Evaluation of Activity of Erythrocyte Pyrimidine 5'-Nucleotidase (P5N) in Lead Exposed Workers: With Focus on the Effect on Hemoglobin.

Kim, Yangho; Yoo, Changhee; Lee, Choong Ryeol; Lee, Ji Ho; Lee, Hun; Kim, Sung Ryul; Chang, Seoung Hoon; Lee, Won Jin; Hwang, Cheon Hyun; Lee, Young Hwan

doi:10.2486/indhealth.40.23

Cited by 14 publications

(5 citation statements)

References 12 publications

(15 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Historically, molecular toxicity was believed to be caused by the displacement of Zn 2+ or Ca 2+ by Pb 2+ ions, and various studies have since demonstrated that Pb 2+ can occupy binding sites for many physiologically essential metals, including: Mg 2+ in pyrimidine 5'-nucleotidase type 1 (135); Zn 2+ in 5-aminolevulinic acid dehydratase (ALAD) (136, 137), resulting in iron deficiency associated with anaemia; and Fe 2+ in divalent metal transporter-1 (DMT1), which appears to be involved in transport and uptake of Pb 2+ (138, 139). The Pb 2+ ion can also occupy Ca 2+ -binding sites, and/or displace Ca 2+ in many proteins, including voltage-gated calcium channels (VGCCs) (140), troponin C (98), CaM (32), PKC (58), parvalbumin (64), and synaptotagmin (40).…”

Section: A New Perspective For the Molecular Basis Of Pb2+ Toxicitymentioning

confidence: 99%

Defining potential roles of Pb²⁺in neurotoxicity from a calciomics approach

et al. 2016

View full text Add to dashboard Cite

Metal ions play crucial roles in numerous biological processes, facilitating biochemical reactions by binding to various proteins. An increasing body of evidence suggests that neurotoxicity associated with exposure to nonessential metals (e.g., Pb2+) involves disruption of synaptic activity, and these observed effects are associated with the ability of Pb2+ to interfere with Zn2+ and Ca2+-dependent functions. However, the molecular mechanism behind Pb2+ toxicity remains a topic of debate. In this review, we first discuss potential neuronal Ca2+ binding protein (CaBP) targets for Pb2+ such as calmodulin (CaM), synaptotagmin, neuronal calcium sensor-1 (NCS-1), N-methyl-D-aspartate receptor (NMDAR) and family C of G-protein coupled receptors (cGPCRs), and their involvement in Ca2+-signalling pathways. We then compare metal binding properties between Ca2+ and Pb2+ to understand the structural implications of Pb2+ binding to CaBPs. Statistical and biophysical studies (e.g., NMR and fluorescence spectroscopy) of Pb2+ binding are discussed to investigate the molecular mechanism behind Pb2+ toxicity. These studies identify an opportunistic, allosteric binding of Pb2+ with CaM that is distinct from ionic displacement. Together, this data suggests three potential modes of Pb2+ activity related to molecular and/or neural toxicity: (i) Pb2+ can occupy Ca2+-binding sites, inhibiting the activity of the protein by structural modulation, (ii) Pb2+ can mimic Ca2+ in the binding sites, falsely activating the protein and perturbing downstream activities, or (iii) Pb2+ binds outside of the Ca2+-binding sites, resulting in allosteric modulation of the proteins activity. Moreover, the data further suggest that even low concentrations of Pb2+ can interfere at multiple points within the neuronal Ca2+ signalling pathways to cause neurotoxicity.

show abstract

Section: A New Perspective For the Molecular Basis Of Pb2+ Toxicitymentioning

confidence: 99%

Defining potential roles of Pb²⁺in neurotoxicity from a calciomics approach

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Pb 2+ has been found to displace Mg 2+ in pyrimidine 5'-nucleotidase type 1 [13], inhibiting the activity of the enzyme. This decreased activity results in increased concentrations of pyrimidines with an increased rate of destruction of red blood cells leading to anemia [14]. Pb 2+ has also been shown to replace Zn 2+ in 5-aminolevulinic acid dehydratase (ALAD) [15, 16], an important enzyme in heme synthesis, resulting in iron-deficiency anemia.…”

