Nutr 302 Quiz 1

• Hunter Gatherer Society?

  Main iron source: Heme iron (high bioavailability)

  Iron repletion

  Priority: Fight pathogens, avoid starvation, and favour storage of energy and nutrients

  Positive genetic pressure for polymorphic gene variants lowering serum iron and increasing iron sequestration

  Iron-witholding phenotype (hepcidin induction)
• Agriculture based society?

  Farming, free access to food, sedentary

  Main Iron source: non heme iron, low bioavailability

  Iron deficiency

  Priority: favour the extraction and intestinal absorption of nutrients

  Positive genetic pressure for polymorphic gene variants increasing serum iron and iron flux toward utlization and storage sites, iron storing phenotype (Hepcidin inhibition)
• Iron regulation pt1?

  Hepicidin originally discovered as a novel antimicrobial peptide in urine; named hepcidin-2 due to expression in liver + weak microbicidal activity.

  • A connection to inflammation was noted as levels increased 100-fold in septic urine.

  • Hepcidin mRNA overexpression in iron-overloaded mouse livers linked it to iron regulation, then a knockout mouse model demonstrated hepcidin suppression caused severe iron overload, establishing its role in iron homeostasis.
• Iron regulation pt2?

  the function of hepcidin in innate immunity was established via lowering

  extracellular iron concentrations, thereby limiting microbial growth.

  • Ferroportin was identified as the iron exporter on macrophages and duodenal enterocytes - and it was established thereafter as the target of hepcidin.
• Importance of iron?

  Considered a micromineral (<100 mg/day needed)

  • Iron complexes result in stable geometry in a molecule or cluster

  (analogous to Lego or scaffolding; linking proteins together)
• Ferrous = 2+ and Ferric = 3+
• Iron required for the?

  the synthesis & activity of many proteins; hundreds of

  biological reactions depend on iron

  • Major component of hemoglobin (delivers oxygen to the body)

  • Critical role in cells assisting in oxygen utilization, enzymatic systems

  (especially for neural development), and overall cell function

  • Essential for brain development
• HEME: most well-known iron containing protein; carries O2

  throughout the body

  e.g. O2 carriers (hemoglobin, myoglobin), e- transfer/transport

  (cytochromes of ETC), activation of O2 or peroxides (cytochrome P450,

  nitric oxide synthase, catalases, some peroxidases)
• NON-HEME: many non-heme proteins require iron; also important in O2 transport & metabolism

  e.g. Fe-S clusters (e- transfer proteins NADH dehydrogenase,

  cytochrome c reductase), single Fe atoms, oxygen bridged Fe
• One Hgb transports up to 4 O2 molecules (RBC ~280 million Hgbs)

  • In lungs, O2 binds to oxyhemoglobin Ö transports via blood to tissues Ö O2 released

  to myoglobin Ö transports to mitochondria Ö aerobic respiration Ö

  • Deoxyhemoglobin in blood picks up 2 H+ + 2 CO2 Ö returns to lungs Ö CO2 released
• Electron Transport Chain?

  Heme and non heme iron containing

  enzymes function as one electron

  carriers (one electron transfers involving

  Fe2+/Fe3+ oxidation states)
• Heme and non heme in etc?

  include cytochromes (most have heme

  prosthetic groups), i.e. Cytochrome b contains the same iron porphyrin as hemoglobin and myoglobin.

  Non-heme proteins include the iron-sulfur (Fe-S) proteins
• Important roles of iron?

  Protein with oxygen-bridged iron (stability)

  • i.e. Ribonucleotide reductase (converts ribonucleotides to deoxyribonucleotides essential for DNA transcription
• Important role of Iron pt2?

  Single-Fe containing metalloenzymes

  • i.e. a-ketoglutarate (citric acid cycle) - critical with Vitamin C for post-translational modification of pro-collagen (pro-collagen must be modified before secreted)

  • i.e. Dioxygenases such as 5-lipoxygenase (eicosanoid synthesis) and

  cysteine dioxygenase (cysteine catabolism & taurine synthesis)
• Functional Iron (78%)

  1. Hemoglobin
  2. Myoglobin
  3. Heme Enzymes
  4. non heme enzymes
• Transport Iron (0.001%)

  1. Transferrin
• Storage Iron (22%)

  Ferritin (+Hemosiderin)
• How much Iron do we need?

  • Greatest need for iron: periods of growth or blood loss

  • Basal Iron Loss per day is from GIT, skin, epithelial lining

  (urinary)

  •= 1.0 mg 70 kg (males), = 0.75 mg 55 kg (females) but menstruation can double loss = 1.5 mg (increased in pregnancy,

  parturition, lactation to 4-5 mg)
• Iron needs?

