scholarly journals Heme biosynthesis depends on previously unrecognized acquisition of iron-sulfur cofactors in human amino-levulinic acid dehydratase

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Gang Liu ◽  
Debangsu Sil ◽  
Nunziata Maio ◽  
Wing-Hang Tong ◽  
J. Martin Bollinger ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Levulinic Acid ◽  
Biosynthetic Pathway ◽  
Aminolevulinic Acid ◽  
Heme Biosynthesis ◽  
Second Step ◽  
Iron Sulfur Cluster ◽  
Iron Sulfur ◽  
Acid Dehydratase ◽  
Amino Levulinic Acid

AbstractHeme biosynthesis and iron-sulfur cluster (ISC) biogenesis are two major mammalian metabolic pathways that require iron. It has long been known that these two pathways interconnect, but the previously described interactions do not fully explain why heme biosynthesis depends on intact ISC biogenesis. Herein we identify a previously unrecognized connection between these two pathways through our discovery that human aminolevulinic acid dehydratase (ALAD), which catalyzes the second step of heme biosynthesis, is an Fe-S protein. We find that several highly conserved cysteines and an Ala306-Phe307-Arg308 motif of human ALAD are important for [Fe4S4] cluster acquisition and coordination. The enzymatic activity of human ALAD is greatly reduced upon loss of its Fe-S cluster, which results in reduced heme biosynthesis in human cells. As ALAD provides an early Fe-S-dependent checkpoint in the heme biosynthetic pathway, our findings help explain why heme biosynthesis depends on intact ISC biogenesis.

Dependence of heme biosynthesis on iron-sulfur cluster biogenesis: human ALAD is an unrecognized iron-sulfur protein

2020 ◽  
Author(s):  
Gang Liu ◽  
Debangsu Sil ◽  
Wing-Hang Tong ◽  
Nunziata Maio ◽  
J. Martin Bollinger ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Biosynthetic Pathway ◽  
Aminolevulinic Acid ◽  
Heme Biosynthesis ◽  
Second Step ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Sulfur Protein ◽  
Iron Sulfur Protein

Abstract Heme biosynthesis and iron-sulfur cluster (ISC) biogenesis are two major mammalian metabolic pathways that require iron. It has long been known that these two pathways interconnect, but the previously described interactions do not fully explain why heme biosynthesis depends on intact ISC biogenesis. Herein we have identified a previously unrecognized connection between these two pathways through our discovery that human aminolevulinic acid dehydratase (ALAD), which catalyzes the second step of heme biosynthesis, is an Fe-S protein. We found that several highly conserved cysteines and an Ala306-Phe307-Arg308 motif of human ALAD are important for [Fe4S4] cluster acquisition and coordination. The enzymatic activity of human ALAD was greatly reduced upon loss of its Fe-S cluster, which resulted in reduced heme biosynthesis in human cells. Our findings explain why heme biosynthesis depends on intact ISC biogenesis, as ALAD provides an early Fe-S-dependent checkpoint in the heme biosynthetic pathway.

δ-Amino Levulinic Acid Dehydratase Activity of Fish Blood as an Indicator of a Harmful Exposure to Lead

1976 ◽  
Vol 33 (2) ◽  
pp. 268-271 ◽  
Author(s):  
Peter V. Hodson
Keyword(s):  
Levulinic Acid ◽  
Significant Inhibition ◽  
Salmo Gairdneri ◽  
Short Term ◽  
Acid Dehydratase ◽  
Amino Levulinic Acid ◽  
Fish Blood ◽  
Dehydratase Activity ◽  
Harmful Effects

The activity of red cell δ-amino levulinic acid dehydratase of rainbow trout (Salmo gairdneri) was depressed after exposure of the fish to lead. Concentrations of lead in water as low as 13 μg/liter caused a significant inhibition of activity after only 4-wk exposure. Assays of this enzyme’s activity may provide a short-term indication of long-term harmful effects of lead.

Use of Blood Lead and Erythrocyte θ-Amino Levulinic Acid Dehydratase Activity to Detect Lead Exposure of Fish Populations

1983 ◽  
Vol 15 (S1) ◽  
pp. 17-21
Author(s):  
P V Hodson
Keyword(s):  
Lead Exposure ◽  
Levulinic Acid ◽  
Blood Lead ◽  
Fish Populations ◽  
Whole Body ◽  
Human Populations ◽  
Lead Uptake ◽  
Acid Dehydratase ◽  
Amino Levulinic Acid ◽  
Dehydratase Activity

The measurement of blood lead concentrations and inhibition of erythrocyte θ-amino levulinic acid dehydratase activity (ALA-D) has been used successfully to diagnose lead exposure in human populations. While blood lead is one of the best indicators of lead exposure, its measurement is expensive, time consuming, subject to bias through contamination and requires highly skilled personnel. The advantages of assaying ALA-D activity are those of cost, speed, sample size and simplicity. Since most organisms possess this enzyme in a variety of tissues, and since its activity is inhibited only by lead, there is potentially a large variety of aquatic species that may be used to monitor “biologically available” lead in aquatic ecosystems. Sessile and migratory species could integrate short-term fluctuations in waterborne lead and provide data on spatial and temporal variations. Fish are convenient organisms to sample and fish blood is a particularly rich source of ALA-D. Laboratory experiments have defined the optimum conditions for blood sampling and assaying ALA-D activity as well as the strong negative correlation between blood lead concentrations and ALA-D activity and between waterborne lead concentrations and ALA-D activity. Other toxic metals (e.g. Cu, Hg, Zn, Cd) and PCB's do not inhibit ALA-D, and factors that increase lead toxicity (e.g. decreased environmental pH) also increase lead uptake and the inhibition of ALA-D. Consequently, ALA-D activity provides a measure of both exposure and effect. Species variation in rates of lead uptake allows a selection of a suitable monitoring species for a given, situation. Preliminary surveys of Lake Ontario fish populations indicate that monitoring of ALA-D activity is technically simple and straightforward, the assay is much cheaper and faster than blood lead or whole body lead analyses, and activity is correlated to other measures of lead in fish.