Section: Introductionmentioning

confidence: 99%

Metal toxicity and opportunistic binding of Pb2+ in proteins

Kirberger

Wong

Jiang

et al. 2013

Journal of Inorganic Biochemistry

View full text Add to dashboard Cite

Lead toxicity is associated with various human diseases. While Ca2+ binding proteins such as calmodulin (CaM) are often reported to be molecular targets for Pb2+-binding and lead toxicity, the effect of Pb2+ on the Ca2+/CaM regulated biological activities cannot be described by the primary mechanism of ionic displacement (e.g., ionic mimicry). The focus of this study was to investigate the mechanism of lead toxicity through binding differences between Ca2+ and Pb2+ for CaM, an essential intracellular trigger protein with two EF-Hand Ca2+-binding sites in each of its two domains that regulates many molecular targets via Ca2+-induced conformational change. Fluorescence changes in phenylalanine indicated that Pb2+ binds with 8-fold higher affinity than Ca2+ in the N-terminal domain. Additionally, NMR chemical shift changes and an unusual biphasic response observed in tyrosine fluorescence associated with C-terminal domain sites EF-III and EF-IV suggest a single higher affinity Pb2+-binding site with a 3-fold higher affinity than Ca2+, coupled with a second site exhibiting affinity nearly equivalent to that of the N-terminal domain sites. Our results further indicate that Pb2+ displaces Ca2+ only in the N-terminal domain, with minimal perturbation of the C-terminal domain, however significant structural/dynamic changes are observed in the trans-domain linker region which appear to be due to Pb2+-binding outside of the known calcium-binding sites. These data suggest that opportunistic Pb2+-binding in Ca2+/CaM has a profound impact on the conformation and dynamics of the essential molecular recognition sites of the central helix, and provides insight into the molecular toxicity of non-essential metal ions.

show abstract

“…It has been demonstrated that at lower concentrations, Pb 2+ induces CaM activity while inhibiting the same at higher concentrations . Although the Pb 2+ binding site is not as explicitly defined as the EF-hand motif, several studies demonstrated that Pb 2+ binding to a variety of proteins affects their conformations, causing functional impairment. − …”

Section: Discussionmentioning

confidence: 99%

Structural Plasticity Allows Calumenin-1 to Moonlight as a Ca²⁺-Independent Chaperone: Pb²⁺ Enables Probing Alternate Inhibitory Conformation

Yadav,

Narayanasamy,

Aradhyam

2023

Biochemistry

View full text Add to dashboard Cite

Human calumenin-1 (HsCalu-1) is an endoplasmic reticulum (ER) and Golgi-resident Ca 2+ -binding protein of the hepta-EF-hand superfamily that plays a vital role in maintaining the cytoplasmic Ca 2+ concentration below toxic levels by interacting with Sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) and ryanodine receptors (RyR), indicating its role in Ca 2+ homeostasis in the ER. HsCalu-1 seems to be able to exhibit structural plasticity to achieve its plethora of functions. In this study, we demonstrate that HsCalu-1 acts as a chaperone in both its intrinsically disordered state (apo form) and the structured state (Ca 2+ -bound form). HsCalu-1 chaperone activity is independent of Ca 2+ and Pb 2+ binding attenuating its chaperone-like activity. Incidentally, Pb 2+ binds to HsCalu-1 with lower affinity (K D = 38.46 μM) (compared to Ca 2+ -binding), leading to the formation of a less-stable conformation as observed by a sharp drop in its melting temperature T m from 67 °C in the Ca 2+ -bound form to 43 °C in the presence of Pb 2+ . The binding site for Pb 2+ was mapped as being in the EF-Hand-234 domain of HsCalu-1, a region that overlaps with the Ca 2+ -dependent initiator of its functional fold. A change in the secondary and tertiary structure, leading to a less-stable but compact conformation upon Pb 2+ binding, is the mechanism by which the chaperone-like activity of HsCalu-1 is diminished. Our results not only demonstrate the chaperone activity by a protein in its disordered state but also explain, using Pb 2+ as a probe, that the multiple functions of calumenin are due to its ability to adopt a quasi-stable conformation.

show abstract

Evaluation of Activity of Erythrocyte Pyrimidine 5'-Nucleotidase (P5N) in Lead Exposed Workers: With Focus on the Effect on Hemoglobin.

Cited by 14 publications

References 12 publications

Defining potential roles of Pb²⁺in neurotoxicity from a calciomics approach

Defining potential roles of Pb²⁺in neurotoxicity from a calciomics approach

Metal toxicity and opportunistic binding of Pb2+ in proteins

Structural Plasticity Allows Calumenin-1 to Moonlight as a Ca²⁺-Independent Chaperone: Pb²⁺ Enables Probing Alternate Inhibitory Conformation

Contact Info

Product

Resources

About

Evaluation of Activity of Erythrocyte Pyrimidine 5'-Nucleotidase (P5N) in Lead Exposed Workers: With Focus on the Effect on Hemoglobin.

Cited by 14 publications

References 12 publications

Defining potential roles of Pb2+in neurotoxicity from a calciomics approach

Defining potential roles of Pb2+in neurotoxicity from a calciomics approach

Metal toxicity and opportunistic binding of Pb2+ in proteins

Structural Plasticity Allows Calumenin-1 to Moonlight as a Ca2+-Independent Chaperone: Pb2+ Enables Probing Alternate Inhibitory Conformation

Contact Info

Product

Resources

About

Defining potential roles of Pb²⁺in neurotoxicity from a calciomics approach

Defining potential roles of Pb²⁺in neurotoxicity from a calciomics approach

Structural Plasticity Allows Calumenin-1 to Moonlight as a Ca²⁺-Independent Chaperone: Pb²⁺ Enables Probing Alternate Inhibitory Conformation