Micronutrient cofactor research with extensions to applications

McCormick, Donald B.

doi:10.1079/nrr200241

Cited by 16 publications

(7 citation statements)

References 175 publications

(152 reference statements)

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“…Evidence for involvement of ATP as a ligand of zinc has been provided, thus demonstrating in principle how biological specificity by LMW species can be achieved. Some kinases phosphorylating vitamins prefer a ZnATP complex over a MgATP complex [57]. In the crystal structures of flavokinase and pyridoxal kinase a bound ZnATP complex was detected [58], [59].…”

Section: The Coordination Of Zinc In the “Free” Zinc Poolmentioning

confidence: 94%

The biological inorganic chemistry of zinc ions

Krężel

Maret

2016

Archives of Biochemistry and Biophysics

591

356

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The solution and complexation chemistry of zinc ions is the basis for zinc biology. In living organisms, zinc is redox-inert and has only one valence state: Zn(II). Its coordination environment in proteins is limited by oxygen, nitrogen, and sulfur donors from the side chains of a few amino acids. In an estimated 10% of all human proteins, zinc has a catalytic or structural function and remains bound during the lifetime of the protein. However, in other proteins zinc ions bind reversibly with dissociation and association rates commensurate with the requirements in regulation, transport, transfer, sensing, signalling, and storage. In contrast to the extensive knowledge about zinc proteins, the coordination chemistry of the “mobile” zinc ions in these processes, i.e. when not bound to proteins, is virtually unexplored and the mechanisms of ligand exchange are poorly understood. Knowledge of the biological inorganic chemistry of zinc ions is essential for understanding its cellular biology and for designing complexes that deliver zinc to proteins and chelating agents that remove zinc from proteins, for detecting zinc ion species by qualitative and quantitative analysis, and for proper planning and execution of experiments involving zinc ions and nanoparticles such as zinc oxide (ZnO). In most investigations, reference is made to zinc or Zn2+ without full appreciation of how biological zinc ions are buffered and how the d-block cation Zn2+ differs from s-block cations such as Ca2+ with regard to significantly higher affinity for ligands, preference for the donor atoms of ligands, and coordination dynamics. Zinc needs to be tightly controlled. The interaction with low molecular weight ligands such as water and inorganic and organic anions is highly relevant to its biology but in contrast to its coordination in proteins has not been discussed in the biochemical literature. From the discussion in this article, it is becoming evident that zinc ion speciation is important in zinc biochemistry and for biological recognition as a variety of low molecular weight zinc complexes have already been implicated in biological processes, e.g. with ATP, glutathione, citrate, ethylenediaminedisuccinic acid, nicotianamine, or bacillithiol.

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Section: The Coordination Of Zinc In the “Free” Zinc Poolmentioning

confidence: 94%

The biological inorganic chemistry of zinc ions

Krężel

Maret

2016

Archives of Biochemistry and Biophysics

591

356

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“…ZnATP rather than MgATP is the preferred substrate for some kinases involved in cofactor biosynthesis: pyridoxal kinase, riboflavin kinase, and NAD kinase. − X-ray structures of the first two enzymes indeed show the interaction with a ZnATP complex. , Noteworthy, MT activates pyridoxal kinase . An equilibrium dialysis showed that ATP removes Zn(II) from MT.…”

Section: Relating Metallothionein Thermodynamics and Kinetics To Cont...mentioning

