Title : Selenium, the Element of Moon in Life on Earth - IRCC

<strong>Selenium</strong>, <strong>the</strong> <strong>Element</strong> <strong>of</strong> <strong>Moon</strong> <strong>in</strong> <strong>Life</strong> on Earth
Selene: Greek Goddess <strong>of</strong> <strong>the</strong> <strong>Moon</strong>
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‣ <strong>Selenium</strong> discovered by Swedish scientist J. J. Berzelius (1817)
‣ Red deposit – rema<strong>in</strong>s after <strong>the</strong> roast<strong>in</strong>g <strong>of</strong> copper pyrites dur<strong>in</strong>g H 2 SO 4
manufactur<strong>in</strong>g
‣ Named after Greek mythological Goddess (<strong>in</strong> Greek, Selene = <strong>Moon</strong>)

Natural Resources <strong>of</strong> Se and its stable Isotopes
Abundance
Se
Atomic Mass – 79.9165
‣ M<strong>in</strong>erals conta<strong>in</strong><strong>in</strong>g selenium are very
uncommon
Mass
Natural
Abundance
74 0.88
76 8.95
77 7.65 (I = ½)
78 23.51
80 49.62
82 9.39
‣ 70 th <strong>in</strong> abundance <strong>of</strong> <strong>the</strong> 88 that are present
naturally <strong>in</strong> <strong>the</strong> earth crust
‣ Most selenium is recovered as a by-product
<strong>of</strong> process<strong>in</strong>g copper ores (Copper Pyrites)
‣ 77 Se is NMR active
White J. R.; Cameron. A. E. Phys. Rev., 1948, 74, 991-1000.

Allotropes <strong>of</strong> <strong>Selenium</strong>
‣ Grey (trigonal) selenium
(Se n helical cha<strong>in</strong> polymers)
‣ Grey (rhombohedral) selenium
(Se 6 molecules)
‣ Three deep-red (monocl<strong>in</strong>ic) forms
(α, β, and γ-selenium conta<strong>in</strong><strong>in</strong>g
Se 8 molecules)
‣ Amorphous red selenium
‣ Black vitreous selenium
‣ Most <strong>the</strong>rmodynamically stable and
<strong>the</strong> densest form: gray (trigonal)
http://en.wikipedia.org/wiki/File:SeBlackRed.jpg
http://www.chemistryexpla<strong>in</strong>ed.com/A-Ar/Allotropes.html

<strong>Selenium</strong> chemistry
Group 16
O
S
Se
Te
Po
‣ Large, s<strong>of</strong>t atom, much s<strong>of</strong>ter than sulfur
‣ Big, squashy atom; its electron clouds large, diffuse and
easily distorted
‣ Nucleus exerts little effect on what happens at <strong>the</strong>
Periphery
‣ Means Se can spread its electron over many neighbors
‣ Dual nature; ability to donate electrons (metallic) and
take electrons (nonmetallic) metalloid

Dissociation Energies (kcal/mol)
H 2 O 119
H 2 S 93
H 2 Se 75
H 2 Te -
pKa
RS - 8.5
RSe - 5.2
~ Physiological pKa
SH
OH
H 2 N
O
Cyste<strong>in</strong>e (Cys)
SeH
OH
H 2 N
O
Selenocyste<strong>in</strong>e (Sec)

Importance <strong>of</strong> <strong>Selenium</strong> and its Derivatives
Materials Chemistry
Se
Metal chalcogenides (CdSe) - Semiconductors
Ligands <strong>in</strong> catalysis

<strong>Selenium</strong> Toxicity
<strong>Selenium</strong> <strong>in</strong> Biology
Selenosis
High blood levels <strong>of</strong> selenium (greater than 100 μg/dL)
Symptoms - Gastro<strong>in</strong>test<strong>in</strong>al upsets, hair loss, white blotchy nails,
garlic breath odor, fatigue, irritability, and mild nerve damage
Bl<strong>in</strong>d Staggers
Acute selenium poison<strong>in</strong>g <strong>in</strong>
cows and sheep caused by
<strong>in</strong>gestion <strong>of</strong> plants with high
selenium content
Alkali Disease
Acute selenium poison<strong>in</strong>g <strong>in</strong>
Cattle (Moxon, 1937)
Severely damaged ho<strong>of</strong>s
Marco Polo (1254-1324) writes for Kublai Khan <strong>in</strong> his travelogue
<strong>in</strong>to Ch<strong>in</strong>a about poisonous plants that animals ate and shed <strong>the</strong>ir
hooves

