FeCuZnKCaMgBiological Inorganic ChemistryELEMENTAL COMPOSITION OF THEADULT HUMAN BODYBulk or Constituent Elements:H, O, C, N, Ca, P, Na, K, S, ClTrace Elements:Mg, Si, F, Fe, Zn, B, Rb, Sr, Br, CuUltra Micro Trace Elements:V, Li, Se, Mn, Ba, Ge, As, Ni, Mo, Cd, I,Sn, Cr, Pb, CoAdapted from J. Chem. Ed. (1985), Vol. 62, No. 11, pp 917Why is oxidation state of a metal important?The chemistry of the different oxidation states of metal ions can be very different!Example 1:• Deoxy hemoglobin contains Fe2+ and in this form it will bind and transport molecular oxygen.• If the Fe2+ is oxidized to Fe3+it is called methemoglobin, and it will not bind oxygen.•Chromium is a naturally occurring element found in rocks, animals, plants, soil, and in volcanic dust and gases. Chromium is present in the environment in several different forms. The most common forms are chromium(0), chromium(III), and chromium(VI).•Chromium(III) occurs naturally in the environment and is an essential nutrient that helps the body use sugar, protein, and fat.• Chromium(VI) and chromium(0) are generally produced by industrial processes. •Breathing high levels of chromium(VI) can cause irritation to the nose, such as runny nose, nosebleeds, and ulcers and holes in the nasal septum. •Ingesting large amounts of chromium(VI) can cause stomach upsets and ulcers, convulsions, kidney and liver damage, and even death. •Several studies have shown that chromium(VI) compounds can increase the risk of lung cancer. Animal studies have also shown an increased risk of cancer.Example 2: Chromium(III) is necessary while Chromium (VI) is toxic•Potassium is one of the mineral responsible for maintaining the electrical stability of the cells of heart and nervous system.•It is frequently referred to as an electrolyte. •Electrolytes are minerals that carry a positive or negative charge when dissolved in a liquid. •Potassium is important in maintaining normal fluid balance. PotassiumKCalciumCa•Calcium is found in our bones, tissue and teeth. •Calcium plays a role in blood clotting, immunity, nerve impulse transmission, and enables our muscles to contract and our hearts to beat.•Osteoporosis is often called the "silent disease" because bone loss occurs without symptoms.Iron MetabolismA 70 kilogram man contains about 3.7 grams of iron.Most of this, almost 70%, is present in hemoglobin. Most of the rest, almost 30%, is stored as ferritin. Remainder is in myoglobin, the cytochromes, other Fe-S proteinsFe• Fe is very active chemically. Always found in bound form.• Iron does not get excreted from the body. • The body's iron content is regulated by controlling absorption.• Iron storage protein• Protein coat formed by 24 subunits• Each molecule can bind thousands of Fe(III) atom FerritinHemachromatosis:Hemachromatosis is an inherited Iron overload disease.Disease affects one in every 200 Americans.Patients are perfectly healthy except for the fact thattheir body absorbs too muc h iron from foods and it isstored in organs.Iron overload can cause people as young as 30 to startdeveloping arthritis, cirrhosis of the liver and heartfailure.But once detected, the treatment for iron overloaddisease is simple: to give blood.Anemia:Iron deficiencyCopp er•Adul t h u mans consu me 0 .6- 1.6 mg Cu/ day•60-70% of this Cu is a bsorbedCu Containing ProteinsCyytochr ome oxida seCuZn sup eroxide dismu tase (Cu ZnSO D)Cu Metallothio nein (Cu MT)Ceruloplasmin•Ma jo r Cu co ntaining pr ote in in the blood plas m a•Has ferr oxida se ac tivity -- oxidizes Fe (II) to Fe( III)•Patients l acking cerulo plasm in accumu late ironin the liver ( aceruloplasm inem ia)Menkes Disease:Copper deficiency due to malabsorption of dietary copper.Reduced copper levels in brain, liver and serum. Reduced activities of several copper containing enzymes.Patients die when they are very young.Wilson's Disease:Excessive copper in liver which eventually leads to excessive copper in the brain. Excessive copper often leads to liver failure, but can also manifest as neurological problems, renal stones, renal tubular damage, copper deposition on the cornea. Treatment:Zinc was approved by FDA in 1997 and it is the most useful drug for treating Wilson's disease. CuZinc is an essential nutrient that humans and animals cannot live without.Our bodies contain about 2 g of zinc, a little less than the amount of iron. Zinc is especially needed for growth and development.When zinc is removed from the Zn containing metallo-enzymes these enzymes don't work. There are about 50 enzymes that require zinc.Also important in zinc-finger proteins that bind to DNA and regulate gene expression. Zinc competes with copper for absorption sites in the intestine. Excess Zn can lead to copper deficiency. RDA = 12 mg/dayZnCopper-Zinc Superoxide Dismutase, an anti-oxidant enzyme• 32 kD Homodimer• 1 Copper and 1 Zinc Binding Site/ Subunit• 1 Intra-subunit Disulfide BondMetal Binding Sites and Superoxide DismutationCu++ O2-+ 2H+Cu2++ H2O2Cu2++ O2-Cu++ O22O2-+ 2H+O2+ H2O2His 46His 48His 80His 120His 63His 71Asp 83CuZnLou GehrigAmyotrophic Lateral Sclerosis(ALS)or Lou Gehrig’sDiseaseCuZnSOD and Amyotrophic Lateral Sclerosis (ALS)Two types of ALS:Sporadic cases:no known causeFamilial:Inherited, butno known causeInherited mutations in CuZnSODALS is a debilitating neurodegenerative disease that causes paralysis and death within a few years of onset of symptomsMotor Neurons in ALSThe hallmark of motor neuron disease is denervation and atrophy of muscle due to loss of spinal motor neurons.QuickTime™ and aAnimation decompressorare needed to see this picture.‘Gain of Function’ Hypothesis: SOD1 mutations cause FALS by conferring a novel toxic property to the mutant protein.• SOD1 knock-out mice exhibit decreased fertility and recovery from axonal injury but do not develop motor neuron disease.• Transgenic mice that over-express WT human SOD1 (in addition to WT mouse SOD1) are normal. Transgenic mice that over-express FALS mutant SOD1 develop motor neuron disease.G37R SOD1
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