Updated: 3/8/2019

Trace Metals

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  • 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
  • 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
  • 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
  • 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)
  • 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
  • Source
    • mainly fluoridated water
  • Deficiency
    • plays a role in bone and teeth formation/strength
      • ↑ bone fractures
      • dental caries
  • Source
    • mainly iodized salt
  • Deficiency
    • plays a role in synthesis of thyroid hormone
      • goiter
      • ↓ thyroid hormone output
  • 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


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