<strong>Selenium</strong> deficiency (1930, Ch<strong>in</strong>a)
‣ Keshan disease, which results <strong>in</strong> an enlarged and poor heart
function
‣ Hypothyroidism (worsens iod<strong>in</strong>e deficiency)
‣ Weakens immune system

<strong>Selenium</strong> Supplements
Boost Your Immune System with <strong>Selenium</strong>
Maximum doses: 400 μg per day
• Serv<strong>in</strong>g Size : 2 Droppers (2 mL) daily <strong>in</strong> water
or juice as ma<strong>in</strong>tenance
• Serv<strong>in</strong>gs Per Conta<strong>in</strong>er : 120
http://www.m<strong>in</strong>eralifeonl<strong>in</strong>e.com/pd-selenium-8oz.cfm

ROS Generat<strong>in</strong>g and Scaveng<strong>in</strong>g Systems
_
ONOO
HOCl
H 2 O 2
H2 O
1 O2 +
Cl
_ MPO
NO O 2 O2 Fe 2+ Fe 3+ H
_
O 2 O 2 H 2 O 2 OH H 2 O
SOD
e
H 2 O
MPO - Myeloperoxidase
2H 2 O
H 2 O + O 2
GPx
catalase
SOD
H 2 O 2
O 2
_
lact<strong>of</strong>err<strong>in</strong>
X
Fe 2+ Fe 3+
NO
OH
ONOO _
oxidative stress
lipid
peroxidation
antioxidant
enzymes
X
oxidation
nitration
nitrosation

Reactive Oxygen Species (ROS)
Damage <strong>of</strong> cell membranes
DNA cleavage
Guan<strong>in</strong>e Oxidation
Neurodegenerative diseases like
Alzheimer, Park<strong>in</strong>son’s
Age<strong>in</strong>g
Inflammation
Certa<strong>in</strong> Cancers

The defense system
‣ Cellular thiols (Glutathione, thioredox<strong>in</strong>e) – Redox Buffers
‣ Antioxidants
– Ascorbic acid
– Vitam<strong>in</strong> E and o<strong>the</strong>r Phenolic compounds
‣ Antioxidant enzymes
Catalase is a hemeprote<strong>in</strong>
– Catalyzes <strong>the</strong> disproportion <strong>of</strong> H 2 O 2
Superoxide dismutase: Cu-Zn-SOD, Fe-SOD, Mn-SOD
– Catalyzes <strong>the</strong> disproportionation <strong>of</strong> HO 2
Sulfiredox<strong>in</strong>e is a cyste<strong>in</strong>e conta<strong>in</strong><strong>in</strong>g enzyme
- Reduction <strong>of</strong> H 2 O 2
Glutathione peroxidase is a selenocyste<strong>in</strong>e conta<strong>in</strong><strong>in</strong>g enzyme
- Reduction <strong>of</strong> H 2 O 2

Selenoenzymes (14 discovered)
‣ <strong>Selenium</strong> Biochemistry Emerged <strong>in</strong> 1973, after <strong>the</strong> discovery two
bacterial enzymes
Enzyme
Formate
dehydrogenases
Glys<strong>in</strong>e reductase
Glutathione
peroxidases (GPx)
Phospholipidehydroperoxide-GPx
Type-I iodothyron<strong>in</strong>e
deiod<strong>in</strong>ase
Reaction
HCOOH → CO 2
+ 2H+ 2e -
Gly + 2e - + 4H + + ADP + P i
→ Acetate
+ NH 4+
+ ATP
H 2
O 2
+ 2GSH → 2H 2
O + GSSG
ROOH + 2GSH → ROH + H 2
O + GSSG
L-Thyrox<strong>in</strong>e + 2e - + H + → 3,5,3'-
iodothyron<strong>in</strong>e + I -
Thioredox<strong>in</strong> reductase NADPH + Trx ox
→ NADP+ Trx red
Selenophosphate
synthatase
Selenoprote<strong>in</strong> P
HSe - + ATP → HSe-PO 3
H 2
+ AMP + P i
Antioxidant?
‣ GSH – Reduced glutathione
‣ ROOH – Lipid hydroperoxide
‣ Trx - Thioredox<strong>in</strong>