The third case of Doss porphyria (δ-amino-levulinic acid dehydratase deficiency) in Germany

2004 ◽  
Vol 27 (4) ◽  
pp. 529-536 ◽  
Author(s):  
M. O. Doss ◽  
T. Stauch ◽  
U. Gross ◽  
M. Renz ◽  
R. Akagi ◽  
...  
Keyword(s):  
Levulinic Acid ◽  
The Third ◽  
Acid Dehydratase ◽  
Amino Levulinic Acid

scholarly journals The Monothiol Single-Domain Glutaredoxin Is Conserved in the Highly Reduced Mitochondria of Giardia intestinalis

2009 ◽  
Vol 8 (10) ◽  
pp. 1584-1591 ◽  
Author(s):  
Petr Rada ◽  
Ondřej Šmíd ◽  
Robert Sutak ◽  
Pavel Doležal ◽  
Jan Pyrih ◽  
...  
Keyword(s):  
Biosynthetic Pathway ◽  
Immunofluorescence Microscopy ◽  
Giardia Intestinalis ◽  
Cluster Assembly ◽  
Mature Protein ◽  
Iron Sulfur Cluster ◽  
Iron Sulfur ◽  
Processing Peptidase ◽  
Mitochondrial Origin ◽  
Active Site Sequence

ABSTRACT The highly reduced mitochondria (mitosomes) of Giardia intestinalis are recently discovered organelles for which, it was suggested, iron-sulfur cluster assembly was their only conserved function. However, only an incomplete set of the components required for FeS cluster biogenesis was localized to the mitosomes. Via proteomic analysis of a mitosome-rich cellular fraction together with immunofluorescence microscopy, we identified a novel mitosomal protein homologous to monothiol glutaredoxins containing a CGFS motif at the active site. Sequence analysis revealed the presence of long nonconserved N-terminal extension of 77 amino acids, which was absent in the mature protein. Expression of the complete and N-terminally truncated forms of the glutaredoxin indicated that the extension is involved in glutaredoxin import into mitosomes. However, the mechanism of preprotein processing is unclear, as the mitosomal processing peptidase is unable to cleave this type of extension. The recombinant mature protein was shown to form a homodimeric structure, which binds a labile FeS cluster. The cluster is stabilized by glutathione and dithiothreitol. Phylogenetic analysis showed that giardial glutaredoxin is related to the mitochondrial monothiol glutaredoxins involved in FeS cluster assembly. The identification of a mitochondrial-type monothiol glutaredoxin in the mitosomes of G. intestinalis thus completes the mitosomal FeS cluster biosynthetic pathway and provides further evidence for the mitochondrial origin of these organelles.

Delta-amino-levulinic acid dehydratase gene and essential tremor

2017 ◽  
Vol 47 (5) ◽  
pp. 348-356 ◽  
Author(s):  
José A. G. Agúndez ◽  
Elena García-Martín ◽  
Hortensia Alonso-Navarro ◽  
Pedro Ayuso ◽  
Gara Esguevillas ◽  
...  
Keyword(s):  
Essential Tremor ◽  
Levulinic Acid ◽  
Acid Dehydratase ◽  
Amino Levulinic Acid

scholarly journals The role and properties of the iron-sulfur cluster in Escherichia coli dihydroxy-acid dehydratase

1993 ◽  
Vol 268 (20) ◽  
pp. 14732-14742
Author(s):  
D.H. Flint ◽  
M.H. Emptage ◽  
M.G. Finnegan ◽  
W. Fu ◽  
M.K. Johnson
Keyword(s):  
Escherichia Coli ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Dihydroxy Acid ◽  
Iron Sulfur ◽  
Acid Dehydratase

Estimation of urinary delta aminolevulinic acid levels in gasoline and petrol pump workers as an index of lead exposure

2022 ◽  
Vol 8 (4) ◽  
pp. 274-277
Author(s):  
Sachin Patharkar ◽  
Neelam Patil ◽  
Siddhesh Thorat ◽  
Alka Nerurkar ◽  
Umesh Shinde ◽  
...  
Keyword(s):  
Lead Poisoning ◽  
Lead Exposure ◽  
Levulinic Acid ◽  
Aminolevulinic Acid ◽  
Petroleum Products ◽  
Safety Measures ◽  
Amino Levulinic Acid ◽  
Main Components ◽  
Urinary Ala ◽  
Petrol Pump

Lead poisoning is a phenomenon which with growing globalization is being a subject of worry.ALA i.e Amino levulinic acid is a precursor of hemoglobin, which is synthesized in mitochondria by two main components succinyl Co-A and glycine in presence of ALA-S i.e. amino levulinic acid-synthase. Urinary ALA (ALA-U) has been a recommended biomarker for lead exposure. Inhibition of Amino levulinic acid-dehydratase (ALA-D) results into activation of ALA-S which further synthesizes ALA, excess of ALA is accumulated in the blood, plasma, urine. Present manuscript is focused on the estimation of levels of ALA in the urine of gasoline and pertol pump workers, by acidifying the urine to extract out ALA and reading it colorimetrically as they are exposed to fumes released by gasoline, petrol, and petroleum products which contains lead. Awareness and safety measures such as protective masks and gears should be provided by the respective organisations to the workers.

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