The brain is a singular organ of unique biological complexity that serves as the command center for cognitive and motor function. As such, this specialized system also possesses a unique chemical composition and reactivity at the molecular level. In this regard, two vital distinguishing features of the brain are its requirements for the highest concentrations of metal ions in the body and the highest per-weight consumption of body oxygen. In humans, the brain accounts for only 2% of total body mass but consumes 20% of the oxygen that is taken in through respiration. As a consequence of high oxygen demand and cell complexity, distinctly high metal levels pervade all regions of the brain and central nervous system. Structural roles for metal ions in the brain and the body include the stabilization of biomolecules in static (e.g., Mg2+ for nucleic acid folds, Zn2+ in zinc-finger transcription factors) or dynamic (e.g., Na+ and K+ in ion channels, Ca2+ in neuronal cell signaling) modes, and catalytic roles for brain metal ions are also numerous and often of special demand.

Metals in Neurobiology: Probing Their Chemistry and Biology with Molecular Imaging

Copper toxicity, oxidative stress, and antioxidant nutrients.

The glutathione transferases are recognized as important catalysts in the biotransformation of xenobiotics, including drugs as well as environmental pollutants. Multiple forms exist, and numerous transferases from mammalian tissues, insects, and plants have been isolated and characterized. Enzymatic properties, reactions with antibodies, and structural characteristics have been used for classification of the glutathione transferases. The cytosolic mammalian enzymes could be grouped into three distinct classes--Alpha, Mu, and Pi; the microsomal glutathione transferase differs greatly from all the cytosolic enzymes. Members of each enzyme class have been identified in human, rat, and mouse tissues. Comparison of known primary structures of representatives of each class suggests a divergent evolution of the enzyme proteins from a common precursor. Products of oxidative metabolism such as organic hydroperoxides, epoxides, quinones, and activated alkenes are possible "natural" substrates for the glutathione transferases. Particularly noteworthy are 4-hydroxyalkenals, which are among the best substrates found. Homologous series of substrates give information about the properties of the corresponding binding site. The catalytic mechanism and the active-site topology have been probed also by use of chiral substrates. Steady-state kinetics have provided evidence for a "sequential" mechanism.

Glutathione transferases--structure and catalytic activity.

Copper Homeostasis and Neurodegenerative Disorders (Alzheimer's, Prion, and Parkinson's Diseases and Amyotrophic Lateral Sclerosis)

https://www.kidney-international.org/article/S0085-2538(15)53124-4/pdf

Cisplatin nephrotoxicity: Mechanisms and renoprotective strategies

The trace metal copper (Cu) plays an essential role in biology as a cofactor for many enzymes that include Cu, Zn superoxide dismutase, cytochrome oxidase, ceruloplasmin, lysyl oxidase, and dopamine beta-hydroxylase. Consequently, Cu transport at the cell surface and the delivery of Cu to intracellular compartments are critical events for a wide variety of biological processes. The components that orchestrate intracellular Cu trafficking and their roles in Cu homeostasis have been elucidated by the studies of model microorganisms and by the characterizations of molecular basis of Cu-related genetic diseases, including Menkes disease and Wilson disease. However, little is known about the mechanisms for Cu uptake at the plasma membrane and the consequences of defects in this process in mammals. Here, we show that the mouse Ctr1 gene encodes a component of the Cu transport machinery and that mice heterozygous for Ctr1 exhibit tissue-specific defects in copper accumulation and in the activities of copper-dependent enzymes. Mice completely deficient for Ctr1 exhibit profound growth and developmental defects and die in utero in mid-gestation. These results demonstrate a crucial role for Cu acquisition through the Ctr1 transporter for mammalian Cu homeostasis and embryonic development.

