Copper Deficiency In Humans

LeeLemonoil

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So according to Peat thyroid function is of the essence for proper copper homeostasis and metabolism. If that is not the case some crucial enzymes like SOD1 will be impaired as may well be other systemic mechanisms.
Shabby thyroid function can cause the accumulation of bio-unavailable copper then turning toxic while not utilising copper for its proper functions. Zinc might prevent or balance out some of that but also might aggravate the issue .
 

Evgenij

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My experience with copper and zinc.

At the end of 2017, I was practicing "HPU therapy" with high doses of zinc, which caused a copper deficiency, or rather, made my bad copper status even worse. In the end I had copper with 54 µg/dL and ceruloplasmin with 16 mg/dl. I felt even more terrible... Then I stumbled across Morley Robbins and understood what was going on. In the meantime I have eaten MANY dried and fresh raw beef liver. Up to 1 kilogram per month. Now my copper has increased to 82 µg/dL and ceruloplasmin to 21 mg/dl. But the interesting thing is that my zinc status has increased massively WITHOUT supplementation. Before the "HPU therapy" zinc was 63 µg/dL. The zinc supplements increased the level to 74 µg/dL. Then I stopped the supplements and the level dropped to 72 µg/dL. But now I have a zinc level of 99 µg/dL (last lab test: 07.01.2020). I have often read that you can increase your zinc levels with copper. Homeostasis? And although the zinc levels have risen, I still have white spots on my fingernails...

I wonder why I don't get higher copper levels with the beef liver, because I eat enough of it. Perhaps there is too little copper in it or I am missing the cofactors? It is known that adrenal function is responsible for the production of Cp. My goal is increase copper to 100 µg/dL and Cp to 30-35 mg/dl.
 

Evgenij

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In this study, up to 8 mg copper per day was administered and an additional 2.4 mg intravenously. The result looks good, but I would never do this therapy because it is not safe.
Case 1

A 53 year-old Caucasian woman was referred to the Neurology Service of Emory University School of Medicine for evaluation of abnormal gait and anemia. The patient initially noted a sensation of painful paresthesias in her feet bilaterally that worsened in severity over time and progressed to the level of her thigh. Over an eight-month period, her ability to ambulate gradually deteriorated such that that on presentation, the patient required a wheelchair. Her past medical history included RYGB surgery for morbid obesity approximately 21 years prior to presentation but no other significant past medical history. She received 1000 µg vitamin B12 subcutaneously monthly for many years, but otherwise received no vitamin or mineral supplementation. Physical exam revealed absent positional and vibratory sensation in the lower extremities to the knee. Fine touch sensation was decreased in a stocking distribution to the level of her thighs, and she had 3+ knee and ankle reflexes bilaterally with an absent Babinski sign. Her gait was broad-based and unsteady. She displayed an intact mental status and cranial nerve examination was unremarkable. She had normal strength, bulk, and tone throughout. Her physical examination was otherwise normal.

Initial laboratory examination revealed hyopochromic anemia [hemoglobin= 9.6 gm/dL (normal=11.4–24.4 gm/dL), MCV= 95.7 fL (normal= 79.3–94.8 fL), MCHC= 32.1 gm/dL, (normal=33.5–35.5 gm/dL), white blood cell (WBC) count 4.7 103/mcL (normal 3.6–11.1 103/mcL)] and severe neutropenia (absolute neutrophil count = 403 cells/uL). Blood platelet count, iron studies, folate, vitamin B12, homocysteine and thiamine levels and syphilis serologies were normal. The patient’s serum vitamin B6 level was low at 2.8 ng/mL (normal= 5–30 ng/mL). The serum 25-hydroxy vitamin D concentration was below normal at 11 ng/mL (normal = 20–57 ng/mL). The serum zinc level was elevated at 228 µg/dL (normal = 60–120 µg/dL). A bone marrow biopsy performed to rule out myelodysplastic syndrome revealed sideroblasts but was otherwise unremarkable. An MRI of the brain showed T2-hyperintensity in the white matter but was otherwise normal and a subsequent lumbar fluid examination was normal. After the initial evaluation failed to identify an etiology, the patient was referred to the Winship Cancer Institute of Emory University, where an extremely low serum copper concentration of 4 ug/dL (normal = 80–155 ug/dL), and ceruloplasmin concentration of 3 mg/dL (normal = 21–53 mg/dL) were identified.

The patient was admitted to Emory University Hospital (EUH) and received intravenous copper at 2.4 mg/day over a six-day period and intravenous vitamin B6 (50 mg/day) over 3 days. She was then discharged home and weekly intravenous copper infusions (copper 2.4 mg over 2–3 hours) were arranged based on serial blood copper levels. In addition, the patient was prescribed a complete high-potency oral multivitamin-mineral preparation twice daily (Women's Ultra Mega®, General Nutrition Centers, Inc., Pittsburgh, PA), oral vitamin B6 (50 mg/day) and oral copper gluconate (two 2 mg tablets taken twice daily for a total of 8 mg oral copper per day). One month after intravenous copper replacement was initiated, both her plasma hematologic indices and serum copper levels had returned to normal. The patient’s paresthesias improved; however, vibratory sensation and proprioception remained absent in the lower extremities. Four months after discharge from the hospital, the patient was able to ambulate with a cane, intravenous copper was discontinued and blood copper levels were maintained within the normal range on oral copper supplementation of 8 mg/day. During the period of observation and copper repletion, the patient reported chronic sharp pain in her legs bilaterally, which worsened over time and then gradually improved."

