Zinc, Copper and Manganese Flashcards
What are Zn, Cu and Mn considered to be?
Usually defined as ‘transition elements’ or metalloenzymes
* (d or f sub-shells of their oxidation states can ‘transfer’ between different states).
* Zinc, technically not transition element, but has the same properties; complexes in which the metal is the central atom- called a Lewis acid or Metal-ligand or ‘metalloenzyme’
Chemical basis for Metalloenzyme complex
metal ion + ligand = metal ion complex
Properties of Metalloenzymes
Metalloenzyme properties are synonymous with Zinc due to over 200-zinc-containg metaloenzymes (20 distinct biological functions)
* Copper and Manganese have important metalloenzyme properties as well
biological roles of metalloenzymes
Four general biological roles of metalloenzymes
* signaling
* structural
* catalytic
* regulatory
prevalance of Zn
one of the most common ions within the cell (except K+ and Mg2+) and Zn2+ is found in every compartment and organelle in the cell (makes it available for metalloenzyme reactions and functions).
* over 200-zinc-containg metaloenzymes (20 distinct biological functions)
Properties of Zn
- A very strong Lewis acid
- Can only function in one valence state (2+) so limits the types of reactions it can be in
Which metalloenzyme is the strongest lewis acid?
Copper
* but not as abundant in the cell as Zn
What are the valence state of Cu and Mn?
Manganese and copper can function in different valence states for redox reactions; Cu1+, Cu2+, Mn2+, Mn3+
* They have more electrons and can be involved in more redox reactions
Physiological roles of Zn
- cytosolic and extracellular Superoxide Dismutase (SOD)
- Zinc-Finger Proteins and transcription factors
What is SOD
superoxide dismutase which catalyze the reaction to remove superoxides.
* Takes the oxide and makes hydrogen peroxide which is still bad but oxide is worse
How does SOD work
Transition metals can cycle through valence states to accept and donate electrons in reduction/oxidation steps.
Different forms of SOD
- Cu/Zn-SOD: intracellular (cytosol) and extracellular fluids
- Mn-SOD: primarily associated with the mitochondria.
What can reduce SOD activity and what happens?
Reduced SOD activity can occur when Cu/Zn and/or Mn is deficient
* increased lipid peroxidation, oxidative stress, reduced energy regulation in mitochondriacan
* affect glucose utilization/insulin balance, etc
What does oxidative stress cause?
It can break down cell tissue and cause DNA damage. This damage can also result in inflammation. These factors can lead to lifelong diseases like diabetes or cancer, in some cases.
Zn role in SOD
Zn2+ serves a structural role in cytosolic and extracellular SOD
* Zinc is important in the folding of the protein
* SOD also requires a redox reaction that utilizes either Cu or Mn
Describe the Zinc-Finger Proteins and transcription factors
During gene transcription there is folding pattern of a sequence of amino acids around Zinc to form a loop or finger that then permits the folded region to stabilize the DNA sequence which can then turn them off or on
* Zinc finger region or ‘motif’ is thought to require 4 amino acid residues.
* many instances of zinc fingers thought to be essential for certain genes; however, limited proof for there existence.
Immune properties of Zn
Zinc involved with the maintenance of B and T cells (lymphocytes)
* Reduced Zinc is associated with decreased thymulin hormone and in turn caused a reduction in the size of the thymus (thymus controls production of T lymphocytes).
Immune properties of Cu
- Copper is thought to help maintain neutrophils and granulocytes, may facilitate maturation process of early stem cells.
- May also regulate T cell proliferation possibly through IL-2 (cytokine) production (mechanism still unclear).
Physiologica roles of Cu
- Ceruloplasmin
- bone mineralization
- SOD
Cu in ceruloplasmin
ceruloplasmin is the protein involved in the transport of copper around the body
* Regulated and secreted by the liver in response to Cu concentrations and other hormones.
* 90% of plasma Cu is bound to Ceruloplasmin
* Ceruloplasmin is also thought be responsible for the oxidation of Fe2+ to Fe3+.
Ceruloplasmin role in iron metabolism
may assist in feroxidase function in mobilizing stores iron
Cu role in bone mineralization
providing the collagen matrix via lysyl oxidase (linkage enzyme which contains Cu).
* Lysyl oxidase can also affect elastin
How does Cu deficiency affect elastin?
thought to be responsible for cardiac dysfunction
during copper deficiency (mechanism unclear)
* elastin helps with constriction so Cu deficiency can lead to too much relaxation
physiological role of Mn
Proteolglycans and Cartilage formation
* Proteoglycan makes up the network of glycoproteins that make up cartilage and consist of a core protein skeleton which provides the scaffolding for elongation of sulphate chains, glycosaminoglycan chains, and Mn is required for the synthesis of glycosaminoglycan.
Affect of Mn deficiency
Deficiency in Mn can result in poor cartilage formation, skeletal and skin abnormalities (including reduced growth, complications with small bones in ear leading to ataxia and imbalance)
Where is absorption of Zn, Cu and Mn regulated?
Absorption is regulated at the intestinal level
* All three are absorbed throughout the small intestine (copper maybe also in the gut)
efficiency of absorption of Zn, Cu and Mn
Due to the presence of both carried-mediated (co-transport) and non- regulated diffusion (passive), overall efficiency is low, but is typically linearly related with amount of mineral available in the diet.
* Most is done with the transporters but high concentration diffusion occurs
Mechanisms for regulating Zn absorption
ZIP4 & Zn-MT respond to Zn status work together to ensure Zn homestasis
* ZIP4 goes up when Zn is low to get more in.
* Zn-MT is upregulated with excess Zn and binds to it to prevent it from going into the body
What is MT?
