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Copper: Deficiency, Overload, Absorption Issues, How Staph Uses Iron, Transferrin, Manganese, Copper, Heme. Carnosine, Molybdenum...

Updated: May 27

This article is not intended to be health care or medical advice. Before you start on any health related regimen, speak to you Primary Care Physician or M.D. first.


Copper is an important nutrient, it supports various immune functions, iron and heme metabolism, and is a co factor in some specific and important enzymes, just a few noted below:

  1. Catalase - an important anti-oxidant enzyme used to neutralize the free radical hydrogen peroxide

  2. DBH - converts dopamine into noreprenephrine

  3. SOD1 - acts on the free radical super oxide, and turns it into hydrogen peroxide

  4. CCO - The copper-dependent enzyme cytochrome c oxidase (CCO) plays a critical role in cellular energy production in mitochondria by catalyzing the reduction of molecular oxygen (O2) to water (H2O), thereby generating an electrical gradient that is required for ATP production. Redox-active copper contained within the CCO enzyme complex is required for the electron transfer reactions that are critical for its function.[12]

  5. Heme - copper is a cofactor in the heme pathway, in particular for the FECH enzyme.

  6. Lysyl oxidase, an enzyme that is important for cross-linking between structural proteins (collagen and elastin), requires copper as a cofactor[20]

  7. CP - Copper is mainly incorporated into ceruloplasmin (CP) in hepatocytes, which is secreted into the blood where it functions predominantly in iron metabolism, facilitating iron release from some tissues.[19]

  8. Copper transporters SLC31A1 and SLC31A2 - when compromised can lead to lower levels of copper absorption

  9. AHYC - converts SAH into homocysteine in the methylation cycle. If compromised be cautious with copper supplementation - as copper inhibits this gene some. If you are compromised here and need copper, consider pulsing and Niacin (B3) that is the cofactor for AHYC.

  10. DAO enzymes needed to break down histamine require copper


Copper Absorption Issues

I came across some articles related to copper absorption that i found interesting, in summary, copper absorption can be compromised due some interesting factors:

  1. Anti biotics use inhibited the key copper transporter CTR1 in mice

  2. In the presence of sulfate copper absorption was dramatically lower. Think sulfur producing bacteria - a very common pattern i see in stool results, overgrowth of sulfur producing bacteria.

  3. In the presence of histadine, copper absorption was dramatically lower, and the double whammy here, copper is needed for the DAO enzyme!

  4. Copper absorption is much greater in the absence of amino acids (protein)!


" The initial rate of apical copper uptake into confluent monolayers of Caco2 cells is greatly elevated if amino acids and serum proteins are removed from the growth media. Uptake from buffered saline solutions at neutral pH (but not at lower pH) is inhibited by either d- or l-histidine, unaltered by the removal of sodium ions, and inhibited by ∼90% when chloride ions are replaced by gluconate or sulfate. Chloride-dependent copper uptake occurs with Cu(II) or Cu(I), although Cu(I) uptake is not inhibited by histidine, nor by silver ions. A well-characterized inhibitor of anion exchange systems, DIDS, inhibited apical copper uptake by 60-70%, while the addition of Mn(II) or Fe(II), competitive substrates for the divalent metal transporter DMT1, had no effect on copper uptake. We propose that anion exchangers play an unexpected role in copper absorption, utilizing copper-chloride complexes as pseudo-substrates. This pathway is also observed in mouse embryonic fibroblasts, human embryonic kidney cells, and Cos-7 cells. The special environment of low pH, low concentration of protein, and protonation of amino acids in the early intestinal lumen make this pathway especially important in dietary copper acquisition."[1]


