Likely Essential Trace Elements by tzv97744


									                        NS 623:
     Molecular Nutrition of Essential Mineral Elements
                Likely Essential
                Trace Elements

                    Dr. Roger A. Sunde
                   Nutritional Sciences
                  University of Wisconsin

         Potential Essential Elements (9-11)

1.  Boron (B): essential for plants
2.  Arsenic (As): best evidence in goats
3.  Chromium (Cr): part of putative glucose tolerance
    factor (GTF) & included in in 2001 DRIs
4. Silicon (Si): role in connective tissue
5. Tin (Sn): role in mucopolysaccharides
6. Cadmium (Cd): growth?
7. Cobalt (Co): ?
8. Lead (Pb): lipid metqabolism?
9. Lithium (Li): growth?
10. Tungsten (W): cofactor?
11. Vanadium (V): mollusks have vanadochromes

        I. Boron Summary

 • Human body content: ?
 • Function: ? (role in crosslinking)
 • Requirement: <1000 ug
 • Deficiency: impaired growth, cell division,
   retinal degeneration
 • Biochemical function: ? R(OH)2=B=(OH)2R
 • Food sources: citrus fruits, grapes

       1st Essentiality Report

1923 Warington showed that B was essential for
1998-9 Curt Eckert found that B supplementation
  was necessary trout and zebra fish
2002 Takano found human gene for borate efflux

       Boron Function (1): Natural
       Organoboron Compounds

Several strains of Streptomyces bacteria synthesize novel
large organic antibiotics that use a central B crosslink    Nielsen, 1997

        Boron Function (2)

• In plants, especially citrus, B deficiency
  results in abnormal cell walls
   – One B role appears to be to
     crosslink pectic polysaccharide
     rhamnogalacturonan II (RG-II)
   – All plants seem to require a lower
     level of B for reproduction
• In bacteria, the quorum sensor
  Autoinducer-2 has recently (2002) be
  shown to contain B

     Dietary Boron Absorption and
• Absorption 90%
• Thought to be absorbed passively as
  B(OH)3 from gut
• Rapidly excreted unchanged in the urine of
  humans and rodents regardless of route of
• Natural sources: fruit-based beverages and
  products, tubers and legumes

    Boron Requirements

• Neither AIs nor RDAs were proposed for B

• Typical intakes are:
  – 2.3 mg B/day for men
  – 1.6-2.0 mg B/day for women

• UL: 20 mg B/day
  – Based on developmental effects in rats
                                             DRI, 2001

    Research Update:
       Boron Essentiality in Fish
        Embryos and in Yeast

      Fig 1: Effect of Boron on Embryonic
      Trout Growth

PreHatch Embryo   Hatched Embryo      2 wk Post Hatch
                                      Top: 9 uM B
                                      Bottom: 2 uM B

                                           Eckert 1998

                               Fig 3: Effect of
                               Concentration on
                               Embryonic Trout
                               Growth (Length)

                                          Eckhert 1998

      Fig 4: Effect of Incubation Boron on
      Embryonic Trout Boron Content

                                          Eckhert 1998

            Research Update:
                  Boron Transporters in
                   Arabidopsis and humans

            Arabidopsis Bor1 gene and

                      WT       Bor1 (-/-)        Bor1 (-/-) + bor1

                                                              Takano 2002

            Bor1-GFP expression in Arabidopsis

(a) Bor1-GFP fusion

   (b) GFP only

                           Bor1-promoter-GFP expression in
      Takano 2002              whole plant (c) and stem (d)

       Boron transport (R) similar to
       Bicarbonate transport (L) in kidney

Kidney bicarbonate transport via anion   Plant borate efflux to xylum, driven by
    exchange, driven by pH gradient             pH gradient (3 alt. models)

                                                              Frommer 2002

       Boron Transporter Family

• A B transporter was recently
  identified in Arabidopsis
• Phylogenetic analysis finds
  homologs in yeast and
  humans, and finds as well 6
  other Arabidopsis proteins

                                                            Frommer reviewing
                                                               Takano 2002

       Research Update:
           Borate crosslinking gene
            required for plant

           Arabidopsis Bor1 gene and
           expression         WT                                         GUT (-/-)