Iodothyron<strong>in</strong>e Deiod<strong>in</strong>ase
T4
T3
Ratio <strong>of</strong> T4/T3 released <strong>in</strong> blood = 20/1
‣ The thyroid is one <strong>of</strong> <strong>the</strong> largest endocr<strong>in</strong>e glands <strong>in</strong> <strong>the</strong> body
‣ This gland is found <strong>in</strong> <strong>the</strong> neck <strong>in</strong>ferior (below) to <strong>the</strong> thyroid cartilage (also known
as <strong>the</strong> Adam's apple <strong>in</strong> men) and at approximately <strong>the</strong> same level as <strong>the</strong> cricoid
cartilage
‣ The thyroid controls how quickly <strong>the</strong> body uses energy, makes prote<strong>in</strong>s, and controls
how sensitive <strong>the</strong> body should be to o<strong>the</strong>r hormones

Catalytic Cycle <strong>of</strong> Iodothiron<strong>in</strong>e Deiod<strong>in</strong>ase
T4
T3
RSSR
+
HI
ESeH
T4
‣ Thiol c<strong>of</strong>actor
Is not yet identified
RSH
ESeI
T3
Berry, M. J.; Banu, L.; Larsen, P. R. Nature 1991, 349, 438.

Glutathione Peroxidase (GPx)
Cytosolic GPx (cGPx) – uses GSH as co-substrate
Reduction <strong>of</strong> hydrogen peroxides and organic peroxides
ROOH + 2GSH
GPx
ROH + GSSG + H 2 O
‣ Tetramer <strong>of</strong> four identical subunits; each subunit conta<strong>in</strong>s a
selenocyste<strong>in</strong>e residue
‣ Catalytic triad – SeCys, Gln, Trp - Selenolate is highly stabilized
H 2 N
COOH
O
H
N
O
SH
N
H
O
OH
-Glu-Cys-Gly
(GSH)

Structure <strong>of</strong> Glutathione Peroxidase
Tetramer <strong>of</strong> four identical subunits; each subunit
(M.W. 21,000 Dalton)
conta<strong>in</strong>s a selenocyste<strong>in</strong>e residue at <strong>the</strong> active site
Trp148
H
N
+
H
SeCys
Se
.....
.....
H 2 N
Gln70
O
Wendel et al. Eur. J. Biochem. 1983, 133, 51

Syn<strong>the</strong>tic Mimics
Wilson, S. R.; Zuker, P, A.; Huang, R. C.; Spector, A. J. Am. Chem. Soc. 1989, 111, 5936.
Rup<strong>in</strong>der, K.; S<strong>in</strong>gh, H. B.; Patel. R. P. Dalton Trans. 1996, 2719.

Catalytic Activity
‣ UV Method us<strong>in</strong>g Benzenethiol as GSH Alternative
Abs
2
‣ Initial reduction rates <strong>of</strong> hydrogen peroxides
Time
‣ UV absorption <strong>in</strong>creases at 305 nm due to <strong>the</strong> formation <strong>of</strong> PhSSPh
C = ( 1 C 0 -2a)/( 1 -2 2 )
C = conc. <strong>of</strong> PhSH, C 0 = Initial conc. <strong>of</strong> PhSH, a = absorption
1 = Molar ext<strong>in</strong>ction coefficient <strong>of</strong> PhSSPh = 1.24 X 10 3 M -1 cm -1
2 = Molar ext<strong>in</strong>ction coefficient <strong>of</strong> PhSH = 9 M -1 cm -1
S<strong>in</strong>ce 1 2 , C = C 0 - 2a/ 1
* Initial reduction rates 1/v vs 1/C plots - L<strong>in</strong>eweaver-Burk plots
* Comparison <strong>of</strong> v 0 at PhSH 1 mM level

