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86 Cards in this Set
- Front
- Back
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The properties of copper that make it suitable for enzyme catalysis |
*can exist in multiple oxidation states *part of many redox reactions -redox role in iron metabolism -pro-oxidant in cu2+ state |
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Copper functions |
Key role in several enzymes involved with: 1. iron metabolism (ceruloplasmin/ferroxidases) 2. antioxidant activity (Cu/Zn SOD) 3. Energy production (cytochrome c oxidase) 4. connective tissue formation (lysyl oxidase) 5. melanin synthesis (tyrosine oxidase) 6. neurotransmitter syn/metab 7. myelin formation Gene expression regulation |
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Ceruloplasmin |
The copper transport protein -also functions as ferroxidase 1. needed for transferrin to pick up and transport iron 2. Ferroxidase oxidizes iron so can be picked up by transferrin *infection and inflamm increases copper in blood* |
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Copper role in iron transport
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acts as a ferroxidase to oxidize iron to be picked up by transferrin |
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Copper antioxidant/immune function |
1. Part of Cu/Zn superoxide dismutase -plays catalytic role 2. part of neutrophils and t-cell production/proliferation |
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Cytochrome C oxidase |
1. Energy metabolism -electron transfer to reduce oxygen to water 2. important in myelin formation -copper def can cause nerve damage |
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Additional Functions |
1. Connective tissue- crosslinks collagen for bone and blood vessels 2. Pigmentation- cu needed for melanin syn 3. neurotransmitter syn- Norepinephrine |
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Copper absorption |
some in stomach Most in SI: 1. uptake across brush border membrane via carrier mediated transport -uses CTR1 and DMT1 *CTR1 transporter copper must be reduced to 1+ form (some) *DMT-1 transporter coupled with H+ or in 2+ form (most) 2. intracellular transport -ATOX1 takes copper to ATP7A 3. ATP7A Export across plasma membrane |
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Copper transport in blood |
1. Cu loosely bound to albumin and transported to liver 2. incorporated into ceruloplasmin in liver 3. ceruloplasmin in blood releases copper to cells |
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Copper storage/excretion |
1. Copper enters cells through CTR1 as free metal -within cells bound to CCS, AAs, or GSH *NO STOARGE POOL Liver is closest thing 2. excreted through biles in feces -cell slough -more excreted when high intake |
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Metallothionien and copper |
Regulates intestinal copper absorption -intracellular protein that binds copper and blocks transcellular transport -role to safely store metal ions -protects cells by scavenging O2 radicals *more expression when high levels of metals -if NOT NEEDED lost when enterocyte sloughs off! |
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Regulatory mechanisms |
Intestine: 1. regulates intestinal copper absorp 2. lost with intestinal cells if not absorbed Liver: 1. copper incorporated into CP sent to blood 2. can store cu in small amt in metallothi 3. amt excreted in bile influenced by intake levels |
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Copper sources |
shelfish nuts legumes liver chocolate bran/germ layer |
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copper bioavailability |
absorb 50-70% oc copper absoprtion influenced by intake enhanced: AA and organic acids decreased: phytates, excess Ca intake, vit. C presence *high dose of Zn supplement can lead to Cu deficiency |
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copper assessment |
1. serum copper 2. ceruloplasmin levels- 3. Activity of RBC Cu/Zn SOD- can detect long term def. |
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copper deficiency |
-zinc supplements can cause def, patietns on TPN *can cause anemia unresponsive to iron treatment, impaired immunity, hypopigmentation -condition called Menke's Syndrome |
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Menke's Syndrome |
-mutation in gene coding for ATP7A, cu cant leave cell -characterized by kinky hair and cerebral degeneration -rarely caught early hard to detect *low levels of Cu in blood, brain, and liver high in intestine spleen kidney |
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Wilson's Disease |
-mutation in gene coding for ATP7B defect in ability to secrete Cu in bile and build up in liver and brain, hepatic cirrhosis and neurological effects -see cu accum in eye (Kayser-Fleisher rings) Treatment: reduce Cu intake, chielation therapy, oral zinc supple |
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Copper deficiency signs |
