Zinc, Copper and Manganese
Transition Metals and Metalloenzymes a) Lewis acid b) Metalloenzyme
- "Transitional elements" - Zn (technically NOT a transitional element) has similar properties (complexes in which the metal is the central atom - called a ____ ____ (a) or metal-ligand or ____ (b))
Food Sources of Manganese
- 0.7 to 1.7 mg per 1 oz nuts - 0.3 to 0.9 mg per 1/2 cup legumes - 0.9 mg per 1/2 cup brown rice, cooked - 0.7 mg per 1/2 cup oatmeal, cooked - 0.3 to 0.5 mg per 6 oz tea - 0.4 to 0.8 mg per 1/2 cup leafy greens - 0.3 to 0.5 mg per 1/2 cup berries
Food Sources of Zinc
- 2.5 to 6.5 mg per 3 oz crab - 3 to 8 mg per 3 oz beef or lamb - 1.7 to 4 mg per 3 oz pork, chicken, turkey - 0.7 to 1.5 mg per 1/2 cup legumes - 1.2 to 1.8 mg per 1 oz dry nuts - 1.6 mg per 1/2 cup ricotta cheese, part skim
Food Sources of Copper
- 3.7 mg per 3 oz oysters - 1.6 mg per 3 oz lobster - 0.3 to 0.6 mg per 1 oz nuts - 0.1 to 0.4 mg per 1/2 cup legumes - 0.13mg per 1/2 cup raw raspberries
Symptoms of Copper Deficiency
- Anemia - Skeletal defects - Cardiac enlargement - Altered pigmentation - Reproductive failure - Lower aortic elasticity - Neutropenia
Storage of Zinc and Copper a) Cytokines b) Glucocorticoids
- Animals fed Zn/Cu and Mn-deficieny diets show rapid decline in plasma [ ], indicating no large pools of storage. - MT thought to be involved in some storage but considered primarily as detoxification protein (binding metals) - Body can control the 'distribution' of Zn from the liver to the plasma by inducing hepatic levels of MT through ____ (a) and ____ (b)
Comments on Bioavailability for Metals
- Calcium and phytates can inhibit Zn and Cu absorption (binding interference?) - High calcium can increase dietary-intestinal loss of Zn
Manganese Toxicity
- Considered to be one of the least toxic minerals (toxicity very rare) - some airborne emissions from combustion and refineries can increase exposure to Mn - Some countries have fuel additives that contain high quantities of Mn - Neurological side effects (chronic); can also affect organs (inc. pancreas)
Absorption Zinc, Copper and Manganese a) Small intestine b) Copper
- Essential transition metals required for biological activity (little known about regulatory mechanisms for absorption). - All 3 are absorbed throughout the ____ ____ (a) - ____ (b) may also be absorbed in the gut - Absorption regulated at the intestinal level - Presence of both carrier-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
Properties of Metalloenzymes a) Protein folding b) Active site
- Metalloenzyme properties are synonymous with Zn due to over 200-Zn-containing metaloenzymes w/ 20 distinct biological functions. - Zn allows ____ ____ (a) to occur - Zn is also in ____ ____ (b) of enzymes which allows rx to occur. - Cu and Mn also have important metalloenzyme properties (only in active site)
Metallothionein and Absorption of Metals a) High b) Decrease
- Metallothionein (MT) is a low MW protein producted intracellularly in response to ____ (a) levels of Zn, Cu, Cd, Hg - Binds to and stores metals within the cell - MT can block or downregulate metals from being delivered to the basolateral side of the cell and ____ (b) the amount of metals absorbed - Enterocytes that accumulate MT-bound metals are eventually sloughed off from the mucosa and excreted - Thought to bind by Zn and Cu by the same mechanism but with different affinity - Can be interfered with by presence of other heavy metals.