1/v (mM m<strong>in</strong>) -1
Catalytic Activity
‣ L<strong>in</strong>eweaver-Burk plots obta<strong>in</strong>ed for 0.01 mM <strong>of</strong> 18. The <strong>in</strong>itial H 2 O 2 concentration
was fixed to 3.75 mM. The <strong>in</strong>itial PhSH concentration (C 0 ) was 1 mM
8
[18] = 0.01 mM
4
0
1.0 1.2 1.4 1.6 1.8 2.0
1/[PhSH] (mM
-1
)
Best Fit : Y = 4.73111X + (-3.04687)
Initial Reduction Rate (v 0 ) = 593.74 µm m<strong>in</strong> -1 . This v 0 was obta<strong>in</strong>ed by
substitut<strong>in</strong>g X = 1 mM <strong>in</strong> <strong>the</strong> above l<strong>in</strong>ear equation.

GPx-Like Activity <strong>of</strong> Chiral Ferrocenyl <strong>Selenium</strong>
Derivatives
Initial Reduction Rates (ν 0
) <strong>of</strong> H 2 O 2 (3.75 mM) with PhSH (1 mM) <strong>in</strong> methanol <strong>in</strong>
<strong>the</strong> presence <strong>of</strong> various selenium catalysts (0.01 mM)
Catalysts ν 0 M m<strong>in</strong>
-1
0.55 (0.18)
Catalysts ν 0 M m<strong>in</strong>
-1
36.10 (0.12)
3.39 (0.37)
3.16 (0.52)
3.83 (0.32)
[R, S; R, S] (+)
[S, R; S, R] (-)
574.01 (23.98)
466.49 (28.26)
5.78 (0.79)
Inactive Catalysts
28.38 (3.88)

Intermediates and Catalytic Cycle
Nucleophilic attack by thiol at
sulfur and not at selenium

Intramolecular Interaction and Thiol Exchange
‣ Strong SeN <strong>in</strong>teraction
‣ Does not favor selenol formation
‣ Thiol exchange occurs
‣ Weak SeN <strong>in</strong>teraction
‣ Favors selenol formation
‣ No thiol exchange
Mugesh, G.; S<strong>in</strong>gh, H. B. Chem. Soc. Rev. 2000, 29, 347−357.
Mugesh, G.; Panda, A.; S<strong>in</strong>gh, H. P.; Punekar, N. S.; Butcher, R. J. Chem. Commun. 1998, 2227−2228.
Mugesh, G.; Panda, A. S<strong>in</strong>gh, H. B.; Punekar, N. S.; Butcher, R. J. J. Am. Chem. Soc. 2001, 123, 839−850.

Group

Group

Acknowledgements
o
o
Pr<strong>of</strong>. Ray J. Butcher
Pr<strong>of</strong>. N. S. Punekar
‣ DST, CSIR, BRNS
‣ Department <strong>of</strong> Chemistry
‣ SAIF and IRCC
‣ IIT Bombay

UGA - Codon
‣ Uracil-Guan<strong>in</strong>e-Aden<strong>in</strong>e (UGA)
‣ This codon is generally a stop codon
‣ The UGA codon is made to encode selenocyste<strong>in</strong>e by <strong>the</strong>
presence <strong>of</strong> a SECIS element (SelenoCyste<strong>in</strong>e Insertion
Sequence) <strong>in</strong> <strong>the</strong> mRNA

Microreview . Thomas Wirth et al.
Recent Advances <strong>in</strong> Organoselenium Chemistry

Application <strong>of</strong> Organoselenium Compounds <strong>in</strong>
Organic Syn<strong>the</strong>sis
Diphenyl Diselenide
Wirth et al., Eur. Org. Chem. 2009, 1639.
CAS Number: 1666-13-3
Commercial

In-Situ 77 Se NMR Studies/Oxazol<strong>in</strong>e Derivatives
Thiol exchange