  AI for infants 0-6 mos is based on mean intake of healthy breastfed infants

  • High needs due to rapid growth, but high bioavailability + sufficient

  iron stores for ~4-6 mos Ö many weaning foods are iron-fortified

  • EARs are based on factorial modelling using basal iron losses, menstrual losses, fetal requirements in pregnancy, growth &

  expansion of blood volume, increased tissue & storage iron
• 45-60% of iron in animal products is in

  the form of heme iron. (e.g., meat, fish, poultry).
• Plant foods (e.g., nuts, fruits, vegetables, grains, tofu), dairy products contain only non-heme iron
• Heme Iron: Animal meat/muscle: red meat, poultry, fish (~25% absorbed)

  • Hydrolyzed from hemoglobin/myoglobin in stomach & small intestine (... HCl,

  proteases)

  • Heme absorbed intact by heme carrier protein 1 (hcp 1)

  • Hydrolyzed to inorganic ferrous Fe & protoporphyrin

  • NB: little regulation of HEME IRON, relatively consistent
• Non-heme Iron: Animal & plant-derived (<17% absorbed)

  • Hydrolyzed from food components in stomach - mostly Fe3+ released into SI (may

  complex to ferric hydroxide Fe(OH)3 - relatively insoluble), some Fe2+ (fairly

  soluble) - Fe2+ absorbed via divalent metal (cation) transporter 1 (DMT1)

  • Fe3+ absorption ֱby acidic environment & chelation of Fe

  Iron Absorption

  Also Zn, Mn, Cu, Ni, Lead
• Iron balance is primarily determined by iron absorption

  Increased Need leads to Incerased Absorption:

  • Iron deficiency

  • Pregnancy

  • Hypoxia

  • Erythropoeisis
• Iron needs due to: Increased Duodenal exposure of

  1. DCYTB
  2. DMT1
  3. ferroportin

  Non - heme regulated by 1. 2. and Heme regulated by 3.
• Enhancers of Iron Absorption:

  • sugars
  • acids
  • acidic pH
  • Mucin
  • meat, fish, poultry factors
• Inhibitors of absorption:

  • Alkaline pH
  • Polyphenols
  • oxalic acid
  • phytic acid
  • phosvitin
  • divalent cations
• When body iron stores are high, expression of brush border transporters decreases, liver secretes hepcidin,

  which binds ferroportin, targeting it for degradation... enterocyte iron is lost in feces
• See Figure 13.3
• Hepcidin inhibits Ferroportin in enterocyte cells

  Enterocytes are sloughed off every 3 days, taking whatever iron is left with them
• Phases of Iron Absportion:

  1. Total dietary Iron intake ~15 mg/day
  2. Amount of Iron available in Ferrous (Fe2+) form & solubilized ~7.5 mg
  3. Actual amount taken up by mucosal cells into Ferritin ~4.0 mg
  4. Final amount released into plasma for re-uptake by Transferrin ~1.5 - 2.0 mg Ferrous to Ferric (Fe3+), oxidized by Hephaestin
• Factors increasing absorption of Iron

  • Meat Factor Protein (MFP) if consumed in the same meal (amino acids?)

  • Vitamin C is acidic, solubilizes Fe3+ (ferric) to Fe2+ (ferrous)

  • Some acids/sugars: i.e. ascorbic, citric, lactic, gastric & tartaric acid facilitate

  absorption of non-heme iron
• Factors decreasing absorption (competing or interfering w/ binding process)

  • Phytates, polyphenols & fibres, soy*, whole grains, nuts

  • Some acids: Oxalates/Oxalic acid (spinach, beets, rhubarb), Tannic acid (tea, coffee)

  • Some minerals/salts: Calcium, Calcium phosphate salts, Zinc, Manganese, Nickel

  • EDTA
• Iron chelators, Fe2+:

  1. Lactate
  2. Fumarate
  3. Gluconate
  4. Citrate

  Fe3+

  1. Sulfate
  2. citrate
• Iron Chelators?

  1. Bind metal ions
  2. major purpose in iron homeostasis
  3. Increase or decrease iron absorption
• Chelator examples:

  Small molecules (EDTA, AAs) or complex proteins (mucin, albumin, transferrin)
• Chelator Iron Homeostasis:

  Binds to, solubilizes & makes iron unavailable (i.e. ox reactions, toxicity, bacterial growth)
• Chelators that increase iron absorption?

  ascorbate & citrate = weak chelators

  – help solubilize iron & transfer it from

  compounds to mucosal cells (some chelated molecules taken up via integrins?)
• Decrease Iron Absorption?

  plant phytates & tannins = iron chelators that prevent uptake & absorption (can

  act as antioxidants if absorbed unbound, i.e. phytic acid)
• Chelators protect cells from iron-mediated toxicity (remove excess /neutralize free iron)

  • Rx: Patients with anemia (ֳhgb) + iron overload (׵cannot give blood)

  • Iron-chelating agents (i.e. desferrioxamine, deferasirox) bind iron specifically (excreted in urine)

  whereas other iron chelators (i.e. EDTA) are broad-spectrum (bind with many different minerals)