Case 2

A 58 year-old Caucasian woman presented with unsteady gait, numbness and paresthesias involving the lower extremities and hands in a stocking-glove distribution. She had initially noted numbness in her feet that progressed over an approximately twelve-month period, coincident with increasing difficulty walking. On presentation, she was confined to a wheelchair. Her past medical history was significant for an unspecified gastric bypass surgery approximately ten years prior to presentation for severe recurrent peptic ulcer disease. She received 400 µg vitamin B12 subcutaneously monthly for many years, but otherwise received no vitamin or mineral supplementation. Physical examination revealed markedly decreased vibratory sensation and proprioception in the lower extremities bilaterally. Both pin-prick and light touch sensations were moderately reduced below the knees. Her gait was ataxic and she was unable to perform a heal-to-shin test. Strength, bulk, tone, and reflexes were normal throughout. Her physical examination was otherwise normal.

Initial laboratory examination demonstrated anemia (hemoglobin = 8.5 g/dL, MCV= 98.4 fL, MCHC = 33.6gm/dl, leukopenia (WBC =1.9 103/mcL) and severe neutropenia (absolute neutrophil count = 475 cells/µL), Blood platelet count, iron studies, folate, vitamin B12, homocysteine and thiamine concentrations, and syphilis serologies were within normal limits. A bone marrow biopsy showed a hypocellular but otherwise normal marrow. An MRI showed T2-hyperintensity in the dorsal columns of the cervical spine and the results of a lumbar puncture examination were unremarkable. Electrophysiology studies revealed a predominately sensory generalized neuropathy. Further laboratory examination demonstrated that the patient was markedly copper deficient, with a serum copper concentration of 2 ug/dL and a serum ceruloplasmin concentration of 2mg/dL, respectively.

Upon replacement with intravenous copper as an inpatient at EUH (2.4 mg daily for 6 days), followed by weekly intravenous copper (2.4 mg) combined with oral supplementation of 8 mg copper/daily, the patient’s hematologic indices normalized after week and her sensation to light touch slowly improved over a several week period. Four months following diagnosis of severe copper deficiency, she remained ataxic due to a residual deficit in proprioception and vibratory sensation in her lower extremities and required a cane for ambulation. However, 7 months following copper repletion (21 weeks of combined intravenous and oral copper therapy followed by 7 weeks of oral copper therapy alone) the patient did not need any assistance in walking and her lower extremity neuropathy continued to improve."

Acquired Copper Deficiency: A Potentially Serious and Preventable Complication Following Gastric Bypass Surgery
I wonder if one has to dose lower with copper(I) compounds because it have a higher bioavailability?
 

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Giraffe

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A study in post-menopausal women found that a moderately high intake of zinc suppressed magnesium balance, but did enhance copper balance:

Table 2 Effect of zinc and copper intakes on magnesium balance during the last 36 days of each 90-day dietary period

As reported earlier (Milne et al, 2001), the moderately high dietary intake of zinc in the present study did not decrease copper balance (−1.6 compared to −1.4 μmol/day with low dietary zinc) when dietary copper was low (15.7 μmol/day or 1 mg/day), and significantly enhanced copper balance (+2.8 compared to −0.8 μmol/day with low dietary zinc) when dietary copper was unquestionably adequate (47.2 μmol/day or 3 mg/day). Moreover, the moderately high dietary intake of zinc did not decrease serum ceruloplasmin or platelet cytochrome c oxidase activity. These findings suggest that some of the changes considered undesirable by a moderately high-zinc intake reported in the past might have been the result of an antagonistic effect on magnesium metabolism, not copper metabolism.

Calcium and magnesium was supplemented because making the basal diet low in copper and zinc resulted in the exclusion of foods high in these minerals.

.....

And here is rat study:

Body temperature and thyroid hormone metabolism of copper-deficient rats - ScienceDirect

This findings indicate that copper deficiency without anemia decreases tissue copper and selenium status and is associated with impaired thyroid hormone metabolism and mild hypothermia in rats at maintained at 24°C.


The rats on the copper deficient diets also had more body fat than the rat with adequate copper intake (CuA).

copper deficient rat.GIF


.....

Foods that provide zinc and copper with other nutrient cofactors are the safest.
:+1
 
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Amazoniac

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- Low copper-2 intake in Switzerland does not result in lower incidence of Alzheimer’s disease and contradicts the Copper-2 Hypothesis

"George Brewer has advanced the hypothesis that the anthropogenic factor causing the current AD epidemic is “free” copper in drinking water, dietary supplements, and meat; he calls this “copper-2,” chemically Cu2+ or Cu(II).[3–5] In contrast, he calls copper in other food, such as vegetables, as “bound” copper or “copper-1,” chemically Cu+ or Cu(I), which is supposedly benign. Why would copper-2 be more toxic than copper-1? Brewer argues that that this is due to the ability of copper-2 to bypass the liver and to appear in the blood already 1–2 h after consumption, while copper-1 takes 1–2 days to pass to the blood stream.[6] It is doubtful whether such a sharp distinction between copper-1 and copper-2 can be made. Once copper ions have been taken up by the body, it is the local environment (oxidizing in blood, reducing in cells) and the binding to proteins and small molecules that dictates the +1 or the +2 oxidation state, irrespective of how the copper entered the body. Also, there is only one very limited study available on the oxidation state of copper in food.[7] Conceivably, the oxidation state of copper is only secondary to other effects it might have."​
 