Transport and Storage of Mn
- Mn thought to bind directly to alpha-2 macroglobulin and then transported to the liver - Though that due to the fact that Mn2+ can exist in the Mn3+ state, it can act in a similar fashion to that of Fe - Fe receptor mediated absorption, transport (transferrin) and maybe storage (ferritin) can all be applied to Mn
Assessment of Zinc, Copper and Manganese Status
- No reliable functional assessment or marker of physiological activity for any of these metals has been determined. - Normally, [Zn] do not vary unless in extreme deficiency, some variation during pregnancy and can be confounded by fluctuation in plasma [albumin] - Ceruloplasmin 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 do not provide and accurate marker of the overall status of these minerals
Excretion a) 150-fold
- Normally very little Zn, Cu and Mn lost through skin and urine - Most loss through feces (sloughing of intestinal cells from GIT; can be significant during high dietary intake when cellular levels of MT greatest) - Most of the GIT loss is from the incorporation of metals into bile (can be concentrated and then excreted) - Mn actively transported in bile from the liver (when not needed); ____ (a) the concentration of plasma in bile. - Almost all copper excretion is via bile
Transport of Zinc and Copper cont. a) Ceruloplasmin b) 90 to 95
- Once Cu reaches the liver, it is repackaged into ____ (a) - _____ % of plasma Cu is bound to ceruloplasmin. - Export of Cu from cells is thought to be regulated by Cu-ATPase-like proteins
Transport of Zinc and Copper a) Alpha-2 Macroglobulin b) 55 to 60 c) 40
- Once absorbed, Cu and Zn bind to albumin (not generally left in plasma as free ions) and transported into the liver for repackaging) - Zn repackaged and bound to ____ ____ (a) - Plasma distribution of bound Zn is usually around ____ % (b) albumin, ____ % (c) alpha-2-macroglobulin and some residual in metaloenzyme complexes
Symptoms of Manganese Deficiency
- Poor growth - Abnormal bone - Impaired glucose tolerance - Poor reproduction - Malformation in offspring
Superoxide Dismutase (SOD) and Zinc, Copper and Manganese a) Intracellular b) Extracellular c) Mitochondria
- SOD catalyzes the reaction to remove superoxide: 2O2- + 2H+ --> H2O2 + O2 - transition metals act as electron acceptors, but can cycle through valence states to accept and donate electrons in redox steps. Different forms of SOD: - Cu/Zn-SOD: ____ (a) and ____ (b) fluids - Mn/Zn-SOD: ____ (c) - reduced SOD activity can occur when Cu/Zn and/or Mn is deficient (reduced lipid peroxidation, oxidative stress, reduced energy regulation in mito; can affect Glc utilization/insulin balance, etc)...ie. body is in an oxidative state
Immune Properties of Zinc and Copper a) B cells b) T cells c) Thymulin hormone d) Neutrophils e) Granulocytes
- Zn and Cu deficiency can impair immune function but mechanism is unclear. - Zn involved with the maintenance of ____ ____(a) and ____ ____ (b) (lymphocytes) - Reduced Zn associated with decreased ____ ____ (c) and in turn cause a reduction in the size of the thymus (T cell maturation) - Cu thought to help maintain ____ (d) and ____ (e); may also facilitate maturation of early stem cell types (myslocytes) - May also regulate T-cell proliferation, possible through IL-2 production (mechanism unclear)
Properties of Zinc cont. a) 2+ b) Superoxide dismutase (SOD)
- Zn is limited in that it can only function in the ____ (a) valence state. - Mn and Cu can function in different valence states for different redox rx. - Zn2+ serves a structural role in cytosolic and extracellular ____ ____ (b) - For SOD to detoxify superoxides it requires a redox reaction that uses either Cu (Cu/Zn-SOD) or Mn (Mn/Zn-SOD).
Properties of Zinc a) Effective dipole
- Zn is one of the most common ions within the cell (except K, Mg) - Zn2+ found in every compartment and organelle in the cell (makes it available for metaloenzyme reactions and functions). - Very strong Lewis acid (Cu stronger but not as abundant) Ex. Zn2+ generates a hydroxyl group from H2O due to the ____ ____ (a) when Zn is bound
Symptoms of Zinc Deficiency
- loss of appetite - poor growth - alopecia - immune dysfunction - hypogonadism - poor wound healing - impaired taste acuity
Manganese, Proteoglycans and Cartilage Formation a) Glycosaminoglycan
- proteoglycans make up the network of glycoproteins that make up cartilage. - proteoglycans consists of a core protein skeleton which provides the scaffolding for elongation of sulphate chains (_____ (a) chains) - Mn required for synthesis of glycosaminoglycan - Mn deficiency can result in poor cartilage formation, skeletal and skin abnormalities (including reduced growth, complications with small bones in ear leading to ataxia and imbalance) - Give examples of where Mn deficiency leads to physiological dysfunction.