                                  P-tube B Pollen tubes Mature Anthers
    • GUT1 gene encodes a
      putative glucosyl
    • GUT1 essential for
      forming RG-II
    • GUT1 essential for
      insertion of B into these

    RGII=rhamnogalacturonan                                                   Iwai 2006

           Boron Summary

• Requirement: no DRI (<1000 ug)
       – Required by plants
       – UL: 20 mg/d
• Deficiency in higher animals:
       – Impaired growth, cell division, retinal degeneration
• Function: ? (role in crosslinking)
       – 3 structural roles in microorganisms, plants
       – B transporters in all phyla
       – Gene identified for B role in plant reproduction

           II. Arsenic

•    Human body content: ?
•    Function: ?
•    Requirement: (1.7-3 ug)
•    Deficiency: impaired growth, reproduction
•    Biochemical role: ?metabolism of

      Dietary Arsenic Absorption and
• Absorption 90% of soluble As; 60-70%
  dietary As
• Transported to liver, reduced to arsenite
  (AsO4-3)and methylated
• Rapidly excreted in the urine
• Natural sources: dairy products, meat,
  poultry, fish, grains

     Arsenic Requirements

• Neither AIs nor RDAs were proposed for As

• Typical intakes are:
   – 2.0-2.9 ug As/day for men
   – 1.7-2.1 ug As/day for women

                                                DRI, 2001

      Arsenic Toxicity

• Arsenic of literature fame is As203
• UL: no UL (NRC limits drinking water to 50 ug/L)
• >10 mg As/kg/d leads to encephalopathy and
  gastrointestinal disturbances
• Poisoning occurs with >1 mg As/kg/d
• Chronic intake of 10 ug As/kg/d produces
  “arsenicism,” with altered pigmentation and
• Organic forms less toxic so danger from fish, etc.,
                                                DRI, 2001

        Research Update:
            SmtB/ArsR family of
             transcriptional repressors

                                                         Busenlehner et al. 2003

        Fig. 2: ArsR operon for
        protection against As excess

  • Found in E. coli and most other prokaryotes
  • Organized in an operon
  • Encodes ArsR Repressor
      – Apo-Repressor binds to O/P blocking transcription
  • Encodes metal efflux system
      – ArsC Arsenate (AsO4-3) Reductase (to arsenite, AsIII, AsO2-1)
      – ArsA ATPase efflux transporter
      – ArsB Diffusion transporter

                                                         Busenlehner et al. 2003

        Fig 3: apoSensor/Repressor Structure
        of ArsR/SmtB Repressors
                              "5 metal binding site

                                "3N metal binding site
• Tunable sensors used in regulation of the
  ArsR/SmtB family of metalloregulatory
  transcription repressors
• Have 2 sets of metal binding sites                     Busenlehner et al. 2003

            Fig 6: ArsR Sensor/Repressor

   • Apo ArsR sensor binds to
     the operator/promoter of the
     operon, repressing
   • Sensor binds As (III) or
     Sb(III) at the "3 metal
     binding site
   • As-ArsR has reduced
     affinity for the O/P site, no
     long binds tightly, allowing

  Busenlehner et al. 2003

  Fig 6: Family
  of ArsR/SmtB

Tunable sensors used in
   regulation of the ArsR/SmtB
   family of metalloregulatory
   transcription repressors
Blue = Co
Purple = Zn
Green = Ni
Pink = Cd
Orange = As
  Busenlehner et al. 2003

             Arsenic Summary

   •   Function: ?
   •   Requirement: (1.7-3 ug)
   •   Deficiency: impaired growth, reproduction
   •   Biochemical role: metabolism of methionine
   •   No RDA, AI or UL
   •   In prokaryotes, As sensors and operons
       exist to specifically recognize and detoxify

       III. Chromium Summary

•   Human body content: 1 mg
•   Function: necessary for insulin function
•   Requirement: AI 35/25 ug T
•   Deficiency: impaired glucose tolerance
      Biochemical role: GTF ?