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Amazoniac

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- 10. The stress of darkness | Generative Energy

"Just as there are multiple hormonal and nervous systems which ensure the reliability of our physiology, we should expect red light to have more than one beneficial function. For example, it could quench excited electrons, desorb inhibitory toxins, maintain enzyme function, mobilize stored copper, and regulate the conductivity of subcellular structures."​
 

ljihkugft7

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Too much sulfur causes copper deficiency:
Studies of a naturally occurring sulfur-induced copper deficiency in Przewalski’s gazelles

Garlic, onions and eggs are the worst. Sulfites contribute too. You will know you have way too much sulfur (or improperly metabolized sulfur) when your pee smells like sulfur and people say you smell like eggs.
To process sulfur molybdenum and vitamin b6 come up. Salt apparently increases sulfur, with copper, calcium and potassium antagonizing it along with "vitamin b15". ( Selenium Sulfur DRI/RDA, benefits, side effects, overdose, toxicity, requirements )

So those with copper deficiency may be having too much sulfur in their diet. Wines, dried fruits have sulfites added and so on.

Salicylates can hinder the pst pathway and thus interfere with metabolism of sulfur. Coconut oil and aspirin are high sources of salicylates. ( a list of foods Salicylate Foods - sensitivity, intolerances and food list. — ATP Science )

Thus consuming too many salicylates with your sulfur may interfere with proper metabolism of sulfur, thereby causing elevated levels that hinder copper absorption.

Excessive sulfur also can induce a selenium deficiency, which is necessary for thyroid function.
High caffeine is touted to interfere with the body utilizing vitamin b6, which is needed for sulfur metabolism.

Thus say a high coffee diet with coconut oil and too many eggs with too many dried fruits could induce excessive sulfur leading to these mineral deficiencies.

I am researching this for myself, as I noted extraordinarily negative effects from consuming raw garlic (2 cloves a day) Mind you large quantities of eggs are a staple in my diet, as is coconut oil.

So much to research.
Thanks for this!
Do you know if it’s the egg yolk or egg white that contains most Sulfur?
 

Ableton

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1 can of oysters has like 1500%rda of zinc and copper, something along those lines.
I trust those ratios more than supplements.

after having a can the other day, I slept extremely well and felt great. Wanted to try megadosing it (1 can every day for a weak) but eventually felt sick after the second can on day 2 + had extreme skin sensitivity (is this copper or zinc?).
So I think I sill stick with a can every 5-7 days or something

also, since introducing regular oysters my waking temps finally improved a bit so the link to hypo might be legit for me
 
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Estimates of copper bioavailability from liver of different animal species and from feed ingredients derived from plants and animals
S Aoyagi 1 , D H Baker, K J Wedekind
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PMID: 8234135 DOI: 10.3382/ps.0721746

Free article
Abstract

Bile Cu accumulation in Cu-depleted chicks fed Cu concentrations between .56 and 1.56 mg/kg was used to estimate Cu bioavailability in several feed ingredients from both plant and animal sources, including liver from different species. Liver from slaughtered animals is rich in minerals and vitamins and is a significant source of Cu in canned pet foods. Liver from different species, however, was found to vary widely in Cu bioavailability (relative to CuSO4.5H2O, which was set at 100%). The bioavailability of Cu in freeze-dried (FD) chicken liver and poultry by-product meal was 116 and 97%, respectively, but that in FD pork liver was not different from zero. Relative bioavailability of Cu in FD beef, sheep, and turkey liver was 82, 113, and 83%, respectively. Copper in FD liver from the rat, a species that does not possess a gall bladder, was 21% bioavailable. Copper in the feed ingredients from plants: corn gluten meal, dehulled soybean meal, cottonseed meal, peanut hulls, and soy mill run was 48, 38, 41, 44, and 47% bioavailable, respectively. In addition, when the fibrous ingredients peanut hulls or soy mill run were added to the basal diet containing .5 mg Cu/kg from CuSO4.5H2O, Cu bioavailability in CuSO4.5H2O was reduced. The results of this study demonstrate a wide variation in Cu bioavailability among feed ingredients originating from plants and animals.

( "The bioavailability of Cu in freeze-dried (FD) chicken liver and poultry by-product meal was 116 and 97%, respectively, but that in FD pork liver was not different from zero." Freeze Dried pork liver no bioavailability? A probable failure of the testing procedure?
 
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Comparison of trace mineral repletion strategies in feedlot steers to overcome diets containing high concentrations of sulfur and molybdenum
Sarah J Hartman 1 , Olivia N Genther-Schroeder 1 , Stephanie L Hansen 1
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PMID: 29546370 PMCID: PMC6095265 DOI: 10.1093/jas/sky088