Anemia Skeletal, dermal, vascular defects Albino CNS disorders |
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Zinc properties that make it suitable for enzyme catalysis |
-metalloenzyme -flexible coordination that is ideal for enzyme active sites -not redox sensitive -electron acceptor |
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3 types of roles for zinc |
1. catalytic 2. structural 3. regulatory |
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Catalytic roles of zinc |
Key enzymatic reactions: 1.respiration (carbonic anhydrase)- gets rid of CO2 2. energy metabolism (fructose 16BP) 3. protein digestion (peptidases) 4. bone formation (alkaline phosphatase) 5. RNA polymerases 6. collagenases 7. heme biosynthesis 8. folate metabolism (polyglutamate hydratase) |
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Structural and regulatory roles of zinc |
1. Zinc fingers (MTF1) 2. antioxidant defense 1. phospholipase C |
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Other important roles of zinc |
1. component of gustin- taste 2. gonad development 3. skin integrity |
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Zinc digestion and absorption |
D: -hydrolysis from AA or nucleic acids in stomach A (depends on level of intake: 1. Transcellular- carrier mediated -brought into cell via ZIP4 and ZNT5 (ZIP4 affected by dietary intake, more with def) -ZNT1 carries out of cell regulated by metallothionien 2. paracellular- diffusion through tight junctions (not regulated) |
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Metallothionien and zinc |
-zinc levels regulated in intestine by this -zinc binding protein produced in response to high zn levels (blocks transcellular movement) |
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more on metallothionien regulation |
1. Zn levels regulated at intestinal level -MT produced in response to high zn -zn stronger inducer than copper 2. no real stoarge site for zn -MT can bind 7 atoms of zn or copper -induced in liver or pancreas -MT levels greatly increased by need -Hepatic MT induced by inflammatory cytokines |
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How is Metallothionien induced |
1. via MTF1 2. promoter in region bound to MTI 3. when zn avail=MTI (zn sensitive inhibitor) dissociation- this allows MTF1 to bind to metal response element 4. transcription of metallothionien gene |
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Zinc transport |
1. travels from intestine to liver via albumin 2. transferred to a2-macroglubulin in liver(40%) or stays on albumin 3. transport to endothelial cells- mostly via albumin endocytosis 4. released in cell cytosol and bound to zinc binding proteins |
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genetic zinc transport disorders |
Acrodermatitis enteropathica -impaired zinc absorption and transport -mutation of gene that codes for ZIP4 -causes slow growth, rashes, impaired wound healing, night blindness, immun sys def. |
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Zinc excretion |
-zn recycling similar to iron 1.mostly lost through fece- pancreatic secretions 2. can be actively secreted if needed -transporters for export upregulated when high zn in blood -ZIP5 from blood to enterocyte, ZNT6 from enterocyte into lumen some urinary loss |
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Zinc sources |
meats seafood bran/germ |
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zinc bioavailability |
about 20% absorbed (more from animal products) heat reduces bioavailability Enhanced: AA and organic acids inhibited: phytates, oxalates, fibers, polyphenols, divalent cations (Ca) |
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Zinc nutrient interactions |
Copper: -zinc increases production of MT -MT has higher affintity for Cu than Zn(will bind cu and hinder abs) Vitamin A: -zinc needed for retinol to retinal conversion -zinc needed for liver syn of RBP Calcium: -increases intestinal zinc losses Def observed with decreased levels of transport proteins |
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Zinc Assessment |
1. Serum zinc- does not change unless extreme def Fasting- increases flood zn infection- decreases blood zinc (liver uptakes zn) 2. acute phase proteins- CRP to see if decrease d/t infection or increased need 3. hair- long tern status |
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Zinc deficiency symptom |
nonspecific- loss of appetite, dermatitis, alopecia, poor growth, night blindness, diarrhea 1. impaired taste acuity 2. impaired immune function and wound healing 3. decrease in retinol mobilization form liver 4. decreased work capacity from muscles(resp) |
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Zinc toxicity |
gi distress, nausea, diziness chronic large oral doses: decreased immune function, reduced copper status, Lower HDL cholesterol *beware of zinc lozenges and denture cream |
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Iron chemistry |
