A method for determining δ-aminolevulinic acid synthase activity in homogenized cells and tissues

Bergonia, Hector A.; Franklin, Michael R.; Kushner, James P.; Phillips, John D.

doi:10.1016/j.clinbiochem.2015.04.023

Cited by 13 publications

(13 citation statements)

References 31 publications

(35 reference statements)

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“…For example, two glycine residues (Gly219 and Gly257) as well as an arginine (Arg258) and a histidine (His179) (both positively charged) are all involved in stabilizing binding to the phosphate moiety of PLP in the enzyme lysine decarboxylase [84]. Mitochondrial δ-aminolevulinic acid synthase (the rate limiting enzyme in pyrrole synthesis) requires pyridoxal phosphate as a cofactor [85], and it has a GxGxxG motif beginning at residue 274 (GAGAGG) and a glycine-rich sequence beginning at residue 417 (GLYGARGGG). It may be that glyphosate’s mechanism of inhibition of this enzyme [58] involves glycine substitution at the phosphate-binding site.…”

Section: Glyphosate and Phosphate Bindingmentioning

confidence: 99%

Glyphosate’s Synergistic Toxicity in Combination with Other Factors as a Cause of Chronic Kidney Disease of Unknown Origin

Gunatilake

Seneff

Orlando

2019

IJERPH

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Chronic kidney disease of unknown etiology (CKDu) is a global epidemic. Sri Lanka has experienced a doubling of the disease every 4 or 5 years since it was first identified in the North Central province in the mid-1990s. The disease primarily affects people in agricultural regions who are missing the commonly known risk factors for CKD. Sri Lanka is not alone: health workers have reported prevalence of CKDu in Mexico, Nicaragua, El Salvador, and the state of Andhra Pradesh in India. A global search for the cause of CKDu has not identified a single factor, but rather many factors that may contribute to the etiology of the disease. Some of these factors include heat stroke leading to dehydration, toxic metals such as cadmium and arsenic, fluoride, low selenium, toxigenic cyanobacteria, nutritionally deficient diet and mycotoxins from mold exposure. Furthermore, exposure to agrichemicals, particularly glyphosate and paraquat, are likely compounding factors, and may be the primary factors. Here, we argue that glyphosate in particular is working synergistically with most of the other factors to increase toxic effects. We propose, further, that glyphosate causes insidious harm through its action as an amino acid analogue of glycine, and that this interferes with natural protective mechanisms against other exposures. Glyphosate’s synergistic health effects in combination with exposure to other pollutants, in particular paraquat, and physical labor in the ubiquitous high temperatures of lowland tropical regions, could result in renal damage consistent with CKDu in Sri Lanka.

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Section: Glyphosate and Phosphate Bindingmentioning

confidence: 99%

Glyphosate’s Synergistic Toxicity in Combination with Other Factors as a Cause of Chronic Kidney Disease of Unknown Origin

Gunatilake

Seneff

Orlando

2019

IJERPH

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“…δ -ALAD inhibition due to thiol group oxidation leads to δ -ALA autoxidation, further δ -ALAD inhibition, additional O 2 ·- generation, and antioxidant system depletion [26, 46]. Excess δ -ALA in the brain disrupts γ -aminobutyric acid/glutamate system causing neurotoxicity and cell death [19, 46] while decreased heme biosynthesis is known to cause neuronal cell dysfunction, since heme is critical for neuronal cell growth, differentiation, and survival [47]. Literature data show that Ni is especially prone to bind to amino acids like cysteine and histidine, small peptides like glutathione, and amine-containing compounds thus accelerating the rate of oxidative damage [28].…”

Section: Discussionmentioning

confidence: 99%

Effect of Zinc on the Oxidative Stress Biomarkers in the Brain of Nickel-Treated Mice

Šulinskienė

Bernotienė

Baranauskienė

et al. 2019

Oxidative Medicine and Cellular Longevity

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The overexposure to nickel due to the extensive use of it in modern technology remains a major public health concern. The mechanisms of pathological effects of this metal remain elusive. The present study was devoted to evaluate the effect of nickel on the oxidative state of the brain cells of mice and to assess whether zinc as redox state modulator could efficiently protect cells against nickel’s neurotoxicity. As oxidative stress biomarkers in the present study, we have measured the concentrations of reduced glutathione, metallothioneins, and malondialdehyde and the activity of the enzyme δ-aminolevulinate dehydratase. For the single metal exposure, mice were i.p. injected once with solutions of NiCl2 and/or ZnSO4; repeated exposure was performed i.p. injecting metal salt solutions for 14 days (once a day). The control mice received i.p. injections of saline. Results of our study demonstrate that single and 14 days of Ni2+ exposure decreased reduced glutathione and increased malondialdehyde contents in the brain of mice. Repeated Ni2+ administration significantly inhibited δ-aminolevulinate dehydratase while increasing brain metallothionein concentration at both exposure periods. Zinc exhibited a protective effect against nickel-induced glutathione and lipid peroxidation in brain cells of mice at both intervals of time, while repeated exposure to this metal significantly raised the brain metallothionein content. Repeated Zn2+ pretreatment protected δ-aminolevulinate dehydratase from Ni2+-induced inhibition and significantly increased metallothionein concentration at both investigated time intervals.

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“…In this context, enzymatic assays, conducted using tissue samples, play only a minor role in the routine diagnosis and management of porphyrias and remain limited to research procedures [79]. This is the case of mitochondrial enzymes, such as ALAS1, CPOX, PPOX, and FECH, which require Epstein-Barr virus-immortalized lymphoblastoid cell lines to dose their activities or HPLC assays to increase the sensitivity [80][81][82][83][84]. On the other hand, the quantification of porphyrins in body fluids is feasible and the preferred choice for the differential diagnosis of porphyrias.…”

Section: Enzymatic Assaysmentioning

confidence: 99%

Laboratory Diagnosis of Porphyria

et al. 2021

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Porphyrias are a group of diseases that are clinically and genetically heterogeneous and originate mostly from inherited dysfunctions of specific enzymes involved in heme biosynthesis. Such dysfunctions result in the excessive production and excretion of the intermediates of the heme biosynthesis pathway in the blood, urine, or feces, and these intermediates are responsible for specific clinical presentations. Porphyrias continue to be underdiagnosed, although laboratory diagnosis based on the measurement of metabolites could be utilized to support clinical suspicion in all symptomatic patients. Moreover, the measurement of enzymatic activities along with a molecular analysis may confirm the diagnosis and are, therefore, crucial for identifying pre-symptomatic carriers. The present review provides an overview of the laboratory assays used most commonly for establishing the diagnosis of porphyria. This would assist the clinicians in prescribing appropriate diagnostic testing and interpreting the testing results.

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A method for determining δ-aminolevulinic acid synthase activity in homogenized cells and tissues

Cited by 13 publications

References 31 publications

Glyphosate’s Synergistic Toxicity in Combination with Other Factors as a Cause of Chronic Kidney Disease of Unknown Origin

Glyphosate’s Synergistic Toxicity in Combination with Other Factors as a Cause of Chronic Kidney Disease of Unknown Origin

Effect of Zinc on the Oxidative Stress Biomarkers in the Brain of Nickel-Treated Mice

Laboratory Diagnosis of Porphyria

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