Free PMC article
Abstract

To compare trace mineral (TM) repletion in feedlot steers after depletion by S and Mo, 72 Red Angus steers blocked by BW (253 ± 14 kg) were assigned (6 steers per pen, fed via GrowSafe bunks) to corn silage depletion diets (depletion, DEP) supplemented with NRC (1996) recommended concentrations of Cu, Mn, Se, and Zn (CON) or supplemented with 0.3% S (CaSO4), 2 mg of Mo/kg dry matter (DM), and no added Cu, Mn, Zn, or Se (antagonist, ANT). Three 62 d TM repletion strategies (repletion, REP) were applied within DEP diets on day 89: 1) Multimin90 injection (contains Cu, Mn, Se, Zn) and 100% of recommended Cu, Mn, Zn, and Se from inorganic sources (ITM), 2) saline injection and 150% of recommended TM from inorganic sources (ING), or 3) saline injection and 150% of recommended TM provided as 25% organic and 75% inorganic sources (BLEND). Subcutaneous injections were given at 1 mL/68 kg BW. Inorganic sources were Cu, Mn, and Zn SO4, and sodium selenite, and organic sources were Availa Cu, Mn and Zn, and SelPlex Se. Repletion period liver and blood were collected on day -10, 14, 28, and 42 and data were analyzed as a 2 × 3 factorial (n = 12 steers per treatment) using Proc Glimmix of SAS with plasma and liver analytes analyzed as repeated measures. Liver Cu, Se, and Mn were decreased (P < 0.01) by ANT during DEP. There were no DEP × REP × day interactions in liver TM (P ≥ 0.18). A DEP × day effect was noted for liver Cu (P < 0.01) and Mn (P = 0.07), where ANT Cu increased linearly from day 0 to day 42, CON Cu was slightly increased on day 14 and day 28, and ANT Mn was lesser than CON Mn on all days except day 42. There were REP × day effects on liver Cu (P < 0.01) and Se (P < 0.01) where status was improved by ITM by day 14, increased in BLEND by day 28, and not different by day 42. Liver Se concentrations were lesser (P < 0.01) in ANT vs. CON throughout repletion. Liver Zn was greater (P < 0.01) on day 0 than day 14, 28, and 42, and concentrations were greater on day 42 than day 28. Glutathione peroxidase activity tended to be lesser (P = 0.07) on day 14 relative to other days. Manganese superoxide dismutase activity was lesser (P < 0.01) on day 14 and 28 compared to day 0 and 42, and tended to be lesser (P = 0.06) in ANT than CON during repletion. Final body weight (BW) and average daily gain (ADG) were not affected by treatment (P ≥ 0.60), and ANT decreased dry matter intake (DMI) (P = 0.04) and improved G:F (P < 0.01) during repletion. All repletion strategies were effective at increasing TM status of steers, and ITM had the most rapid recovery of Cu and Se status, followed by BLEND, and ING.
 
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Any ideas on this? I saw conflicted results toward the gluconate.

Lack of effects of copper gluconate supplementation
W B Pratt, J L Omdahl, J R Sorenson

PMID: 2931973 DOI: 10.1093/ajcn/42.4.681

Abstract

A double-blind study was done giving 10 mg of copper/day as copper gluconate or placebo capsules for 12 wk. The seven subjects receiving copper gluconate had no change in the level of copper in the serum, urine, or hair. There was also no change in the levels of zinc or magnesium. There was also no significant change in levels of hematocrit, triglyceride, SGOT, GGT, LDH, cholesterol, or alkaline phosphatase. The side effects of nausea, diarrhea, and heartburn were the same in the subjects receiving copper gluconate and subjects receiving placebo capsules.
 

Mauritio

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Any ideas on this? I saw conflicted results toward the gluconate.

Lack of effects of copper gluconate supplementation
W B Pratt, J L Omdahl, J R Sorenson

PMID: 2931973 DOI: 10.1093/ajcn/42.4.681

Abstract

A double-blind study was done giving 10 mg of copper/day as copper gluconate or placebo capsules for 12 wk. The seven subjects receiving copper gluconate had no change in the level of copper in the serum, urine, or hair. There was also no change in the levels of zinc or magnesium. There was also no significant change in levels of hematocrit, triglyceride, SGOT, GGT, LDH, cholesterol, or alkaline phosphatase. The side effects of nausea, diarrhea, and heartburn were the same in the subjects receiving copper gluconate and subjects receiving placebo capsules.
Following
 
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Amazoniac

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- Coordination chemistry of copper proteins: How nature handles a toxic cargo for essential function

"Plentiful and diverse hypotheses on the origin of life on Earth have included the archaic notion of spontaneous generation, the classic theory of a primordial soup, the exotic idea of panspermia or exogenesis, and modern hydrothermal vent theories. While emphasis usually focuses on the origin of organic compounds as the building blocks of life, modern theories include the contribution of metals in the process. Of particular interest for this review article is copper, a metal that was likely unavailable when life arose on Earth but became pivotal for evolution of complex organisms. At the time of abiogenesis, Earth's oceans were void of oxygen and abundant in H2S. As a result, copper would have existed primarily in the form of extremely insoluble sulfides. The rise of oxygen-producing photosynthetic bacteria dramatically altered the metal composition of the early oceans as the new oxidative environment altered the solubility, and thus availability, of metal ions [1]."

"A glance at the solubility products of metal sulfides of biologically relevant first row transition metals, shown in Table 1 [2,3], reveals the limited diversity of available free metal ions that developing life could utilize for metalloproteins."

1610811136931.png

"The first enzymes to incorporate metals likely appropriated Fe2+ and Mn2+, as these were the most soluble and abundant. It was the utilization of Mn2+ that led to the rise of photosynthetic cyanobacteria and the mass production of O2 2.7 billion years ago (GYA) [4]. It is believed that for the first 200–300 million years O2 produced by cyanobacteria in the upper ocean was consumed by the oxidation of Fe2+ to Fe3+, resulting in the precipitation of iron from the ocean surface as Fe(OH)3. Continued oxygen generation stratified the ocean, with upper zones becoming oxic and the deeper waters remaining anoxic. The anoxic layer is also believed to have become more sulfidic via continental weathering and the action of sulfate reducing bacteria [5]. The increased sulfide content would also contribute to the loss of oceanic iron via the formation of insoluble pyrite (FeS2) [6], which, accompanied by continued oxygenation of the ocean and precipitation of iron as Fe(OH)3, eventually resulted in the mass precipitation of iron from the ocean. Concurrently, copper was liberated from insoluble sulfide via oxidization of Cu(I) to the more soluble Cu(II)."