free iron is toxic- extra OH-, complexed with proteins |
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key roles of iron |
O2 metabolism electron transfer immune function cognitive performance |
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iron containing proteins |
1. Heme proteins -hemoglobin (delivers 02) -myoglobin (O2 reservoir in muscle) -oxygenases, peroxidases -ETC components (cytochromes) 2. Iron sulfur cluster proteins -Aconitase, succinate dehydrogenase, NADH dehydrogenase 3. Iron containing enzymes (nonheme) -mononuclear (hydroxylases, syn of carnitine, tyrosine, dopamine, etc.) -dinuclear (ribonucleotide reductase) |
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Heme proteins |
1. Fe2+ protoporphyrin IX: can bind 02 (goes up in iron deficiency) 2. Hemoglobin: -Fe+protoporphyrin = heme -4 hemes + globin = hemoglobin -delivers O2 to tissues, binds in lungs -returns CO2 to lungs |
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More heme proteins |
1. Cytochrome P450 -detoxifies and makes substrates water soluble (most cytochromes give electrons, don't transfer O2 like cytochrome C oxidase) 2. Peroxidase (catalase) -rids peroxides |
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Iron-sulfur cluster proteins |
-either 2Fe-2S or 4Fe-4S centers -Role in enzyme reaction catalysis -role in electron transfer reaction (NADH,succinate dehyd) -iron sensing proteins (Aconitase) *when enough Fe present, cluster intact. When Fe low, Aconitase inactive and acts as IRP* |
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Other non-heme containing proteins |
1. monooxigenases and dioxygenases -insert oxygen atoms into substrates *require substrate, Fe2+, and iron reducing agent like Vit. C -ex: tryptophan hydroxylase |
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Iron Storage |
1. Ferritin- primary storage form -apoferritin: w/o iron, soluble yet biologically available, iron stored as Fe3+(by ferroxidase) -Hemosiderin: also hold iron, mostly during overload, fe less available here |
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Iron transport |
1. Transferrin- main transporter -made in liver, high affinity for Fe3+ -stays about 1/3 saturated 2. transferrin receptors -affintity for TF proportional to degree of saturation -homodimer, disulfide bridge -each receptor can bind 2 Fe |
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Transferrin Cycle |
1. Take in TF and receptor in a vesicle 2. Acidify it and iron released from transferrin 3. Iron put into mitochondria or ferritin 4. transferrin receptor released back to surface |
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Regulation of Iron |
1. transcription level- some (Tf, TfR) 2. Post-transcriptional level- most -IRE (iron response elements) in mRNA of ferritin, TfR, IREG1 -IRP (iron regulating protein) only bind IRE when LOW iron -ferritin and IRE binds > blocks ferritin syn |
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Iron digestion/absorption |
-Absorb 10-15%, when low stores, absorb more Heme: absorbed intact by endocytosis after globin cleavage -heme oxygenase releases ferrous iron from heme in cell (RLS) Nonheme: needs to be reduced to be absorbed -iron binds DMT1 and enters cell -exported out of cell by IREG1 (ferroportin) -oxidized by hephaestin to 3+ -loaded onto transferrin or stored as ferritin in cell |
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Rate limiting step in iron absorption |
Heme oxygenase releases ferrous iron from heme inside cell *heme iron absorption |
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Non-heme iron abs reduced by |
phytic/oxalic acid polyphenols high doses of 2+ charge ions like Cu or Ca high body iron stores low stomach acidity |
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Non-heme iron abs increased by |
acidic pH free AA (glu,asp) Organic acids low iron status meat factor |
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Iron excretion |
Not much excretion conserved and recycled well by RBCs 1. RBC goes to liver after 120 days 2. iron removed from heme by heme oxygenase 3. rest of heme to billirubin and to bile for excretion |
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biggest iron pool |
heme in hemoglobin |
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Additional reg of iron metab |
Hepcidin- made by liver
acts on enterocytes and macrophages -holds onto iron and doesnt let leave cell *inflamm increases hepcidin so iron doesnt leave cell |
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Iron assessment |
1. Storage -ferritin: relative to body stores, most sensitive because only decreased with iron def., but not specific 2. Functional -Soluble TfR: BEST shows TfR presence -total and % sat of transferrin -RBC volume and Free protoporphyrin: late 3. Anemia- Hb finally effected, not good indicator alone 4. total iron binding capacity -better for positive iron balance |
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Iron Deficiency Causes |