Physiological Roles of Copper: Bone Mineralization a) Lysyl oxidase
- provides the collagen matrix via ____ ____ (a) (linkage enzyme which contains Cu) - also effects elastin (thought to be responsible for cardiac dysfunction during Cu deficiency)
Physiological Roles of Copper: Ceruloplasmin a) 6 b) Liver c) 90 d) Transferrin
- transport of copper around the body (glycoprotein capable of storing ____ (a) Cu atoms) - regulated and secreted by the ____ (b) in response to [Cu] and other [hormones] - ____% (c) of plasma Cu bound to ceruloplasmin - ceruloplasmin also thought to be responsible for the oxidation of Fe2+ to Fe3+ to be taken up by ____ (d)
AI for Manganese
0 to 0.5 years: 0.003 mg/day 0.5 to 1 year: 0.6 mg/day 1 to 3 years: 1.2 mg/day 4 to 8 years: 1.5 mg/day 9 to 13 years (male): 1.9 mg/day 14 to 18 years (male): 2.2 mg/day > 19 years (male): 2.3 mg/day 9 to 13 years (female): 1.6 mg/day 14 to 18 years (female): 1.6 mg/day > 19 years (female): 1.8 mg/day Lactation: 2.0 mg/day Pregnancy: 2.6 mg/day
RDA for Copper
0 to 0.5 years: 0.20 mg/day (AI) 0.5 to 1 year: 0.22 mg/day (AI) 1 to 3 years: 0.34 mg/day 4 to 8 years: 0.44 mg/day 9 to 13 years: 0.70 mg/day 14 to 18 years: 0.89 > 19 years: 0.90 mg/day Lactation: 1.30 mg/day Pregnancy: 1.00 mg/day
RDA for Zinc
0 to 0.5 years: 2.0 mg/day (AI) 0.5 to 1 year: 3.0 mg/day 1 to 3 years: 3.0 mg/day 4 to 8 years: 5.0 mg/day 9 to 13 years (male): 8.0 mg/day 14 to 18 years (male): 11.0 mg/day > 19 years (male): 11.0 mg/day 9 to 13 years (female): 8.0 mg/day 14 to 18 years (female): 9.0 mg/day > 19 years (female): 8.0 mg/day Lactation: 12.0 mg/day Pregnancy: 11.0 mg/day
Copper Absorption
1. Cu2+ can be transported in via Fe transporter but not very efficient. 2. In the lumen, Cu2+ is reduced to Cu+ by - Dcytb - Steap2 3. Cu+ transported in at BB membrane via Ctr1 4. Binds MT at high levels to prevent too much going into the cell. 5. ATP7A and ATOX1 secrete Cu into plasma NB: Vit C can reduce Cu2+ to Cu+
Zinc Absorption a) ZIP4 b) ZnT1 c) Albumin
1. Dietary Zinc - goes into enterocyte using ____ (a) transporter on BB membrane - Zn can be used within cell to make zinc proteins - Can also be shuttled into organelles - Zn not bound to proteins transported OUT by ____ (b), bound to ____ (c) and then transported in circulation.
Four General Biological Roles of Metalloenzymes
1. Signalling 2. Structural 3. Catalytic 4. Regulatory
Physiological Properties of Zinc a) Motif b) 4 c) IGF-1
1. Zinc-Finger Proteins and Transcriptional Factors - folding pattern of an AA sequence around Zn to form a loop or finger that permits the folded region to stabilize the DNA sequence - Zinc finger region or ____ (a) is thought to require ____ (b) AA residues 2. Physiological Evidence - Zn deficiency can stunt growth in children - Impaired ____ (c) action thought to be involved in this process (receptor is activated by a particular promotor region that contains a Zinc finger DNA binding protein). --> ie. the issues are due to receptor defect, not growth factor defect (signalling cascade not initiated)
Zinc Toxicity a) 6 - 10
As little as ____ - ____ times the RDA can initiate some toxic side effects, reduce HDL levels, impair immunity, induce copper deficiency and induce vomiting and fatigue
Regulatory Absorption of Zinc (Diagram)
High Zn status prevents more from being absorbed
Zinc Absorption (Diagram)
Just know ZIP4, ZnT1, Zn-MT and Albumin
Lewis Acid
Lewis Acid (electron acceptor) + Lewis Base (electron donor) = metallocomplex Zn2+ + carboxypeptidase = metalloenzyme complex
Copper and Genetic Disorders
Menke's Syndrome (ATP7A mutation) and Wilson's Disease (ATP7B mutation) Copper toxicity.
Chemical Basis for Metalloenzyme Complex
Simplest term: Acid + Base -> Complex Generalized: Electron acceptor (Lewis Acid) + Electron donor (Lewis base) -> Complex Specific: Metal Ion (ex. Zn2+) + Ligand (ex. AA or H2O) -> Metal Ligand Complex. Take home message: Zn is in active site of protein and being used as a Lewis Acid allows the reaction to take place)
Copper Toxicity
____ mg/day (a) can cause side effects such as weakness, anorexia, vascular dysfunction and if maintained chronically, can be fatal.