"Copper is a critical enzyme cofactor in the body but also a potent cellular toxin when intracellularly unbound. Thus, there is a delicate balance of intracellular copper, maintained by a series of complex interactions between the metal and specific copper transport and binding proteins. The gastrointestinal (GI) tract is the primary site of copper entry into the body and there has been considerable progress in understanding the intricacies of copper metabolism in this region. The GI tract is also host to diverse bacterial populations, and their role in copper metabolism is not well understood. In this study, we compared the isotopic fractionation of copper in the GI tract of mice with intestinal microbiota significantly depleted by antibiotic treatment to that in mice not receiving such treatment. We demonstrated variability in copper isotopic composition along the length of the gut. A significant difference, ∼1.0‰, in copper isotope abundances was measured in the proximal colon of antibiotic-treated mice. The changes in copper isotopic composition in the colon are accompanied by changes in copper transporters. Both CTR1, a copper importer, and ATP7A, a copper transporter across membranes, were significantly down-regulated in the colon of antibiotic-treated mice. This study demonstrated that isotope abundance measurements of metals can be used as an indicator of changes in metabolic processes in vivo. These measurements revealed a host–microbial interaction in the GI tract involved in the regulation of copper transport."


To all those who have an overgrowth of sulfur producing bacteria, who take copper supplements with meals, or who are on regular anti biotic therapy, this may be interesting to explore.


Copper Deficiency & Immune Compromise

"Copper is an essential micronutrient for most organisms that is required as a cofactor for crucial copper-dependent enzymes encoded by both prokaryotes and eukaryotes. Evidence accumulated over several decades has shown that copper plays important roles in the function of the mammalian immune system. Copper accumulates at sites of infection, including the gastrointestinal and respiratory tracts and in blood and urine, and its antibacterial toxicity is directly leveraged by phagocytic cells to kill pathogens. Copper-deficient animals are more susceptible to infection, whereas those fed copper-rich diets are more resistant. As a result, copper resistance genes are important virulence factors for bacterial pathogens, enabling them to detoxify the copper insult while maintaining copper supply to their essential cuproenzymes. Here, we describe the accumulated evidence for the varied roles of copper in the mammalian response to infections, demonstrating that this metal has numerous direct and indirect effects on immune function. We further illustrate the multifaceted response of pathogenic bacteria to the elevated copper concentrations that they experience when invading the host, describing both conserved and species-specific adaptations to copper toxicity. Together, these observations demonstrate the roles of copper at the host–pathogen interface and illustrate why bacterial copper detoxification systems can be viable targets for the future development of novel antibiotic drug development programs."[4]


Copper Destroys At A Touch (Staph MRSA)

"The pandemic of hospital-acquired infections caused by methicillin-resistant Staphylococcus aureus (MRSA) has declined, but the evolution of strains with enhanced virulence and toxins and the increase of community-associated infections are still a threat. In previous studies, 107 MRSA bacteria applied as simulated droplet contamination were killed on copper and brass surfaces within 90 min. However, contamination of surfaces is often via finger tips and dries rapidly, and it may be overlooked by cleaning regimes (unlike visible droplets). In this new study, a 5-log reduction of a hardy epidemic strain of MRSA (epidemic methicillin-resistant S. aureus 16 [EMRSA-16]) was observed following 10 min of contact with copper, and a 4-log reduction was observed on copper nickel and cartridge brass alloys in 15 min. A methicillin-sensitive S. aureus (MSSA) strain from an osteomyelitis patient was killed on copper surfaces in 15 min, and 4-log and 3-log reductions occurred within 20 min of contact with copper nickel and cartridge brass, respectively. Bacterial respiration was compromised on copper surfaces, and superoxide was generated as part of the killing mechanism. In addition, destruction of genomic DNA occurs on copper and brass surfaces, allaying concerns about horizontal gene transfer and copper resistance. Incorporation of copper alloy biocidal surfaces may help to reduce the spread of this dangerous pathogen."[7]


However - Copper Stress Has Led To Mecilllin Resistant Staph Microbes - Eeek

"Copper toxicity has been a long-term selection pressure on bacteria due to its presence in the environment and its use as an antimicrobial agent by grazing protozoa, by phagocytic cells of the immune system, and in man-made medical and commercial products. There is recent evidence that exposure to increased copper stress may have been a key driver in the evolution and spread of methicillin-resistant Staphylococcus aureus, a globally important pathogen that causes significant mortality and morbidity worldwide. Yet it is unclear how S. aureus physiology is affected by copper stress or how it adapts in order to be able to grow in the presence of excess copper. Here, we have determined quantitatively how S. aureus alters its proteome during growth under copper stress conditions, comparing this adaptive response in two different types of growth regime. We found that the adaptive response involves induction of the conserved copper detoxification system as well as induction of enzymes of central carbon metabolism, with only limited induction of proteins involved in the oxidative stress response. Further, we identified a protein that binds copper inside S. aureus cells when stressed by copper excess. This copper-binding enzyme, a glyceraldehyde-3-phosphate dehydrogenase essential for glycolysis, is inhibited by copper in vitro and inside S. aureus cells. Together, our data demonstrate that copper stress leads to the inhibition of glycolysis in S. aureus, and that the bacterium adapts to this stress by altering its central carbon utilisation pathways."[3]


