Likely Essential Trace Elements by tzv97744

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

                    Dr. Roger A. Sunde
                   Nutritional Sciences
                  University of Wisconsin




                                      (9-
         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




                                                         1
       1st Essentiality Report

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




       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




                                                                            2
     Dietary Boron Absorption and
     Sources
• 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
  administration
• 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




                                                         3
      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
                               Boron
                               Concentration on
                               Embryonic Trout
                               Growth (Length)




                                          Eckhert 1998




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




                                          Eckhert 1998




                                                         4
            Research Update:
                  Boron Transporters in
                   Arabidopsis and humans




            Arabidopsis Bor1 gene and
            expression




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


                                                              Takano 2002




            Bor1-
            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)




                                                                            5
       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
            reproduction




                                                                                   6
           Arabidopsis Bor1 gene and
           expression         WT                                         GUT (-/-)




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


    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
     methionine




                                                                                          7
      Dietary Arsenic Absorption and
      Sources
• 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
  keratosis
• Organic forms less toxic so danger from fish, etc.,
  reduced
                                                DRI, 2001




                                                            8
        Research Update:
            SmtB/ArsR family of
             metalloregulatory
             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




               apoSensor/Repressor
        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




                                                                                   9
            Fig 6: ArsR Sensor/Repressor

   • Apo ArsR sensor binds to
     the operator/promoter of the
     operon, repressing
     translation
   • 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
     transcription




  Busenlehner et al. 2003




  Fig 6: Family
  of ArsR/SmtB
  Repressors



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
       As




                                                      10
       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
   recovery




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




                                                                     11
    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
  supply




                                                            12
       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
  mucopolysaccharides
• Requirement: (50 mg)
• Deficiency: impaired growth; skeletal defects
• Biochemical role: ? RO-Si(OH)-OR




                                                            13
    Silicon-
    Silicon-deficient Chicks




                                                   Carlisle, 1997




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




                                             Carlisle 1997




    Dietary Silicon Absorption and
    Sources
• 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




                                                                    14
      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: ?




                                                     15
      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
  isomerase
• 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
  rats
• Biochemical role: ?
• European tolerable intake: 3 mg/week
                                 Reichlmayr-Lais & Kirchgessner, 1997




                                                                            16
                  Pb-
     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
  areas




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




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




                                                                       17
       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
      differentiation




                                                                    18
     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




                                                      19
     Vanadobin

• 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
                               mushrooms
                             • The form of V has
                               been determined
                             • The function is
                               unknown



                                                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-
    containing
• Three different V-peroxidases have been
  crystallized
  – first detected in brown algae Acophyllum
    nodosum
  – also in red algae, fungi and lichen




                                                                20
    V-dependent haloperoxidases




    V-BPO dimer




                           VO4
                           Bound to His




H-bonding
around V
center




                                          21
    +Potentially Essential Elements




   Is that all potential essential
   elements?




    Lecture Objectives:

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




                                             22
          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
      essentiality/function
    • Differences in diseases between species
      suggests altered distribution/level of protective
      mechanisms
    • Evidence, that biology can specifically recognize
      handle an element, makes it a candidate for
      essentiality in higher animals and humans




                                                                23

								
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