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Toxic and Physiological Metal Uptake and Release by Human Serum Transferrin.

ABSTRACT: An atomistic understanding of metal transport in the human body is critical to anticipate the side effects of metal-based therapeutics and holds promise for new drugs and drug delivery designs. Human serum transferrin (hTF) is a central part of the transport processes because of its ubiquitous ferrying of physiological Fe(III) and other transition metals to tightly controlled parts of the body. There is an atomistic mechanism for the uptake process with Fe(III), but not for the release process, or for other metals. This study provides initial insight into these processes for a range of transition metals-Ti(IV), Co(III), Fe(III), Ga(III), Cr(III), Fe(II), Zn(II)-through fully atomistic, extensive quantum mechanical/discrete molecular dynamics sampling and provides, to our knowledge, a new technique we developed to calculate relative binding affinities between metal cations and the protein. It identifies protonation of Tyr188 as a trigger for metal release rather than protonation of Lys206 or Lys296. The study identifies the difficulty of metal release from hTF as potentially related to cytotoxicity. Simulations identify a few critical interactions that stabilize the metal binding site in a flexible, nuanced manner.

SUBMITTER: Reilley DJ

PROVIDER: S-EPMC7300305 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Toxic metal pollution influences the lives of diverse aquatic organisms and humans who consume contaminated aquatic products. However, its potential impacts on aquatic organism health and, thus, ecological health, have been neglected in many regions. This research was carried out to contribute to filling that knowledge gap. Three freshwater fish species in the Nhue-Day River basin, Vietnam, have been chosen to study the bioaccumulation of metals (Zn, Cu, Pb, and Cd) in the tissues (livers, kidneys, gills) and their effects on fish physiological health (changes in the oxidative-GST activity, and physiological biomarkers-energy reserves, respectively) from 2013 to 2017. The extensive results revealed significant spatial and temporal variations in metal concentrations in tissues of common carp (Cyprinus carpio), silver carp (Hypothalmic molitrix), and tilapia (Oreochromis niloticus), and well correlated to their concentration in the water (p < 0.05). Fish bioaccumulated metals in the following order: Zn > Cu > Pb > Cd, with more in the kidneys and livers (spring and summer) than in other tissues. Metal accumulation in O. niloticus and C. carpio was higher than in H. molitrix. Biomarker responses (except for glycogen variation) were also higher during warm seasons. Changes in metal levels in water and fish tissues caused variations in biomarkers in the respective fish tissues, particularly in the livers, as demonstrated by significant correlations of metal concentrations in water and fish tissues to biochemical and physiological responses (p < 0.05). The findings suggest that metal pollution in the river basin adversely impacts the physiological health of both wild and cultured fish. Seasonal shifts in the levels of metal accumulation and biomarkers could be connected to species-specific differences in physiology and the levels of metals in environments. This biomarker set is simple but effective in assessing the impact of metal pollution on fish health and, hence, the aquatic ecosystem. This is one of the first biomonitoring studies to assist in designing better water management strategies for the Nhue-Day River basin.

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Toxic and Physiological Metal Uptake and Release by Human Serum Transferrin.

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