Copper and Staph Again - PhD Thesis On The Impact and Response

"All microorganisms require transition metals for key metabolic processes, thus during infection microbial access to essential metals is tightly regulated by the host in a process termed nutritional immunity. Iron acquisition is critical to the pathogenesis of the formidable human pathogen, Staphylococcus aureus, which utilizes heme-uptake systems and two high affinity iron-scavenging siderophores, staphyloferrin A (SA) and staphyloferrin B (SB) for iron acquisition. In this study, I identify sbnI as encoding a transcription factor required for expression of genes in the sbn operon, the biosynthetic operon for SB synthesis. I also show that SbnI is a novel hemoprotein, where binding to heme abrogates its ability to bind DNA. Thus this work proposes a novel mechanism in which S. aureus controls SB synthesis in response to heme. Although free iron is scarce in the host, copper at the hostpathogen interface is found in excess. Copper is highly reactive and in macrophages is imported into phagosomes where it exerts bactericidal effects. S. aureus flourishes within macrophages and therefore must resist copper-mediated killing. I demonstrate that the USA300 strain of Community-Associated MRSA relies on CopAZ and CopBL for copper detoxification; where CopA and newly identified CopB are copper-translocating efflux pumps, CopZ is a copper-binding chaperone, and CopL is a novel copper-responsive lipoprotein. Finally, CopAZ, in accord with CopBL, aid in S. aureus survival in murine macrophages. This study examines two important facets of nutritional immunity and the virulence factors used by S. aureus to overcome obstacles posed by the host in maintaining metal homeostasis."[5]


Staph Uses Both Iron, Heme, and Manganese For Virulence

"Transition metals are essential nutrients to virtually all forms of life, including bacterial pathogens. In Staphylococcus aureus, metal ions participate in diverse biochemical processes such as metabolism, DNA synthesis, regulation of virulence factors, and defense against oxidative stress. As an innate immune response to bacterial infection, vertebrate hosts sequester transition metals in a process that has been termed “nutritional immunity.” To successfully infect vertebrates, S. aureus must overcome host sequestration of these critical nutrients. The objective of this review is to outline the current knowledge of staphylococcal metal ion acquisition systems, as well as to define the host mechanisms of nutritional immunity during staphylococcal infection."[6]


The capability of S. aureus to cause disease is facilitated by production of a diverse array of virulence factors [6]:

  • S. aureus overcomes nutritional immunity to obtain iron from the host

  • S. aureus produces siderophores to steal iron from transferrin

  • Iron acquisition by siderophores contributes to staphylococcal virulence

  • S. aureus preferentially acquires iron from heme and hemoproteins

  • Heme acquisition is essential to the virulence of S. aureus

  • The role of manganese in staphylococcal infection

    • Bacteria, like humans, must acquire manganese and regulate its intracellular concentration. Manganese-dependent bacterial enzymes are necessary for myriad processes, including carbohydrate and amino acid metabolism, signal transduction, stringent response, and defense against oxidative stress [136]. Thus, the success of bacterial pathogens in human infection depends on the ability to obtain this critical nutrient from host tissues. Likewise, prevention or resolution of infection is aided by host mechanisms that sequester manganese from invading pathogens.