"The advent of O2, the disappearance of soluble iron, and the concurrent solubilization of copper resulted in dramatic changes in the chemistry and biochemistry of early life [7]. Iron had become an essential element, acting as a cofactor in many enzymes. The precipitation of insoluble iron required a reinvention in the mechanisms used to acquire it. Early life adjusted by excreting organic acids and strong iron chelators (siderophores) to solubilize the metal, and developed sophisticated methods by which to then obtain it [1]. Organisms also evolved methods to sequester Fe3+ for later use, most notably via ferritin, the ubiquitous iron storage protein [8]."

"The rise of O2 altered the redox chemistry of the environment. In the absence of O2, life had adapted to reaction systems in the lower portion of the redox potential spectrum, limited by the H2S/S and H2/H+ potentials ranging 0.0 to −0.4 V at a pH of 7 [9]. The presence of O2 increased the upper limit of the range to 0.8 V, leading to oxidation and degradation of organic compounds and cellular components vital for life. Soluble copper also proved hazardous to early life as it can potentially replace essential metal cofactors, including Zn [10] and Fe [11], in proteins, and catalyze the formation of reactive oxygen species (ROS) that have been associated with DNA/RNA lesions, protein oxidation, and lipid peroxidation [12–16]. Oxygen would eventually transform from poison to a necessity as the final electron acceptor to produce ATP in aerobic respiration. Life would also evolve uses for copper, thus transforming a potential poison into a useful and required cofactor. As a result, life evolved highly sophisticated networks that would allow organisms to acquire, transport, sequester, and export copper to maintain requisite amounts while preventing accumulation of toxic levels."

"[..]protein copper binding sites are dominated by histidine, cysteine, and methionine residues, shown in Fig. 1. This occurrence is in agreement with the Hard and Soft Acids and Bases (HSAB) principle [17,18]."

1610811147029.png

"[..]other amino acids also participate, but these three are the most common."

"Applying HSAB to the metal of interest, we see that Cu(I) is a soft acid while Cu(II) is borderline, thus, we would expect copper binding sites to be dominated by amino acids containing side chains with soft or borderline ligands. Amino acids with nitrogen and sulfur donor atoms, histidine and cysteine and methionine, respectively, would therefore be preferred over amino acids with hydroxyl, carboxyl, or primary amine side chains, as found in serine and tyrosine, aspartate and glutamate, and asparagine, glutamine, and arginine, respectively."

- Proteinogenic amino acid - Wikipedia

"Histidine contains an imidazole functional group that contains two nitrogens, both of which can be protonated, with pKa values of ~6 and 14 [?︎] for the free amino acid. These values can be altered by the protein environment and by coordination to metal ions. Loss of the first proton provides a neutral imidazole nitrogen donor, whereas loss of the second proton provides an anionic imidazolate. With two nitrogen donors on opposite sides of the ring, imidazolate can bridge two metal ions."

1610811165616.png

Source: the internet.

- histidine titration curve - Google Search

"The thiol side chain of cysteine also contains a proton (pKa ~8.5) that must be removed so that the anionic thiolate becomes the active metal-binding functionality. The thiolate sulfur can also bridge two metal centers. Cysteines are redox active and can oxidize to form disulfide cross-linked cystine."

"Methionine, in contrast, does not form cross links and does not contain a protonatable side chain. Its thioether functional group therefore provides a neutral sulfur donor that does not have the same pH dependence as histidine and cysteine and is less prone to oxidation than cysteine (although it can be oxidized under some conditions to methionine sulfoxide and methionine sulfone). The methionine side chain is also considerably more hydrophobic than the other two residues, a property that can influence solvent accessibility and protein–protein contacts."

"Another important feature of the ligand set (both its composition and its geometric arrangement) is its influence on the reduction potential of the metal center. For cuproenzymes, this feature is critical for executing catalytic redox function. For copper transport proteins, on the other hand, this feature is critical for avoiding redox cycling of copper between Cu(I) and Cu(II). Which is the toxic species, Cu(I) or Cu(II)? The answer is neither, but both. It is important to think of copper not as a static ion, but rather in the context of its coordination environment, which ultimately dictates its reactivity. If the coordination environment shifts the reduction potential positive, the metal will be held in its Cu(I) state, whereas a more negative potential will favor Cu(II). The dangerous window occurs when the Cu center can be reduced from Cu(II) to Cu(I) (by ascorbic acid or glutathione for example), then oxidized back to Cu(II) by O2 or H2O2 to generate hydroxyl radicals, then the cycle continues. Coordination environments that favor Cu(I) (such as the sulfur-rich sites seen in many of the copper transport examples described below) can therefore avoid toxic reactivity by making it harder to oxidize the metal center under the prevailing biological conditions."

"The chemical properties of this small ligand set thus provide a choice of nitrogen or sulfur donor, neutral or anionic charge, pH-dependent or independent metal coordination, hydrophobic or hydrophilic character, the ability to bridge multiple metal centers, and different susceptibilities and consequences of oxidation of both the ligand and the metal."

