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: 2.71). 05/1995; 27(2):169-79. DOI: 10.1007/BF02110032
Source: PubMed

ABSTRACT 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.

  • Source
    • "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 . "
  • Source
    • "This process regulates cellular Na + /K + concentrations and hence their gradients across the plasma membrane, which are required for vital functions such as membrane co-transports, cell volume regulation and membrane excitability (Jorgensen, 1986; Doucet, 1988). In a recent report Ávila et al. (2006) described that the activity of d-ALAD, another thiol-containing enzyme that catalyzes the condensation of two aminolevulinic acid molecules with the formation of porphobilinogen, which is a heme precursor (Jaffe, 1995), was decreased by diethyl 2-phenyl-2-tellurophenyl vinylphosphonate in brain, liver and kidney of rats. Of particular toxicological importance , d-ALA-D inhibition may impair heme biosynthesis and can result in the accumulation of aminolevulinic acid (ALA), which has some prooxidant activity (Bechara et al., 1993; Emanuelli et al., 2001). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The objective of this study was to verify the effect of the organochalcogen 3-butyl-1-phenyl-2-(phenyltelluro)oct-en-1-one on some parameters of oxidative stress in the brain of 10-day-old rats. Cerebral cortex was incubated for 1h in the presence or absence of 1, 10 or 30 microM of 3-butyl-1-phenyl-2-(phenyltelluro)oct-en-1-one and thiobarbituric acid reactive substances (TBARS), carbonyl, sulfhydryl, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione S-transferase (GST), nitric oxide (NO) production and the release of the cytosolic enzyme lactate dehydrogenase (LDH) were measured. The organotellurium was not capable to alter TBARS and carbonyl assays. In contrast, the compound at 10 and 30 microM provoked a reduced of protein thiol groups measured by the sulfhydryl assay. Furthermore, the activity of the antioxidant enzyme CAT (10 and 30 microM) and GPx (1, 10 and 30 microM) was reduced by the organochalcogen. On the other hand, the activity of SOD and GST were enhanced respectively by 1, 10 and 30 microM of the compound. Furthermore, NO production was also increased by 30muM of this organochalcogen. Finally, we verified that the organotellurium was capable of enhance the LDH release at 30 microM concentration. Our findings indicate that this organotellurium compound induces in vitro oxidative stress in the cerebral cortex of rats being potentially toxic for the brain of rats.
    Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 02/2009; 47(4):745-51. DOI:10.1016/j.fct.2009.01.004 · 2.61 Impact Factor
  • Source
    • "The δ-ALA-D enzyme is essential for all aerobic organisms and takes part in the route of formation of tetrapirrolic molecules (heme and chlorophyll). The main importance of these compounds is their function as prosthetic groups of proteins, such as hemoglobin, myoglobin, cytrochromes, catalase and peroxidase [1]. This enzyme is sensitive to oxidant agents in vitro and also can be decreased in situations associated with oxidative stress, including diabetes [2] [3] [4]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: This study analyzed the influence of type 2 diabetes mellitus and primary hypothyroidism on the activity of the delta-aminolevulinate dehydratase (δ-ALA-D) in human blood. Design and methods: δ-ALA-D enzyme activity was determined in normal (healthy) people (n = 29), compensated (DMC, n = 11) and non-compensated diabetic patients (NDMC, n = 23), and in patients with compensated (CH, n = 19) and non-compensated primary hypothyroidism (NCH, n = 10). The determination of lead, copper, zinc and magnesium was performed by graphite furnace atomic absorption spectrometry. Results: This study shows that δ-ALA-D activity was decreased (P < 0.05) in situations associated to hyperglycemia maintained for long periods (HbA 1c high). Another finding of this study suggests that states of hypofunction of the thyroid gland, when non-compensated, increase the activity of δ-ALA-D (P < 0.001). In addition, copper was elevated in HNC, zinc was diminished in DMC, HC and HNC, and magnesium was diminished in the HNC group. Conclusion: This result points out that there is a correlation among diabetes, hypothyroidism and δ-ALA-D activity.
    Clinical Biochemistry 02/2007; · 2.28 Impact Factor
Show more