                              TDRI (1998-2001); M/F; x-y for range

       1st Essentiality Report

1959 Mertz reported that CrIII is the factor involved
   in maintenance of glucose tolerance (GTF)
1977 Jeejeeboy reported Cr supplementation (250
   ug/day) to a patient with insulin resistance
   reversed the insensitivity and promoted

• Some evidence that is necessary for normal
  glucose tolerance/insulin production
• No good evidence for enhanced athletic

    Glucose Tolerance Factor

                                 Offenbacher et al., 1997

    Reported Serum Cr Values in
    Normal, Fasted Subjects
    Year        nmol Cr/L   Subjects
    1962        10,000      5
                3,269       3
    1968        446         16
    1973        90          10
    1973        30          15
    1978        3.08        17
    1985        2.5         76
    1987        2.88        52

     Dietary Chromium Absorption
     and Sources
• Absorption only 0.4-2.5% from CrIII
• Excreted in the feces
• Natural sources: widely distributed in food

       Markers of Cr Status

•   Balance studies
•   Urinary Cr
•   Plasma Cr
•   Blood glucose and insulin

But used average Cr intake in food, 13.4 ug
  Cr/1000 kcal, and medium energy intake to
  calculate AI

                                                DRI, 2001

      Cr Requirements
• 1989 ESADDI:
    – 50-200 ug Cr/day
• 2001 AI:
    – Women: 25 ug Cr/day
    – Men: 35 ug Cr/day
    – From average Cr content of foods
• Typical intakes in this range
• No UL

• And no known Cr proteins, binding proteins,
  operons in biology!!

                                                DRI, 2001

       IV. Silicon Summary

• Human body content: 3500 mg, mostly in
  bone, connective tissue, skin
• Function: crosslinking component of
• Requirement: (50 mg)
• Deficiency: impaired growth; skeletal defects
• Biochemical role: ? RO-Si(OH)-OR

    Silicon-deficient Chicks

                                                   Carlisle, 1997

    Role of Si on Growth of epiphyseal
    cartilage in 14-d chick embryo in
   Cartilage Weight               Hydroxyproline Content
                                           + 0.2 mM metasilicate
          + 0.2 mM metasilicate

                                             Carlisle 1997

    Dietary Silicon Absorption and
• Si thought to be well absorbed
• As much as 50% of ingested Si is excreted
  in the urine
• Natural sources: beverages including beer,
  coffee and water

      Silicon Requirements

• Neither AIs nor RDAs were proposed for Si

• Typical intakes are:
    – 40 mg Si/day for men
    – 19 mg Si/day for women
• UL 2001: not possible to establish a UL

                                         DRI, 2001

      V. Tin Summary

•   Human body content: 9-70 mg
•   Function: ?
•   Requirement: (1-2 mg)
•   Deficiency: impaired growth
•   Biochemical function: ?
•   Food sources: canned foods

      VI. Cadmium Summary

• Human body content: ?
• Function: ?
• Requirement: ?
• Deficiency: Anke has fed goats diets low in
  Cd for multiple generations, and observed
  depressed growth and reproductive failure
• Biochemical role: ?

      VII. Cobalt Summary

• Human body content: 1.1 mg
• Function: as vitamin B12 in enzymes
• Requirement: 2.4 µg B12 T 0.10 µg Co
• Deficiency: pernicious anemia; ataxia
• Biochemical function: methylmalonyl CoA
• Food sources: meat
                              TDRI (1998-2001); M/F; x-y for range
                              # RDA, 10th ed., (1989); M/F; x-y for range
                              * RDA, 9th ed. (1980).

      CzrA Sensor regulates operon for
      protection against Co excess

• Another member of the
  SmtB/ArsR super family of
  protective transport
  operons in bacteria

                                                 Busenlehner et al. 2003

      VIII. Lead Summary
• Human body content: ?
• Human intake estimated at 0.3-0.6 mg/day
• Absorption: 5-15%
• Function: involved in lipid metabolism
• Requirement: ?
• Deficiency: 20 ppm Pb produces anemia and
  decreased growth in 2nd-generation Pb-deficient
• Biochemical role: ?
• European tolerable intake: 3 mg/week
                                 Reichlmayr-Lais & Kirchgessner, 1997

