Overview Definition micronutrients required in the diet for necessary cellular functions Major examples iron (Fe) copper (Cu) zinc (Zn) chromium (Cr) fluoride (F) iodide (I) selenium (Se) Others V, Mo, Mn, Co, and Ni Function part of metalloenzyme enzyme has no activity without the metal metal is fixed metal:protein is constant example carbonic anhydrase part of metal-containing enzyme enzyme may have activity without the metal metal is reversibly bound metal:protein ratio is variable example glycogen phosphorylase kinase Oxidative stress organometallic side reactions that damage tissue many metals undergo the Fenton reaction in vivo oxidation of metal and donation of an electron to oxygen most common metals that undergo reaction are Fe2+ and Cu+ creation of hydroxyl radicals heme iron can generate superoxide radicals (O2*) reactions happen frequently, but the body can defend itself with anti-oxidants oxidative stress occurs when pro-oxidants > anti-oxidants. examples of oxidative stress damage stroke Parkinson’s Alzheimer’s Iron Source diet recycled from destroyed erythrocytes Forms ferrous iron (Fe2+) dangerous causes oxidative stress found in hemoglobin ferric iron (Fe3+) less dangerous methemoglobinemia (metHb) occurs when Fe3+ is found in hemoglobin Absorption Fe-containing compounds are solubilized in low stomach pH Fe3+ is reduced to Fe2+ (requires vitamin C) in intestine so it can cross gut lumen ferroportin brings Fe3+ into bloodstream from enterocytes mediates amount of Fe released into the blood hepcidin inhibits ferroportin antibacterial because it lowers the availability of iron in the plasma Storage must be immediately used or stored to prevent: bacterial utilization Fe required for growth formation of iron oxides free radicals (Fe + O2) site hepatocytes (main) enterocytes macrophages stored as ferritin (Fe3+) hemosiderin binds excess Fe3+ to prevent from entering the blood Transport carried as Fe3+ by transferrin in the blood transferrin chelates the Fe3+ and transports it in the blood to tissues. maintains solubility and keeps unreactive transferrin receptors on cells endocytose transferrin:Fe complex Fe3+ released into cell triggered by low pH transferrin returns to cell surface to be used again ferroxidase (aka ceruloplasmin) oxidizes Fe2+ to Fe3+ for transport and storage ferritin can also oxidize Fe for storage Excretion no cellular mechanism for iron excretion lost from blood loss and removal of skin cells and other epithelial cells Toxicity beyond the sequestration capacity of ferritin causes oxidative stress Disorders in iron handling hereditary hemochromacytosis Copper Role human metabolism like other metals, free copper is potentially toxic by donating electrons creates hydroxyl radicals and other reactive oxygen species copper is a cofactor for many metalloproteins examples lysyl oxidase (collagen synthesis) tyrosinase (melanin synthesis) Transport albumin and ceruloplasmin carry copper in the blood similar role to transferrin in iron transport metallothionein is a carrier of copper, zinc, and many other metals role in preventing oxidative stress in the cell thiol groups from many cysteine residues mediate binding Excretion excess copper removed in the bile unlike iron with no mechanism of excretion Deficiency causes excess zinc metallothionein carries both copper and zinc copper is displaced when zinc concentrations rise symptoms a function of what enzymes require copper ferroxidase catalyzes oxidation of iron from Fe2+ to Fe3+ result is microcytic anemia lysyl oxidase crosslinks collagen fibers result is poor wound healing aortic dissection Disorders in copper handling Wilson's disease Menke’s disease X-linked gene mutation in ATP7A ATP-dependent copper efflux protein aka Ehlers-Danlos syndrome type IX inability of enterocytes to release absorbed copper copper at toxic levels in small intestine and kidneys copper in circulation and in brain at low levels symptoms presents like a copper deficiency seizures, failure to thrive, and neurodegeneration steel-colored and brittle hair due to role of copper in metalloprotein lysyl oxidase which crosslinks collagen for added strength at low serum concentrations of copper, this enzyme cannot function Zinc Function hundreds of enzymes require zinc important examples carbonic anhydrase ACE (angiotensin I converting enzyme) RNA and DNA polymerase Transport metallothionein carries zinc competes with copper Deficiency causes poor diet alcoholism liver unable to handle zinc properly symptoms impaired collagenase delayed wound healing impaired zinc finger transcription factor motifs hypogonadism ↓ adult hair (axillary, facial, and pubic) ↓ in senses dysgeusia (lack of taste) anosmia (lack of smell) diarrhea hair loss (alopecia) Chromium Deficiency causes total parenteral nutrition (TPN) symptoms a function of what proteins/enzymes require chromium hypothesized to play a role as part of glucose tolerance factor ↓ glucose tolerance Flouride Source mainly fluoridated water Deficiency plays a role in bone and teeth formation/strength ↑ bone fractures dental caries Iodine Source mainly iodized salt Deficiency plays a role in synthesis of thyroid hormone goiter ↓ thyroid hormone output Selenium Deficiency causes total parenteral nutrition (TPN) symptoms plays a role in glutathione peroxidase that protects against oxidative stress damage to tissues with high metabolic activity muscle pain cardiomyopathy