetone. The presence of PfALAD in P. falciparum can be demonstrated by Western blot analysis and immunoelectron microscopy. The enzyme has been localized to the apicoplast of the malaria parasite. Homology modeling studies reveal that PfALAD is very similar to the enzyme species from Pseudomonas aeruginosa, but manifests features that are unique and different from plant ALADs as well as from those of the bacterium. It is concluded that PfALAD, while resembling plant ALADs in terms of its alkaline pH optimum and apicoplast localization, differs in its Mg 2؉ independence for catalytic activity or octamer stabilization. Expression levels of PfALAD in P. falciparum, based on Western blot analysis, immunoelectron microscopy, and EDTA-resistant enzyme activity assay reveals that it may account for about 10% of the total ALAD activity in the parasite, the rest being accounted for by the host enzyme imported by the parasite. It is proposed that the role of PfALAD may be confined to heme synthesis in the apicoplast that may not account for the total de novo heme biosynthesis in the parasite.Studies in this laboratory had demonstrated that the malaria parasites (Plasmodium falciparum and Plasmodium berghei) are capable of heme biosynthesis de novo, despite acquiring large amounts of heme from the host red cell hemoglobin in the intraerythrocytic stage (1, 2). Inhibition of the de novo heme biosynthetic pathway leads to death of the parasite and the pathway is therefore a drug target (1-3). Studies on the enzymes of the heme-biosynthetic pathway have revealed that the first enzyme, ␦-aminolevulinate synthase, is coded for by the parasite genome and is localized in the parasite mitochondrion (4, 5). Studies from this laboratory have shown that the second enzyme of the pathway, ␦-aminolevulinate dehydratase (ALAD), 1 in the parasite is of host origin and evidence was provided to show that the enzyme is translocated (imported) from the host red cell into the parasite and is functional (2, 3).At the same time genome sequence data available for P. falciparum indicates that the parasite genome codes for ALAD (PfALAD) and other enzymes of the heme-biosynthetic pathway. Sato et al. (6) have shown by phylogenetic amino acid sequence analysis derived from truncated...

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5‐Aminolaevulinic Acid Dehydratase

Cooper

Erskine

2004

Handbook of Metalloproteins

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The enzyme 5‐aminolaevulinic acid dehydratase (ALAD, E.C.4.2.1.24), sometimes referred to as porphobilinogen synthase, catalyzes the second step in the biosynthesis of tetrapyrroles involving the condensation between two 5‐aminolaevulinic acid (ALA) molecules to form the pyrrole porphobilinogen (PBG). The X‐ray structures of several ALADs have been determined showing that the enzyme forms a large homo‐octameric structure with all eight active sites on the outer surface. Each subunit adopts the triose phosphate isomerase (TIM) barrel fold with an N‐terminal arm, which forms extensive intersubunit interactions. Pairs of monomers associate with their arms wrapped around each other to form compact dimers. Four dimers, which interact principally via their arm regions, form the octamer, which has a large solvent‐filled cavity in the center. The active site of each subunit is located in a pronounced cavity formed by loops at the C‐terminal ends of the strands forming the TIM barrel. In humans, hereditary deficiencies in ALAD give rise to the rare disease Doss porphyria, and the sensitivity of the enzyme to inhibition by lead ions is thought to be one of the main problems in acute lead poisoning. ALADs from many species (except plants and some bacteria) have a zinc ion at the active site, which has been implicated in the catalytic mechanism and is readily displaced by the inhibitor lead. These ALADs have a cysteine‐rich motif that coordinates the active site zinc ion (α‐site). In contrast, ALADs from plants and some bacteria have a number of mutations in the metal‐binding motif that replace the cysteine residues with other amino acids. Two of the cysteines are replaced by aspartate, which is thought to be more appropriate for coordination of magnesium ions, which these enzymes apparently require instead of zinc. Some ALADs have an additional zinc or magnesium binding site located between the subunits of the octamer (β‐site) that has more of a structural or activating role. Early inhibitor binding studies defined the interactions made by only one of the two substrate moieties (P‐side substrate) that bind to the enzyme during catalysis. Biochemical and crystallographic data showed that P‐side substrate binds by forming a Schiff base with the enzyme at Lys247 ( Escherichia coli ALAD numbering). Until very recently there has been little evidence that binding of the second substrate moiety (A‐side substrate) involves formation of a Schiff base with the enzyme. However, the structures of diacid inhibitors provided an improved definition of the interactions made by both the substrate molecules (A‐ and P‐side). The most intriguing result was the finding that 4,7‐dioxosebacic acid forms a second Schiff base with the enzyme involving Lys195 ( E. coli ALAD numbering), suggesting that A‐side substrate makes the same interaction during catalysis. This finding has been substantiated by the demonstration that the inhibitor 5‐fluorolaevulinic acid binds by making Schiff bases with both the active site lysine residues. Current proposals for the catalytic mechanism involve the binding of both substrate moieties by formation of Schiff bases with the active site lysines.

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Porphobilinogen synthase, the first source of Heme's asymmetry

Cited by 146 publications

References 65 publications

Pharmacology and toxicology of diphenyl diselenide in several biological models

Pharmacology and toxicology of diphenyl diselenide in several biological models

δ-Aminolevulinic Acid Dehydratase from Plasmodium falciparum

5‐Aminolaevulinic Acid Dehydratase

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