    • Bacterial acquisition of manganese is facilitated by high-affinity transporters

    • Manganese acquisition contributes to the virulence of bacterial pathogens

    • Vertebrate hosts sequester manganese as an innate immune response to bacterial infection

  • The contribution of zinc to the host-pathogen interaction

    • Dynamic changes in zinc distribution occur in response to infection and inflammation

  • Exploiting transition metals to battle bacterial pathogens: the example of copper


Carnosine Regulates Intra Cellular Copper Transport:

"Notably, we also found that presence of CAR in the extracellular medium, per se, improves Cu inward translocation. In fact, cells grown without any CAR pretreatments (control cells) exhibit different fluorescence-quenching signals (from the cell-entrapped probe triggered by Cu) just incubated with high concentrations of Cu alone, or combined with equimolar CAR; i.e., Cu intake is significantly amplified when Cu is administered as Cu-CAR complex rather than as Cu alone. Thus, there is a CAR-enhancing effect on both Cu intracellular levels in the long term, and Cu absorption in the very short term, according to the net increase of intracellular Cu content observed in cells preexposed to CAR for 24 h and the net increase in Cu entry in cells just exposed to the dipeptide, respectively."[8]

Carnosine Can Bind and Chelate Copper, Manganese and Zinc In That Order of Preference

"A thermodynamic study on the interactions of a naturally occurring dipeptide, l-carnosine, and three transition metal cations, Cu2+, Mn2+ and Zn2+, is reported. Their characterization in solution evidences the chelating properties of carnosine that give rise to different types of metal complexes. Potentiometric data allowed to obtain a speciation model for each system, which includes species with 1:1 metal to ligand ratio for both Mn2+- and Zn2+- carnosine systems and 1:1 and 1:2 metal to ligand ratios for Cu2+. The dependence of formation constants of the complex species on ionic strength (in the range 0.15 ≤ I/mol/L ≤ 0.98) and temperature (288.15 ≤ T/K ≤ 310.15) was defined, as well as changes in enthalpy and entropy. 1H NMR titrations were also performed in the study of the Zn2+- carnosine system, and the results of the analysis of experimental data confirmed potentiometric ones. The integration with further investigation by High Resolution (HR) Matrix Assisted Laser Desorption Ionization (MALDI) Mass Spectrometry (MS) allowed to obtain the formation of species with 1:2 metal to ligand ratios for also Mn2+- and Zn2+- carnosine systems and to clarify the chelating mode. Finally, sequestering ability of carnosine towards Cu2+, Mn2+ and Zn2+ was quantified in physiological conditions (pH = 7.4, T = 310.15 K and I = 0.15 mol/L), and a sequestration profile of the dipeptide clearly describes its highest sequestering ability with respect to the Cu2+ ion, compared to that towards Mn2+ and Zn2+ cations."[9]


"Copper is dangerous when it is present in excess, mainly because it can participate in the Fenton reaction, which produces radical species. As a consequence of copper pollution, people are involuntarily exposed to a copper overload under sub-clinical and sub-symptomatological conditions, which may be very difficult to detect. Thus, we investigated (i) the possible use of the chelator molecules carnosine and neocuproine to prevent the Cu overload-induced damage on cellular lipids and proteins, as tested in human cell culture systems, and (ii) the differential response of these two chelating agents in relation to their protective action, and the type of copper ion involved in the process, by using two types of human cultured cells (HepG2 and A-549). Cu treatment clearly enhanced (p<0.01) the formation of protein carbonyls, thiobarbituric acid-reactive substances (TBARS) and the concentration of nitrate plus nitrites, with a concomitant decrease in cell survival, as estimated by the trypan dye exclusion test and lactate dehydrogenase leakage. Simultaneous treatment with Cu and carnosine or neocuproine indicated that carnosine is more efficient than neocuproine in protecting both types of cells from the effect of cupric ions on both the cell-associated damages and the decrease in the cellular viability. This observation was supported by the fact that carnosine is not only a complexing agent for Cu(II), but also an effective antioxidant that can dismutate superoxide radicals, scavenge hydroxyl radicals and neutralize TBARS formation. Carnosine should be investigated in more detail in order to establish its putative utility as an agent to prevent copper-associated damages in biological systems."[10]