insufficient intake inadequate absorption excess iron loss increased need (pregnancy) defective release of stores malabsorptive disorders |
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Why fatigue in iron def? |
many parts of energy metabolism need iron |
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Iron toxicity |
fatigue, organ failure, bronzing, multiple organ failure |
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Hemochromatosis |
uncontrolled iron absorption -mutated gene inhibits transferrin to TfR |
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Vitamin B6 vitamers |
PN > PNP PM > PMP PL > PLP *Active form of B6 |
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Functions of B6 |
1. Transamination reactions 2. Decarboxylation reactions 3. 1 carbon metabolism 4. CHO metabolism (glycogen phosphorylase) 5. heme synthesis 6. Conversion of tryptophan to niacin |
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Transamination |
catalyzed by PLP-dependent aminotransferase 1. Amino acid is taken off and bound to PLP (schiff base) leaving ketacid and pmp 2. a different a-keto acid reacts with PMP and process reverse |
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B6 as coenzyme |
catalyzes reaction for conversion of serine to glycine |
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B6 and heme synthesis |
Needed for rate limiting step of heme sythesis |
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B6 and synthesis of Niacin |
The synthesis of niacin from tryptophan requires B6 -60:1 ratio of tryptophan to niacin |
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B6 sources |
PN- plant foods PM, PL- animal foods meat starchy veg noncitrus fruit nuts cereal |
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B6 absorption |
through passive diffusion by carriers sent to liver transported as PLP in blood bound to albumin dephos then aborbed them phosd again |
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B6 storage/excretion |
stored in liver excreted in urine *always dephosd before crossing membranes *PNP and PMP can be converted to PLP via pyridoxine phosphate oxidase |
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B6 assessment |
Plasma PLP- best test xanthurenic acid excretion- higher in urine in def |
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folate coenzyme form |
THF- tetrahydrofolate |
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Folate functions |
1. amino acid metabolism 2. nucleotide synthesis (purine/pyrimidine) |
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Folate metabolism |
involves: 1. reduction of pterin moiety 2. addition of glutamates 3. acquisition and oxidation/reduction of 1 carbon units at the N-5 or N-10 positions |
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Folate forms |
1. THF 2. 5-methyl THF 3. 5,10 methylene THF |
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Folate key pathways for AA and nucleic acid metabolism |
1. Serine to glycine pathway -yields 5,10 methylene THF 2. Methylene pathway: Homocysteine to methionine *requires B12 -uses 5-methyl THF to regenerate THF 3. Histidine catabolism: histidine to glutamate depends on THF -produces FIGLU for folate status assessment 4. Thymidilate pathway -requires 5,10 methylene THF |
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folate and glycine metabolism |
5,10 methylene THF required for -serine to glycine -glycine degredation |
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Folate and neurotransmitters |
needed for choline to be converted to acetylcholine |
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Folate and Methionine resynthesis |
1. B12 converts 5-methyl THF to THF -5 methyl THF used for methionine 2. THF can be converted to 5,10 methylene THF -this is used for nucleic acid syn and serine syn 3. 5,10 methylene THF is converted to 5 methyl THF which is a methyl donor *Without B12 methyl groups stuck> METHYL FOLATE TRAP (THF cannot be regenerated) |
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Folate transport |
-delivered to cells as 5-methyl THF stored and used as THF |
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folate bioavailability |
syn- 85-100% foods- about 50% *conjugase inhibitors |
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Dietary Folate Equivalents |
d/t diff in bioavailability of both forms |
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Folate toxicity |
insomnia gi distress irritability |
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foalte assessment |
serum folate- recent intake RBC folate- folate stores plasma homocysteine levels FIGLU |
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2 enzymatic reactions that require B12 |
1. methionine synthase- homo to methion 2. methylmalonyl coa mutase |
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B12 TRANSPORT |
via transcobalamin *B12 in methylcobalamin in blood |
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b12 source |
micro org |