"Copper A and B centers, CuA and CuB respectively, are both found in cytochrome c oxidase (CcO), a large multidomain protein that is the last enzyme in the electron transport chain (Fig. 5) [50]. The mixed valence CuA center is located in the Cox2 domain and contains 2 copper atoms bridged by 2 cysteine residues, both in tetrahedral geometry. The first is also coordinated by a histidine and a methionine, while the second is coordinated by a histidine and the carbonyl oxygen of a glutamate residue. The CuA site is believed to be the cyctochrome c electron acceptor, which then donates the electron to the internal heme. In the CuB site, located in the Cox1 domain, copper is bound by 3 histidine residues in a trigonal pyramidal geometry. The open face of the CuB is believed to be part of an oxygen binding site involved in electron transfer from the heme."


"Protein networks involved in copper resistance are predominantly found in prokaryotes, particularly gram-negative bacteria [134]. Bacteria remove excess copper from the cytosol by utilizing the ATPase CopA. While this effectively removes the poisonous metal from a gram-positive bacterium, gram-negative bacteria still need to manage copper that enters the periplasm."

"Eukaryotes employ different strategies to deal with excess cellular copper, one example being sequestration via metallothionein. Many studies have shown that the metallothionein plays a role in copper detoxification [162–165]. Other studies suggest that it may store the metal until it is required for insertion into apo-copper chaperones [166,167] and apo-copper enzymes [163,164]. These theories are certainly not mutually exclusive. Metallothionein is a small protein, 53 amino acids, containing 12 cysteine residues, and has been observed to bind between 6 and 8 equivalents of copper [168,169]."

"Enzymes and proteins that utilize copper as a cofactor bind the metal in high affinity, high coordinate environments (i.e. coordination numbers 4–5) that prevent loss of the metal during redox cycling. Copper trafficking proteins, on the other hand, promote metal lability either by having low affinity binding sites with moderate coordination numbers (usually ~4), or by having fewer ligands (i.e. coordination numbers 2–3) that bind with high affinity. Both of these strategies retain the metal but allow transfer under appropriate conditions. Furthermore, the metal cargo is usually conveyed as the more labile Cu(I) oxidation state. The binding sites are dominated by methionine, histidine, and cysteine residues, as predicted by the HSAB principle. Each one of these amino acids has unique copper binding properties, including oxidation state specificity, affinity, and pH dependence. These properties have been exploited by nature when evolving different copper proteins that perform different functions. As histidine is the only borderline ligand, it has the ability to effectively bind both Cu(I) and Cu(II), as opposed to the soft methionine and cysteine ligands that more effectively bind Cu(I). Cysteine exhibits the strongest affinity for copper as a result of the electrostatic character of the coordinate covalent bond that is lacking in histidine and methionine interactions with copper. Histidine and cysteine bind copper via protonatable side chains with pKa values for the free amino acids of 6 and 8, respectively, and thus exhibit pH-dependent binding affinity."

"As we have observed, the coordination chemistry of the electron transfer proteins and the oxidoreductases is dominated by higher coordination environments comprised of mostly histidine residues. Histidine can accommodate cycling between both oxidation states of copper without a considerable decrease in binding affinity that may result in the metal vacating the binding site. Cysteine is also commonly found in these binding sites, presumably to increase affinity for Cu(I), preventing metal loss. Methionine is rare in these binding sites and when found is usually a weakly coordinated axial ligand."

"The high affinity copper transport proteins, or Ctr proteins, are perhaps some of the most diverse in terms of the variety of binding sites found in different versions expressed across the eukaryotic branch of life. While yeast and human Ctr1 (yCtr1 and hCtr1, respectively) have been the most studied, both structurally and biologically, a fair amount of biology is also known about the green algae version of Ctr1 (crCtr1). Each of these organisms binds copper with motifs of varying composition, yCtr1 with just methionine residues, hCtr1 with histidine and methionine, crCtr1 with cysteine and methionine; however, all three copies also contain a conserved methionine motif in the second transmembrane domain involved in transport of copper through the pore. The N-terminal, extracellular binding sites are most similar to those of the copper resistance proteins in that they bind copper with low affinity, presumably to facilitate movement of copper along the distribution network. They differ in mode of binding: the resistance proteins bind copper in highly organized binding sites with amino acids that can be of considerable distance from each other in primary sequence, while the Ctr1 proteins bind copper in flexible contiguous motifs. The C-terminal binding sites are more similar to those observed in the intracellular copper proteins with coordination environments dominated by cysteine residues, with the occasional histidine. These are also presumed to be labile binding sites can hand off copper to the copper chaperone proteins."


"We recently published a detailed analysis on how the individual chemical characteristics of the amino acids methionine, cysteine, and histidine affect Cu(I) binding by model Mets motif peptides of the sequence MG2MXG2M, where X is either Met, His, or Cys [204]. Comparison of the relative Cu(I) binding affinities revealed that at neutral pH Cys binds more tightly than His, and His more tightly than Met (pH 7.4 Cys>His>Met); at acidic pH Cys still exhibits the greatest affinity, however, Met binds more tightly than His (pH 4.5 Cys>Met>His). Cys is the most susceptible to oxidation, followed by Met, with His the most resistant to oxidation (Cys>Met>>His). Together, these findings highlight how the chemical properties of these amino acids, notably their susceptibility to oxidation and how their metal binding affinity depends on pH, provide preferences for use of certain amino acids over others in certain environments. For example, incorporation of cysteine is ideal for copper accumulation in hypoxic environments where the metal is scarce, as is the case for certain green algae [209]. Methionine, on the other hand, is well suited for copper accumulation in acidic, oxidative environments, as is the case for yeast [210] and likely in the human small intestine. Histidine would be preferred in neutral, oxidative environments where methionine-rich motifs may not bind tight enough, which may be the scenario in the extracellular environment of higher organisms."