confidence: 99%

The Bioinorganic Chemistry of Mammalian Metallothioneins

2021

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The functions, purposes, and roles of metallothioneins have been the subject of speculations since the discovery of the protein over 60 years ago. This article guides through the history of investigations and resolves multiple contentions by providing new interpretations of the structure-stability-function relationship. It challenges the dogma that the biologically relevant structure of the mammalian proteins is only the one determined by X-ray diffraction and NMR spectroscopy. The terms metallothionein and thionein are ambiguous and insufficient to understand biological function. The proteins need to be seen in their biological context, which limits and defines the chemistry possible. They exist in multiple forms with different degrees of metalation and types of metal ions. The homoleptic thiolate coordination of mammalian metallothioneins is important for their molecular mechanism. It endows the proteins with redox activity and a specific pH dependence of their metal affinities. The proteins, therefore, also exist in different redox states of the sulfur donor ligands. Their coordination dynamics allows a vast conformational landscape for interactions with other proteins and ligands. Many fundamental signal transduction pathways regulate the expression of the dozen of human metallothionein genes. Recent advances in understanding the control of cellular zinc and copper homeostasis are the foundation for suggesting that mammalian metallothioneins provide a highly dynamic, regulated, and uniquely biological metal buffer to control the availability, fluctuations, and signaling transients of the most competitive Zn(II) and Cu(I) ions in cellular space and time.

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“…Pyridoxal kinase and riboflavin kinase, controlling cofactor biosynthesis, prefer a Zn-ATP over a Mg-ATP complex [98]. X-ray structures of these enzymes show the binding of a Zn-ATP complex [99,100].…”

Section: Zinc In Coenzyme Metabolismmentioning

confidence: 99%

The redox biology of redox-inert zinc ions

Maret

2019

Free Radical Biology and Medicine

180

124

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Zinc(II) ions are redox-inert in biology. Yet, their interaction with sulfur of cysteine in cellular proteins can confer ligandcentered redox activity on zinc coordination sites, control protein functions, and generate signalling zinc ions as potent effectors of many cellular processes. The specificity and relative high affinity of binding sites for zinc allow regulation in redox biology, free radical biology, and the biology of reactive species. Understanding the role of zinc in these areas of biology requires an understanding of how cellular Zn2+ is homeostatically controlled and can serve as a regulatory ion in addition to Ca2+, albeit at much lower concentrations. A rather complex system of dozens of transporters and metallothioneins buffer the relatively high (hundreds of micromolar) total cellular zinc concentrations in such a way that the available zinc ion concentrations are only picomolar but can fluctuate in signalling. The proteins targeted by Zn2+ transients include enzymes controlling phosphorylation and redox signalling pathways. Networks of regulatory functions of zinc integrate gene expression and metabolic and signalling pathways at several hierarchical levels. They affect enzymatic catalysis, protein structure and protein-protein/biomolecular interactions and add to the already impressive number of catalytic and structural functions of zinc in an estimated three thousand human zinc proteins. The effects of zinc on redox biology have adduced evidence that zinc is an antioxidant. Without further qualifications, this notion is misleading and prevents a true understanding of the roles of zinc in biology. Its antioxidant-like effects are indirect and expressed only in certain conditions because a lack of zinc and too much zinc have pro-oxidant effects. Teasing apart these functions based on quantitative considerations of homeostatic control of cellular zinc is critical because opposite consequences are observed depending on the concentrations of zinc: pro-or anti-apoptotic, pro-or anti-inflammatory and cytoprotective or cytotoxic. The article provides a biochemical basis for the links between redox and zinc biology and discusses why zinc has pleiotropic functions. Perturbation of zinc metabolism is a consequence of conditions of redox stress. Zinc deficiency, either nutritional or conditioned, and cellular zinc overload cause oxidative stress. Thus, there is causation in the relationship between zinc metabolism and the many diseases associated with oxidative stress. Highlights• Redox-inert zinc ions regulate some aspects of redox biology and the biology or reactive species.• Control of cellular zinc homeostasis determines antioxidant-like or pro-oxidant effects.• Zinc deficiency and overload cause oxidative stress.• Disorders of zinc metabolism are a cause or consequence of diseases associated with oxidative stress.Abbreviations ER, endoplasmic reticulum; GCL, glutamate cysteine ligase; MT, metallothionein; MTF-1, metal regulatory element (MRE)-binding transcription factor-1; NOS, nitric oxide syntha...

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Micronutrient cofactor research with extensions to applications

Cited by 16 publications

References 175 publications

The biological inorganic chemistry of zinc ions

The biological inorganic chemistry of zinc ions

The Bioinorganic Chemistry of Mammalian Metallothioneins

The redox biology of redox-inert zinc ions

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