Porphobilinogen synthase, the first source of Heme's asymmetry

Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Journal of Bioenergetics (Impact Factor: 3.21). 05/1995; 27(2):169-79. DOI: 10.1007/BF02110032
Source: PubMed


Porphobilinogen is the monopyrrole precursor of all biological tetrapyrroles. The biosynthesis of porphobilinogen involves the asymmetric condensation of two molecules of 5-aminolevulinate and is carried out by the enzyme porphobilinogen synthase (PBGS), also known as 5-aminolevulinate dehydratase. This review documents what is known about the mechanism of the PBGS-catalyzed reaction. The metal ion constituents of PBGS are of particular interest because PBGS is a primary target for the environmental toxin lead. Mammalian PBGS contains two zinc ions at each active site. Bacterial and plant PBGS use a third metal ion, magnesium, as an allosteric activator. In addition, some bacterial and plant PBGS may use magnesium in place of one or both of the zinc ions of mammalian PBGS. These phylogenetic variations in metal ion usage are described along with a proposed rationale for the evolutionary divergence in metal ion usage. Finally, I describe what is known about the structure of PBGS, an enzyme which has as yet eluded crystal structure determination.

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    • "ALAD catalyses the condensation of two δ-aminolevulinic acid (ALA) molecules to form the pyrrole porphobilinogen (PBG). Four PBG molecules are linked together by porphobilinogen deaminase and then cyclized by uroporphyrinogen synthase to form uroporphyrinogen III, which can be further modified to produce different metallo-prosthetic groups such as heme, chlorophyll and vitamin B12.[78910] ALAD catalyzes the formation of an asymmetric pyrrole from two identical substrates. Single-turnover experiments have proven that the first substrate molecule entering the active site finally forms the propionate side of the product PBG and the second molecule forms the acetate side. "
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    ABSTRACT: Background: The emergence of multi drug‑resistant strains of Staphylococcus aureus, there is an urgent need for the development of new antimicrobials which are narrow and pathogen specific. Aim: In this context, the present study is aimed to have a control on the staphylococcal infections by targeting the unique and essential enzyme; porphobilinogen synthase (PBGS) catalyzes the condensation of two molecules of δ‑aminolevulinic acid, an essential step in the tetrapyrrole biosynthesis. Hence developing therapeutics targeting PBGS will be the promising choice to control and manage the staphylococcal infections. 4,5‑dioxovalerate (DV) is known to inhibit PBGS. Materials and Methods: In view of this, in this study, novel dioxovalerate derivatives (DVDs) molecules were designed so as to inhibit PBGS, a potential target of S. aureus and their inhibitory activity was predicted using molecular docking studies by molecular operating environment. The 3D model of PBGS was constructed using Chlorobium vibrioform (Protein Data Bank 1W1Z) as a template by homology modeling method. Results: The built structure was close to the crystal structure with Z score − 8.97. Molecular docking of DVDs into the S. aureus PBGS active site revealed that they are showing strong interaction forming H‑bonds with the active sites of K248 and R217. The ligand–receptor complex of DVD13 showed a best docking score of − 14.4555 kcal/mol among DV and all its analogs while the substrate showed docking score of − 13.0392 kcal/mol showing interactions with S199, K217 indicating that DVD13 can influence structural variations on the enzyme and thereby inhibiting the enzyme. Conclusion: The substrate analog DVD13 is showing significant interactions with active site of PBGS and it may be used as a potent inhibitor to control S. aureus infections.
    06/2014; 6(3). DOI:10.4103/0975-7406.135246
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    • "In order to confirm the induction of canal formation the expressions of the genes encoding the d - aminolevulinic acid dehydratase ( ALAD ; described here ) and the Iroquois homeobox pro - tein ( to be published ) were monitored . The enzyme ALAD catalyzes the synthesis of porphobilinogen from two molecules of d - aminolevulinic acid ( Jaffe , 1995 ) . Starting from porphobilinogen the end products of the tetrapyrrole pathway , such as heme , chlorophyll and corrins , are involved in a series of biosynthetic pathways , from electron transport to photosynthesis ( reviewed in : Cable et al . "

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    • "However, it is known that PBG-synthase contains two sites binding to zinc with different affinities (Dent et al., 1990). The B site of the enzyme binds Zn 2+ with relatively low affinity, and the maintenance of their sulfhydryl groups in a reduced state is fundamental for the enzyme activity (Jaffe, 1995, Barbosa et al., 1998). Zinc is an essential metal involved in several metabolic functions (Fang et al., 2002). "
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    ABSTRACT: This work evaluated the delayed effects of mercury and the effectiveness of zinc in preventing such effects. Pups were pre-treated with 1 daily dose of ZnCl(2) (27 mg/kg/day, by subcutaneous injections) from 3rd to 7th postnatal day and received 1 daily dose of 5 mg/kg of HgCl(2), for 5 subsequent days (8-12 days old). Animals were euthanized 21 days after the end of Hg-exposure. Porphobilinogen-synthase activity as well as zinc and mercury contents was determined in the liver and kidneys. Alanine aminotransferase, aspartate aminotransferase and lactic dehydrogenase activities as well as urea, creatinine and glucose levels were analyzed in plasma or serum. Some animals were considered more sensitive to mercury, since they did not recover the body weight gain and presented an increase of renal and hepatic mercury content, urea and creatinine levels; a decrease in renal porphobilinogen-synthase and alanine aminotransferase activities, as well as a decrease in the liver and an increase in kidney weights. Some animals were considered less sensitive to mercury because they recovered the body weight and presented no biochemical alterations in spite of mercury in the tissues. Zinc prevents partially or totally the alterations caused by mercury even those that persisted for a long time after the end of exposure. These findings suggest that there is difference among the animals regarding the sensitivity to mercury.
    Ecotoxicology and Environmental Safety 12/2010; 74(3):480-6. DOI:10.1016/j.ecoenv.2010.11.011 · 2.76 Impact Factor
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