⬑ [204] A comparison of methionine, histidine and cysteine in copper(I)-binding peptides reveals differences relevant to copper uptake by organisms in diverse environments

"Copper trafficking proteins include integral membrane proteins that transport copper across cell and organelle membranes, copper chaperones responsible for shuttling the cofactor to respective cuproenzymes, and resistance proteins utilized to prevent accumulation of toxic levels of copper.[1–4] In contrast to the enzymes and proteins that utilize copper as a cofactor and therefore bind copper in coordination sites that prevent loss of the metal during redox cycling, copper trafficking proteins must provide labile sites that enable metal transfer. To accomplish metal selectivity and promote lability, these sites are often specific for copper in its reduced, +1 oxidation state and bind with either low affinity or with low coordination number so as to facilitate ligand exchange reactions for metal transfer. Methionine, an amino acid that is rarely found in the active sites of cuproenzymes, is emerging as a critical residue involved in mechanisms of copper transport.[5] When methionine is found at a cuproprotein active site, it is typically a weakly coordinated axial ligand that plays a supporting role in addition to histidine and cysteine side chains, as in electron-transfer blue copper proteins, for example. The membrane-bound copper transport proteins of the Ctr1 family, however, contain methionine-rich sites, or “Mets motifs” that can accommodate Cu(I) binding in flexible, thioether-only binding sites of the form MX1–2MX1–2M (where X is a non-coordinating amino acid).[6]"

"Each of these amino acids, methionine, histidine, and cysteine, exhibits different Cu(I) binding characteristics that can vary based on environmental conditions like pH and the presence of oxygen. These different characteristics appear to have been utilized during evolution to fine-tune the binding affinity of copper trafficking proteins under specific conditions, allowing them to function optimally."

"Yeast acidify their surrounds to pH 4–5.[19] As cysteine and histidine have ionizable sides chains with pKa values of 8 and 6, respectively, their ability to bind copper should diminish as the pH decreases. Cysteine is also susceptible to oxidation, forming disulfide bonds with neighboring cysteine residues. Mets motifs would therefore appear to be optimal for yeast because they exhibit an affinity for Cu(I) that is independent of pH, and they are less susceptible to oxidation."

"Some green algae express cysteine in addition to methionine on the N-terminus of Ctr proteins. The best studied of these are the green alga Chlamydomonas versions of the protein containing six Cys-Met motifs, the most common being CX2MX2MX2CX5/6C.12 These algae often grow in hypoxic, nutrient-poor environments,20 where the low oxygen content results in the precipitation of Cu(I) as insoluble sulfide salts.21 To compensate for the low environmental levels of copper, Chlamydomonas Ctr evolved to bind the metal with an affinity 10–20 times greater than that of the yeast version of the protein.7,22,23 Methionine motifs, exhibiting micromolar KD values,6 alone would not be able to accommodate this high affinity of copper transport, requiring utilization of another copper binding amino acid. Oxidation of cysteine is less problematic considering the hypoxic environment."

"Humans and other mammals express histidine and methionine on the cell surface portion of their Ctr proteins. In separate work, we have examined the copper-binding properties of model peptides containing histidine and methionine residues located on the N-terminus of human hCtr1 and characterized a Cu(II) binding site composed of an H2N-XXH amino terminal copper/nickel (ATCUN) motif as well as a high affinity Cu(I) site in a mixed coordination environment of histidine and methionine.[24] These histidine and methionine motifs are found in the oxidative extracellular environment at physiological pH 7.4. Cysteine would not be suited for these conditions as it could easily be oxidized. At this pH, Cu(II) is not soluble in its aquated form, and is usually found stabilized in extracellular copper binding proteins such as ceruloplasmin and serum albumin. Histidine is likely required by hCtr1 as methionine motifs alone are presumably not strong enough to recruit copper from these carrier proteins. The methionine motifs likely play a more important role in copper acquisition in the small intestine, where the pH ranges from acidic to neutral pH (5–7.3).[25] At acidic pH dietary copper is soluble and histidine is likely not the best Cu(I) ligand due to the protonatable side chain."

"Combined, the results obtained from this study of model peptides elucidate an evolutionary preference for methionine, histidine, or cysteine utilization in the N-terminal regions of Ctr1 proteins of different organisms that have adapted to acquire copper in drastically different environments. While yeast import copper from acidic yet oxic environments, some green algae acquire this nutrient from acidic, copper-depleted and hypoxic environments, whereas mammalian Ctr1 proteins operate in both acidic and neutral oxic conditions. To accomplish the same function of copper acquisition under these different environmental conditions, yeast, green algae, and human Ctr1 proteins incorporate methionine, methionine/cysteine, and methionine/histidine motifs, respectively."

"The methionine/histidine motifs expressed by humans and other mammals have been proposed to facilitate transfer of copper from extracellular proteins like ceruloplasmin and serum albumin to the Ctr1 protein in the oxidative extracellular environment.[24] Histidine is optimal for this function, as the methionine motifs do not exhibit a strong enough affinity to remove copper from these proteins. Methionine, on the other hand, may play a more critical role in copper uptake under acidic conditions, as would be found in the small intestine, for example."

