Table 1.
Copper content of human organs, tissues, and bodily fluids.
Fig 1.
Copper homeostasis in the human body.
Under copper homeostatic conditions, the amount of copper that enters an adult human body is the same that leaves the body. Because an average diet provides more copper than the minimum amount required (top), most dietary copper is excreted through feces (bottom). Importantly, most of the copper in the gastrointestinal tract is of endogenous origin (left) so that copper homeostasis is primarily maintained by balancing secretion and reabsorption, rather than through the diet. Circulating copper (right) is mostly bound to ceruloplasmin, and only 5% of circulating copper is not bound to carrier macromolecules. The majority of the copper secreted into the digestive tract (through bile) or into the bloodstream (through ceruloplasmin) comes from the liver, which is the primary organ regulating copper homeostasis.
Fig 2.
Copper distribution across organs.
An average adult human contains approximately 110 mg of copper, the majority of which is ligated in the bones (including bone marrow) and skeletal muscle (top). However, the highest concentration of copper is found in the kidney and liver (bottom), which are the organs chiefly responsible for copper homeostasis. Notice that common infection sites—lung, blood, and the GI tract—can be considered copper poor. GI, gastrointestinal.
Fig 3.
Copper delivery to the phagolysosome.
Pro-inflammatory signals, such as IFγ and LPS, stimulate professional phagocytes to overexpress the copper-transport proteins CTR1, CTR2, and ATP7A. Copper concentration (gray circles) in the phagocyte cytoplasm increases through copper import by CTR1, and copper mobilization from intracellular storage vacuoles by CTR1 and CTR2. Cytosolic copper is captured by the ATOX1 chaperone and delivered to ATP7A, which is trafficked to the early lysosome from the Golgi apparatus and drives copper accumulation in the early lysosome. Upon phagocytosis of an invading microorganism, the maturing phagosome fuses with copper-rich lysosomes, exposing the microorganism to high copper levels. If copper fails to accumulate in the phagolysosome, lysis of engulfed bacteria is compromised and intracellular proliferation can occur. Copper is also required for the biosynthesis of many extracellular signals, including PGE2, TNFα, and IL1B and IL6. IFγ, interferon-γ; IL, interleukin; LPS, lipopolysaccharide; PGE2, prostaglandin E2; TNFα, tumor necrosis factor α.
Fig 4.
Copper resistance in human pathogens.
Despite individual variations, most human pathogens share a common pattern of copper resistance proteins, involving four key functions: copper sensing (green), export (blue), chelation (ochre), and oxidation (magenta). The first three functions (sensing, export, and chelation) are common to the majority of pathogens, and many also include the fourth function (oxidation). In some cases, the copper-homeostasis suite can also vary across different strains or serotypes (most notably in S. aureus and S. enterica). Copper oxidation only occurs outside of the cytosol, and it may contribute to slowing down copper entry into the cytosol. All P-type ATPases belong to a single family (CopA) which is conserved across the tree of life (including eukaryotes). Different subfamilies of the ATPase may feature different terminal metal-binding domains, and these are homologous to that organism’s cytosolic chaperone. (A) Streptococcus pneumoniae contains a minimal set of copper-homeostasis proteins, including the CopY sensor, the CopA exporter, and the CupA chaperone. (B) The common USA300 strain of Staphylococcus aureus contains two copper-efflux pumps (CopA and CopB/X) as well as a cell-surface associated chelator (CopL) and multicopper oxidase (Mco). (C) Mycobacterium tuberculosis has a minimum copper-homeostasis system with the CtpV efflux pump, the MymT metallothionein, and the MmcO oxidase; however, this system is controlled by two separate (but homologous) regulators: CsoR for CtpV, and RicR for MymT and MmcO. (D) As a gram-negative organism, Escherichia coli features a rich suite of periplasmic copper-homeostasis proteins, including the CusSR two-component sensory system, the CusCBA efflux pump, the CusF chaperone, and the CueO oxidase. Copper homeostasis in the E. coli cytoplasm is minimal, with only the CueR regulator, the CopA pump, and the CopZ chaperone dealing with copper homeostasis in this compartment. (E) Although related to E. coli, Salmonella enterica sv. Typhimurium lacks systems for periplasmic copper sensing or efflux; conversely, it carries a duplication of the cytoplasmic copper-homeostasis system (the Gol proteins) and an additional copper-storage protein (Csp3). (F) Pseudomonas aeruginosa features copper sensing and efflux both in the cytosol and the periplasm, but no periplasmic copper chelator or oxidase have been identified to date.