Metallothionein
* a low molecular weight protein produced intracellularly in response to high levels of Zn or Cu (also cadmium and mercury).
What is MTs role?
Overall, MT decreases the absorption of metal by binding (and maybe store) metals within the cell, thus, MT can block or reduce metals from being delivered to the basolateral side of the cell if they are consumed in excess.
* Thought to bind Zn and Cu by same mechanism
What happens to MT-bound metals in enterocytes?
Enterocytes that accumulate MT-bound metals are eventually sloughed off from the mucosa and excreted.
What can interfere with with MT role?
Can be interfered with by presence of other heavy metals.
Mechanisms for Cu absorption
Ctr1 & CuMT
* Main form transported into enterocyte in Cu1+ through Ctr1
What is the problem with MT if excess Zn but low Cu? (or vicerversa)
Eating excess Zn upregulates MT which may also bind to Cu and therefore may impair Cu transport
What can inhibit Zn and Cu absorption?
Calcium and phytates (binding) can inhibit zinc and copper absorption (negatives bind positives)
* High calcium inhibits zinc absorption, but the mechanism is unclear. It may increase binding of Zn to phytate or fiber. It may increase Zn excretion into feces independent of Zn absorption.
Transport of Zn
Once absorbed, Cu and Zn bind to albumin (not generally left in plasma as free ions) and transported to the liver for re-packaging.
* Zinc is re-packaged and bound to alpha-2 macroglobulin.
* copper is also re-packaged into Ceruloplasmin
Plasma distribution of bound- Zn and Cu
- Zn - usually around 55-60% albumin; 40% alpha-2 macroglobulin; some residual in metaoenzymes complexes.
- Cu - 90-95% of plasma Cu is bound to Ceruloplasmin
Significance of Cu-ATPase-like proteins
Regulates export of Cu from cells
* Diseases such as Menke’s Syndrome (ATP7A mutation) and Wilson’s disease (ATP7B mutation) are proof that genetic mutations in this protein can cause accumulation and/or loss of Cu from certain cell types (different isoforms explain different side effects)
Wilsons disease
inherited disorder in which excessive amounts of copper accumulate in the body, particularly in the liver, brain, and eyes (ATP7B mutation)
* consequently liver disease (Children/teenagers) and neuropsychiatric symptoms (20s) are the main features
Menkes syndrome
X-linked recessive disorder that affects copper transport leading to copper deficiency.
* The onset of Menkes disease typically begins during infancy, affecting about 1 in 100,000 to 250,000 newborns.
* Infants do not live past the age of 3.
Storage of Zn and Cu
Animals that are fed Zn/Cu and Mn-deficient diets show a rapid decline in the plasma concentrations of these metals suggesting that there no large pools of storage
* Metallothionein thought to be involved in some storage but considered primarily as detoxification protein (binding heavy metals).
How does the body control the ‘distribution’ of zinc from the liver to the plasma
by inducing hepatic levels of MT through cytokine and glucocorticoids.
Transport and Storage of Mn
- Manganese is thought to bind directly to alpha-2 macroglobulin and then transported to the liver
- It is thought due to the fact that Mn2+ can exist in the Mn3+ state, it can act in a similar fashion to that of iron, thus Fe receptor mediated absorption, transport (transferrin) and maybe storage (ferritin) can all be applied to Mn as well.
- not sure if this is competitive
Excretion of Zn, Cu and Mn
Normally very little Zn, Cu and Mn lost through urine or skin. Most loss through feces; including sloughing of intestinal cells from the GIT (can be significant during high dietary intake when cellular levels of Metallothionein are greatest). Most of the GIT loss is from the incorporation of metals into bile (can be concentrated and then excreted).
* Mn is actively transported in bile from the liver (when not needed), 150 fold the concentrations of plasma in bile.
* Almost all copper excretion is via the bile.
Zn food sources
- seafood especially oysters
- meats, especially red and organ
- whole grain products
- not fruit or veg; phytates can reduce
Zn RDAs
- M - 15 mg/d
- F - 12 mg/d
- ↑ in pregnancy and lactation
Food sources of Cu
- organ meats
- nuts
- shellfish or beef but NOT chicken, dairy or some fish
Cu RDAs
- M/F - 1.5-3.0 mg/d
- Pregnancy and lactation up a little
Mn food sources
- whole grain products
- nuts
- tea
- not seafood, meats or dairy
Mn RDAs
- Adult females lower than adult males
- Pregnancy and lactation up a little
Assessment of Zn, Cu and Mn status
No reliable functional assessment or marker of physiological activity for any of these metals has been determined.
* Normally Zinc concentrations do not vary unless in extreme deficiency, some variation during pregnancy and can be confounded by fluctuation in plasma albumin concentrations.
* Ceruplasmin is thought to be a good marker of Cu status but is very sensitive to acute inflammation (underlying colds and small infections can raise levels significantly).
* Urinary concentrations does not provide an accurate marker of the overall status of these minerals (Excreted mostly in feces).
Symptoms of Deficiency
- Zn: poor growth, mmune dysfunction, pooe wound healing
- Cu: skeletal defects, cardiac enlargement, lower aortic elasticity
- Mn: Abnormal bone
Zn toxicity
as little as 6-10 times the RDA can initiate some toxic side effects, reduced HDL levels, impaired immunity, induced copper deficiency, vomiting and fatigue.
Cu toxicity
10 mg/day can cause side effects; weakness, anorexia, vascular dysfunction and if maintained chronically can be fatal
Mn toxicity
No evidence of Mn toxicity from food. Some airborne emissions from combustion and refineries can increase exposure to Mn. Some countries have fuel additive that contain very high quantities of Mn. Neurological side effects (chronic) and can affect organs including pancreas.