High Zinc Intake Hinders Copper Absorption Despite Its High Affinity

"Metals like copper and zinc are absorbed into the mucosal cells by attaching to intracellular ligands like metallothionein. Interestingly, a high oral zinc consumption stimulates metallothionein synthesis in the intestinal cells. However, zinc and copper compete for intestinal absorption, but copper has a stronger affinity for metallothionein than zinc; therefore, a high zinc intake hinders copper absorption. Consequently, a sustained high zinc consumption can result in a severe copper deficit.[11]


Molybdenum Can Intefere With Copper Absorption

"Excess dietary molybdenum has been found to result in copper deficiency in grazing animals (ruminants). In the digestive tract of ruminants, the formation of compounds containing sulfur and molybdenum, known as thiomolybdates, prevents the absorption of copper and can cause fatal copper-dependent disorders (16, 17). Tetrathiomolybdate (TM) is a molecule that can form high-affinity complexes with copper, controlling free copper (copper that is not bound to ceruloplasmin), and inhibiting copper chaperones and copper-containing enzymes. TM's ability to lower free copper levels is exploited in the treatment of Wilson's disease, a genetic disorder characterized by copper accumulation in tissues responsible for hepatic and neurologic disorders. Neurologic worsening has been linked with toxic levels of free copper in the serum of neurologically presenting patients. TM therapy seems able to stabilize neurologic status and prevent neurologic deterioration in these patients, as opposed to the standard initial treatment of choice ."[12]


Copper Toxicity - And Potential Chelators

"Penicillamine is a useful agent for the mobilization and elimination of copper in Wilson's disease. Adverse reactions that may occur are usually reversible when the drug is discontinued temporarily." [16]. Similar for Triethylenetetramine. [18] Black Russian Rhubarb is an often used strong copper chelator used by those who practice mineral balancing. However, just because levels of copper rise on hair mineral tests after taking russion rhubarb does not mean you were copper toxic - just that you are excreting it now:).


The mix of articles cited below and summarized above show that copper deficiency can leave one vulnerable to various infections. Copper deficiency can be from diet, GI tract mal absorption issues, genetic transporter issues for copper, microbiome imbalance and other factors. The implications of copper deficiency are wide, and the summaries show how some opportunistic agents like Staph use various minerals to exploit the host. Given that these minerals include zinc, iron, copper, manganese, and proteins like Heme, its important cannot be over stated. If you would like to discuss the above implications in detail and review your associated genetics please contact me to schedule an appointment or book one on-line.


References

[1] Acquisition of dietary copper: a role for anion transporters in intestinal apical copper uptake.

Published in American Journal of… 1 March 2011. Biology, Medicine. American journal of physiology. Cell physiology

[2] Antibiotic treatment affects the expression levels of copper transporters and the isotopic composition of copper in the colon of mice

Kerri A. Miller kamiller@ucalgary.ca, Fernando A. Vicentini, Simon A. Hirota, +1, and Michael E. Wieser . APPLIED BIOLOGICAL SCIENCES Edited by Katherine H. Freeman, Pennsylvania State University, University Park, PA, and approved February 7, 2019 (received for review August 16, 2018). March 8, 2019. 116 (13) 5955-5960. https://doi.org/10.1073/pnas.1814047116

[3] Copper stress in Staphylococcus aureus leads to adaptive changes in central carbon metabolism

Emma Tarrant 1Gustavo P Riboldi,. Metallomics. . 2019 Jan 23;11(1):183-200.

doi: 10.1039/c8mt00239h. PMID: 30443649. PMCID: PMC6350627. DOI: 10.1039/c8mt00239h

[4] Copper microenvironments in the human body define patterns of copper adaptation in pathogenic bacteria. Francesca Focarelli, Andrea Giachino, Kevin John Waldron. Biosciences InPLOS Pathogens. https://doi.org/10.1371/journal.ppat.1010617 July 21, 2022

[5] Iron and Copper Homeostasis in Staphylococcus aureus Holly A. Laakso, The University of Western Ontario Supervisor: Heinrichs, David E., The University of Western Ontario A thesis submitted in partial fulfillment of the requirements for the Doctor of Philosophy degree in Microbiology and Immunology © Holly A. Laakso 2018. Western University Scholarship@Western Electronic Thesis and Dissertation Repository 2-1-2018 2:30 PM.