"Understanding the differences among this series of seemingly simple 8 amino acid peptides helps reveal how biological systems adapt to acquire an essential nutrient like copper. The pH dependence on Cu(I) binding and the susceptibility to oxidation of peptides containing clustered Met/His/Cys motifs highlights how Nature uses the chemical differences among imidazole, thiolate, and thioether functional groups to optimize copper acquisition under very different environmental conditions."
 

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Would anyone be able to help me understand the difference between the Copper GHK peptide and the Copper CHK?
 
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- Intravenous and oral copper kinetics, biodistribution and dosimetry in healthy humans studied by [64Cu]copper PET/CT

"Following absorption in the intestines, copper is transported into the portal blood circulation by the ATP7A transporter located in the basolateral membrane of the enterocytes (Nyasae et al. 2007). In the portal vein, copper is bound to albumin, in particular, and to other plasma proteins in a highly exchangeable pool (Winge 1984; Matte et al. 2017). Albumin-bound copper in systemic plasma has a half-life of 10–20 min (Janssens and Van den Hamer 1982) and is effectively extracted during the hepatic first pass (> 80%) (Cousins 1985)."

"After oral administration, the biodistribution was dominated by the hepatic first pass extraction of 64Cu, whereas uptake in organs other than the liver, kidneys, and red bone marrow was negligible when compared with intravenous administration. Moreover, the total %AD [administered dose] taken up from the intestines and measured in source organs did not exceed 50%, which is in accordance with net intestinal copper absorption studies in pigs and humans (Matte et al. 2017; Turnlund et al. 1989). It should be noted that the intestinal absorption of copper is affected by the dietary composition and our results therefore only reflect conditions in the 6 h fasting state (Wapnir 1998)."

1628688314396.png



1628688352519.png

"In the liver, copper is incorporated in ceruloplasmin (biological half-life: 13 h) and then redistributed into the systemic circulation 2–3 days after administration, creating a second peak in blood concentration, also known as the ceruloplasmin wave (Sternlieb 1980; Marceau and Aspin 1972). In the present study, the blood concentration of 64Cu steadily increased after the peak following administration, reflecting copper incorporation into ceruloplasmin. The arterial blood to plasma radioactivity ratio was approximately 55% and increased over the first 90 min, possibly reflecting copper uptake in erythrocytes by the anion exchanger located in the erythrocyte membrane (Alda and Garay 1990)."

1628688401644.png

"To our knowledge, dosimetry estimates for oral administration of 64Cu have not previously been reported. As expected, the radiation dosimetry of 64Cu after oral and intravenous administration differed significantly. While the liver was exposed to a high radiation dose after oral administration, equal or higher doses were received by the intestines due to high amounts of unabsorbed radiotracer. In this context, it is important to acknowledge that the radiation dose to the intestines depends on the individual intestinal transit time, unlike for intravenous administration; in our study, one participant received 925 μGy/MBq to the right large intestine. Consequently, the radiation dosimetry of 64Cu by oral administration may differ substantially between individuals, necessitating a cautious approach to total oral dose used in future studies."

"Because of the dominant hepatic first-pass extraction of copper following ingestion, the concentration of Cu in systemic blood may not be a reliable measure when assessing how well pharmaceuticals impair absorption of copper in the intestine."


I'd have to contact the authors to know the corresponding masses of doses used, but expect them to be low.

"The 64Cu solution was administered as an intravenous bolus injection (n = 4; median dose 73.5 MBq, range 66–116 MBq) or dissolved in water and swallowed (n = 2; median dose 65.5 MBq, range 57–74 MBq)."​

↳ [44] Copper Intestinal Absorption in the Rat: Effect of Free Fatty Acids and Triglycerides
 
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- Comparison of copper and zinc in vitro bioaccessibility from cyanobacteria rich in proteins and a synthetic supplement containing gluconate complexes: LC–MS mapping of bioaccessible copper complexes

Abstract said:
An analytical procedure was proposed to estimate bioaccessibility of copper and zinc in Spirulina Pacifica tablets with respect to that of copper and zinc in gluconate complexes. Spirulina is the common name for diet supplements produced primarily from two species of cyanobacteria, namely Arthrospira platensis and Arthrospira maxima. Spirulina tablets are an excellent source of proteins, vitamins and minerals. To obtain information about the bioavailability of these elements, an in vitro bioaccessibility test was performed by application of a two-step protocol which simulated the gastric (pepsin) and intestinal (pancreatin) digestion. The species obtained were investigated by size exclusion chromatography on a chromatograph coupled to a mass spectrometer with inductively coupled plasma (SEC–ICP–MS) and an on-capillary liquid chromatograph coupled to an electrospray mass spectrometer (μ-HPLC–ESI–MS). Both copper and zinc were found to be highly bioaccessible in Spirulina tablets (90–111 %) and those containing gluconate complexes (103 % for Cu and 62 % for Zn). In Spirulina tablets, copper was found to form two types of complex: (1) polar ones with glycine and aspartic acid and (2) more hydrophobic ones containing amino acids with cyclic hydrocarbons (phenylalanine, histidine, proline and tyrosine). Zinc and copper were also proved to form complexes during the digestion process with products of pepsin digestion, but the stability of these complexes is lower than that of the complexes formed in Spirulina. The results proving the involvement of proteins in the enhancement of copper and zinc bioaccessibility will be useful for the design of new copper and zinc supplements.
 

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