https://www.pnas.org/content/pnas/98/12/6842.full.pdf

Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development

Copper is an essential cofactor for approximately a dozen cuproenzymes in which copper is bound to specific amino acid residues in an active site. However, free cuprous ions react readily with hydrogen peroxide to yield the deleterious hydroxyl radical. Therefore, copper homeostasis is regulated very tightly, and unbound copper is extremely low in concentration. Copper imported by the plasma membrane transport protein Ctr1 rapidly binds to intracellular copper chaperone proteins. Atox1 delivers copper to the secretory pathway and docks with either copper-transporting ATPase ATP7B in the liver or ATP7A in other cells. ATP7B directs copper to plasma ceruloplasmin or to biliary excretion in concert with a newly discovered chaperone, Murr1, the protein missing in canine copper toxicosis. ATP7A directs copper within the transgolgi network to the proteins dopamine beta-monooxgenase, peptidylglycine alpha-amidating monooxygenase, lysyl oxidase, and tyrosinase, depending on the cell type. CCS is the copper chaperone for Cu,Zn-superoxide dismutase; it delivers copper in the cytoplasm and intermitochondrial space. Cox17 delivers copper to mitochondria to cytochrome c oxidase via the chaperones Cox11, Sco1, and Sco2. Other copper chaperones may exist and might include metallothionein and amyloid precursor protein (APP). Genetic and nutritional studies have illustrated the essential nature of these copper-binding proteins; alterations in their levels are associated with severe pathology.

Intracellular Copper Transport in Mammals

Interactions between the essential dietary metals, iron and copper, have been known for many years. This review highlights recent advances in iron-copper interactions with a focus on tissues and cell types important for regulating whole-body iron and copper homeostasis. Cells that mediate dietary assimilation (enterocytes) and storage and distribution (hepatocytes) of iron and copper are considered, along with the principal users (erythroid cells) and recyclers of red cell iron (reticuloendothelial macrophages). Interactions between iron and copper in the brain are also discussed. Many unanswered questions regarding the role of these metals and their interactions in health and disease emerge from this synopsis, highlighting extensive future research opportunities.

/pdf/metabolic-crossroads-of-iron-and-copper-313w3smfhz.pdf

Metabolic crossroads of iron and copper

The glutathione peroxidase activity of glutathione S-transferases

Experiments were conducted in suckling mice to investigate copper-dependent anemia. Brindled (Mobr/y) mice, which are not anemic, were compared to their normal brothers (Mo+/y) as well as to anemic suckling mice that were copper-deficient (-Cu) because their dams were consuming a diet low in copper and a fourth group of suckling mice that served as dietary controls (+Cu). Compared to +Cu and Mo+/y mice, -Cu mice were smaller and exhibited cardiac hypertrophy and significant atrophy of lymphoid tissues (spleen and thymus), Mobr/y mice were also small and demonstrated modest atrophy of both liver and spleen. Cu levels were decreased in all -Cu mouse tissues studied, whereas Fe levels tended to be unaltered. Mobr/y mice also exhibited lower tissue Cu levels in soft tissues, except for kidney and small intestine; however, Cu levels in Mobr/y mice were greater than in -Cu mice. Functional copper deficiency was demonstrated in -Cu tissues by decreases in cytochrome c oxidase (CO) and cuprozinc-superoxide dismutase (SOD). The magnitude of the change was tissue specific. Mobr/y tissues, which were low in Cu, also exhibited decreased SOD and CO activity. However, the drop in Mobr/y tissue was less than in -Cu tissue. This was most pronounced in bone marrow, where both CO and SOD were four times higher in Mobr/y than in -Cu mice. Both Mobr/y and -Cu mice had low serum ceruloplasmin activities. The presence of anemia in -Cu mice and the absence of anemia in Mobr/y mice may result from a more severe copper-deficient state in erythropoietic tissues in -Cu mice rather than from differences in ceruloplasmin activity.

Changes in Tissue Growth, Concentrations of Copper, Iron, Cytochrome Oxidase and Superoxide Dismutase Subsequent to Dietary or Genetic Copper Deficiency in Mice

Joseph R. Prohaska

Papers

Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development

Intracellular Copper Transport in Mammals

Metabolic crossroads of iron and copper

The glutathione peroxidase activity of glutathione S-transferases

Changes in Tissue Growth, Concentrations of Copper, Iron, Cytochrome Oxidase and Superoxide Dismutase Subsequent to Dietary or Genetic Copper Deficiency in Mice