     Offspring of Pb-deficient Rats

                            Reichlmayr-Lais & Kirchgessner, 1997

     IX. Lithium Summary

• Human body content:
• Function: ?
• Requirement: (650 ug/day?)
• Deficiency: Rats and goats on low Li diets showed
  higher mortality as well as reproductive and
  behavioral abnormalities
• Biochemical role: ?
• Food sources: vegetables; drinking water in some

     Tissue Li in Rats fed 15 ng Li/ g for
     two generations

                                      Pratt, Pickett & O’Dell, cited
                                             by Schrauzer 2002

       Tissue Li in Goats fed <1 ug Li/g
       vrs. 12.7 ug Li/g

                                                  Anke, cited by
                                                   Schrauzer 2002

       X. Tungsten Summary
• Human body content: ?
• Function: ?
• Requirement: ?
• Deficiency: ?
• Biochemical role: Potential role as tungsten
  cofactor; a number of bacterial enzymes use
  W-substituted MoCo
• Food sources: ?

       XI. Vanadium

• Human body content: 1 mg
• Function: ? (lipid metabolism)
• Requirement: (100 ug)
• Deficiency: altered thyroid peroxidase in rats;
  elevated abortions in goats
• Biochemical role: vanadochrome in tunicates
  /green RBC
    – Mimics insulin and can stimulate cell proliferation and

     Dietary Vanadium Absorption
     and Sources
• Absorption <5%
• Thus most excreted in the feces
• Natural sources: grains; mushrooms,
  shellfish, black pepper are rich in V

    Vanadium Requirements

• Neither AIs nor RDAs were proposed for V
• Typical intakes are:
  – 6-18 ug V/day for men and women
• UL 2001: 1.8 mg V/day
  – Based on renal toxicity

                                          DRI, 2001

    Research Update:
       Vanadium compounds,
        proteins and enzymes


• Some mollusks (tunicates, ascidians) accumulate
  V to exceed the concentration in sea water by 4
  million fold
• The V compound from blood cells has been
  named vanadobin
• Suggested functions include:
   – Production of cellulose
   – Reversibly trapping oxygen under low oxygen tension
   – Acting as an antimicrobial agent

     Amavadine from Amanita mushrooms

                             • V is found in high
                               concentrations in a
                               few species of
                             • The form of V has
                               been determined
                             • The function is

                                                Nielsen, 1997

      Vanadium Enzymes
• V-Haloperoxidases
  – catalyze oxidation of halides (I-, Br-, Cl-) in
    presence of peroxides
  – heme and non-heme groups
  – non-heme divided into metal-free and V-
• Three different V-peroxidases have been
  – first detected in brown algae Acophyllum
  – also in red algae, fungi and lichen

    V-dependent haloperoxidases

    V-BPO dimer

                           Bound to His

around V

    +Potentially Essential Elements

   Is that all potential essential

    Lecture Objectives:

• Review current status of trace element
• Focus and emphasize
  – Novel molecular biology
  – Models at multiple phylogenetic levels
  – Homeostasis
• Review trace element deficiency and
• Build cases general concepts and future
  research needs

          General Concepts
•   Number of essential elements
•   Number of essential nutrients
•   Concept/definition of essentiality
•   General roles for essential elements
•   DRI RDA/EAR/AI concepts
•   Homeostasis
    –    Negative feedback loops
    –    Shapes of curves
    –    Hypo I: sensors exit
    –    Hypo II: sensors can be used for to determine status
         and requirements

          General Concepts (2)
• Control points for gene expression
     –   Transcription
     –   Translation
     –   mRNA stability
     –   Protein degradation
     –   Position of component (transporters)
• Themes in detoxification mechanisms
     –   Store as inorganic precipitate
     –   Chelate multiple ions
     –   Pump into vacuole
     –   Export
     –   Use enzyme as simple chelator
• Dual function for proteins

         General Concepts (3)
    • Conserved proteins and regulation across
      phylogenetic levels
    • Conserved motifs (Zn fingers, Ferritin structure,
      Se incorporation)
    • Low levels of free metal in biology
    • Chaperones
    • Use of inborn errors/knockouts to show
    • Differences in diseases between species
      suggests altered distribution/level of protective
    • Evidence, that biology can specifically recognize
      handle an element, makes it a candidate for
      essentiality in higher animals and humans


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