[6] Metal ion acquisition in Staphylococcus aureus: overcoming nutritional immunity. James E. Cassat & Eric P. Skaar. Semin Immunopathol (2012) 34:215–235 DOI 10.1007/s00281-011-0294-4

[7] Lack of Involvement of Fenton Chemistry in Death of Methicillin-Resistant and Methicillin-Sensitive Strains of Staphylococcus aureus and Destruction of Their Genomes on Wet or Dry Copper Alloy Surfaces. Authors: Sarah L. Warnes, C. William Keevil ASM Journals. Applied and Environmental Microbiology. Vol. 82, No. 7. https://orcid.org/0000-0003-1917-7706

[8] Carnosine modulates the Sp1-Slc31a1/Ctr1 copper-sensing system and influences copper homeostasis in murine CNS-derived cells

Amilcare Barca 1Stefania Ippati. Am J Physiol Cell Physiol . 2019 Feb 1;316(2):C235-C245.

doi: 10.1152/ajpcell.00106.2018. Epub 2018 Nov 28. PMID: 30485136. DOI: 10.1152/ajpcell.00106.2018

[9] Binding ability of l-carnosine towards Cu2+, Mn2+ and Zn2+ in aqueous solution

Author links open overlay panelChiara Abate a, Donatella Aiello . Journal of Molecular Liquids

Volume 368, Part B, 15 December 2022, 120772. https://doi.org/10.1016/j.molliq.2022.120772

[10] Carnosine and neocuproine as neutralizing agents for copper overload-induced damages in cultured human cells. Nathalie Arnal 1María J T de AlanizCarlos A Marra. Chem Biol Interact

. 2011 Jul 15;192(3):257-63. doi: 10.1016/j.cbi.2011.03.017. Epub 2011 Apr 8.

PMID: 21501601. DOI: 10.1016/j.cbi.2011.03.017

[11] Copper and Zinc Feud: Is This Myelodysplasia or Myelodysplastic Syndrome?

Monitoring Editor: Alexander Muacevic and John R Adler. Cureus. 2022 Jul; 14(7): e26789.

Published online 2022 Jul 12. doi: 10.7759/cureus.26789. PMCID: PMC9371592

PMID: 35971347

12. Linus Pauling Institute - Molybdenum

13. Helz GR, Erickson BE. Extraordinary stability of copper(I)-tetrathiomolybdate complexes: possible implications for aquatic ecosystems. Environ Toxicol Chem. 2011;30(1):97-102.

14.  Alvarez HM, Xue Y, Robinson CD, et al. Tetrathiomolybdate inhibits copper trafficking proteins through metal cluster formation. Science. 2010;327(5963):331-334. 

15.  Brewer GJ, Askari F, Dick RB, et al. Treatment of Wilson's disease with tetrathiomolybdate: V. Control of free copper by tetrathiomolybdate and a comparison with trientine. Transl Res. 2009;154(2):70-77.

16. A Copper-Chelating AgentPenicillamine (Cuprimine). Council on Drugs

September 14, 1964. JAMA. 1964;189(11):847-848. doi:10.1001/jama.1964.03070110049012

17. Cu2+ selective chelators relieve copper-induced oxidative stress in vivo

Ananya Rakshit,a Kaustav Khatua. Chem Sci. 2018 Nov 7; 9(41): 7916–7930. doi: 10.1039/c8sc04041a. PMCID: PMC6202919. PMID: 30450181

18. Therapeutic Potential of Copper Chelation with Triethylenetetramine in Managing Diabetes Mellitus and Alzheimer’s Disease Garth J.S. Cooper. Copper Chelation for Diabetes and Related Dementia. Drugs 2011; 71 (10): 1281-1320 0012-6667/11/0010-1281

[19] Intersection of Iron and Copper Metabolism in the Mammalian Intestine and Liver. Caglar Doguer, Jung-Heun Ha, and James F. Collins, Compr Physiol. Author manuscript; available in PMC 2019 Apr 12. Compr Physiol. 2018 Sep 14; 8(4): 1433–1461. Published online 2018 Sep 14. doi: 10.1002/cphy.c170045. PMCID: PMC6460475. NIHMSID: NIHMS1017910. PMID: 30215866

[20] Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing




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