Copper, Selenium, Iodine (pt1)

what kind of element is copper

transition metal

property of transition metal

accept and donate electrons (similar to iron)

what are the two redox states of copper

cuprous reduced (Cu1+) and cupric oxidized (Cu2+)

copper food sources

seafood, oysters, legumes, cocoa

how much copper does the average person ingest a day

1.3 mg/d

where is copper absorbed

intestine

where does Cu go once absorbed

liver

main site of Cu processing

liver

What happens to Cu once it travels to liver

incorporated into protein and distributed to tissues

how is Cu different from iron

can be excreted

how is copper excreted

bile

how much Cu do we absorb a day

0.8mg/d

how much Cu do we excrete a day? why

0.4mg/d - we consume more Cu than we need

CTR1

Cu1+ importer at apical membrane of enterocyte and hepatocyte

what does CTR1 do

pumps Cu into cytosol to attach to proteins

ATP7A

transports Cu to pump into Golgi body to support cuproenzyme synthesis and exporter of Cu1+

How is Cu transported

in plasma, maybe bound to albumin or alpha2-macroglobulin

what form is dietary copper in

Cu2+

what happened to homozygous knockout mice for CTR1

postnatal weight/growth was stunted + 3 weeks after birth, all die, kinky whiskers

ATP7A meaning

copper transporting ATPase 1 (ATP7A)

What happens to ATP7A when Cu is in excess?

protein moves to basolateral membrane to pump Cu into blood

free copper

can catalyze reactive oxygen species

copper chaperones

bind Cu and deliver to specific organelles

Copper Chaperone examples

CCS, ATOX1, COX17

ATP7B

pumps Cu into bile with an influx in concentration

Wilson’s disease

mutation in ATP7B

Ceruloplasmin (CP

main Cu contain protein in bloodstream/plasma

contains 6 tightly bound Cu atoms

what did knockout experiemnt of CP reveal

ceruloplasmin is not necessary for Cu transport BUT disrupts iron metabolism

ceruloplasmin function in iron metabolism

ferroxidase

Cu function

in vivo as a cofactor for many important enzymes

Cofactor for what enzyme

cytochrome oxidase - electron transport chain

Superoxide Dismutase 1

Cu serves as catalytic role in electron transfer during dismutation rxn converting superoxide into hydrogen peroxide

Zn function in dismutation

structural role - holds superoxide dismutase together

dopamine monooxygenase

used to transform dopamine into norepinephrine

what happens to copper in dopamine → norepinephrine reaction

Cu1+ → Cu2+ so ascorbate must act to return Cu to active form

function of ascorbate

reduces metals and enzymes to keep them active (Cu and Fe)

Tyrosinase

Cu-containing enzyme that converts tyrosine to melanin

Loss of fxn of tyrosinase leads to what

albinism

how much Cu is in the body and where is it

~100mg, 40% of which is in your muscle

copper loss

97% fecal loss mainly through billiary excretion

plasma copper

severe deficiency only

what are you measuring when you measure serum copper

the amount of copper in ceruloplasmin

why is ceruloplasmin not a good measure of deficiency

sensitive to acute inflammation

why is no good indicator of copper deficiency a problem

in the cattle industry to determine what cows are copper deficient

characteristics of copper deficiency

anemia, neutropenia, hypopigmentation, brain development, anatomical and functional abnormalities of skeleton, immune system dysfunction

menkes disease is a mutation in

ATP7a

functionally what happens in Menkes Disease

mucosal block to Cu absorption resulting in low Cu plasma level

physical characteristics of menkes disease

kinky hair disease: stubby white hair, depigmentation of skin + hair, death at young age

cytochrome c oxidase biological activity

cellular respiration

superoxide dismutase biological activity

free radical scavenging

ceruloplasmin biological activity

Fe/Cu transport

Hephaestin biological activity

Fe transport

beta-hydroxylase biological activity

production

sulfhydryl oxidase biological activity

cross-linking of keratin

cytochrome c oxidase malfunction symptom

CNS degeneration, ataxia, muscle weakness

superoxide dismutase malfunction symptom

CNS degeneration

ceruloplasmin/hephaestin malfunction symptom

anemia

dopamine malfunction symptom

ataxia

sulfhydryl oxidase malfunction symptom

abnormal hair and dry skin

Wilsons disease malfunction

ATP7b mutation

Wilson’s disease functional problem

block of Cu efflux into the bile

what does Cu do in Willson’s disease

Cu accumulates in liver and other tissues leading to fibrosis, cirrhosis and liver failure

Cu accumulation in brains leads to neurological damage, ataxia, dystonia, rigidity.

When do Wilson’s disease symptoms begin

b/w 12 and 23 years of age

Hallmark signs of Wilson’s disease

cornea of eye (Kayser-fleisher ring) Copper atoms depositing on eye.

Tx of Wilson’s Disease

penicillamine (chelation therapy) or high dose zinc treatment

Cu RDA

900mcg

Cu UL

10,000 mcg

what type of element is selenium

other nonmetal

Se RDA

55 mcg

dietary sources of selenium

brazil nuts, tuna, fish

what does the amount of selenium in foods depend on

concentration in the soil

organic forms of Se

selenomethionine, methionine, selenocysteine, cysteine

inorganic forms of Se

selenate + selinite

where are selenomethionine found

main form in plants

where is selenocysteine found

form biosynthesized by animals

where are inorganic forms of Se found?

plants, supplements, animal feed

Se absorption

we don’t know, especially inorganic forms

we do know we can absorb selenomethionine and selenocysteine through amino acid transporters

how much of organic forms of Se is absorbed

~100%

selenate absorption rate

~90%

selenite absorption rate

~50%

what does not happen in Se deficiency

Se absorption rate does not increase

selenocysteine (Sec)

sometimes called the 21rst amino acid

all 25 proteins encoded in human proteome use selenocysteine

how is Sec made

independent Sec insertion machinery responsible for putting Sec on 25 proteins

SECIS

selenocysteine insertion sequence

how do we know we only have 25 human selenoproteins?

25 mRNAs contain SECIS to trigger interdependent machinery to add selenoprotein on them

function of selenoproteins

participate in antioxidant and anabolic processes

iodothyronine deiodinases

glutathionine peroxidases

fxns as Se buffer, meaning it can be mobilized from here

selenoprotein P

major Se transport protein, up to 10 Se atoms

SELP

Selenoprotien P

how much plasma Se is found in SELP

80%

What was the 1st selenoprotein to be identified

Glutathione peroxidase 1 in 1957

What enzyme accounts for >50% of total body Se

glutathione peroxidase 1

Glutathione peroxidase 1 function

converts hydrogen peroxide produced by superoxide dismutase into water to protect against free radicals

Keshan disease

selenium deficiency, named after Keshan county in China province which has low selenium in soil their

How many people were affected by Se deficiency in China

1.2 million people since 1950s

Se blood levels in US vs China

125 mcg/L vs 15mcg/L

Se excretion

methylselenol thorugh urinary excretion

How are pharmacological doses expelled

expired in breath as dimethylselenide (selenium w/ 2 methyl groups)